Adrenocortical growth and cancer.

Adrenocortical Growth and Cancer Lucile Lef` evre,1–3 J´ erˆ ome Bertherat,*1–4 and Bruno Ragazzon1–3 ABSTRACT The adrenal gland consists of two distinct parts, the cortex and the medulla. Molecular mechanisms controlling differentiation and growth of the adrenal gland have been studied in detail using mouse models. Knowledge also came from investigations of genetic disorders altering adrenal development and/or function. During embryonic development, the adrenal cortex acquires a structural and functional zonation in which the adrenal cortex is divided into three different steroidogenic zones. Significant progress has been made in understanding adrenal zonation. Recent lineage tracing experiments have accumulated evidence for a centripetal differentiation of adrenocortical cells from the subcapsular area to the inner part of the adrenal cortex. Understanding of the mechanism of adrenocortical cancer (ACC) development was stimulated by knowledge of adrenal gland development. ACC is a rare cancer with a very poor overall prognosis. Abnormal activation of the Wnt/β-catenin as well as the IGF2 signaling plays an important role in ACC development. Studies examining rare genetic syndromes responsible for familial ACT have played an important role in identifying genetic alterations in these tumors (like TP53 or CTNNB1 mutations as well as IGF2 overexpression). Recently, genomic analyses of ACT have shown gene expression profiles associated with malignancy as well as chromosomal and methylation alterations in ACT and exome sequencing allowed to describe the mutational landscape of these tumors. This progress leads to a new classification of these tumors, opening new perspectives for the diagnosis and prognostication of ACT. This review summarizes curC 2015 American rent knowledge of adrenocortical development, growth, and tumorigenesis. Physiological Society. Compr Physiol 5:293-326, 2015.

Introduction Adrenocortical cancer (ACC) is a very aggressive tumor with a poor outcome. The pathophysiology of this cancer is only partially explained, but studies have been limited due to the rarity of this tumor. Understanding the mechanisms of adrenal development and growth is important for a better understanding of adrenal tumorigenesis and the subsequent development of new treatments. A great deal of progress has been made in this field in animal and in vitro models, as well as through the investigations of rare genetic disorders associated with abnormal adrenal development. In the field of adrenocortical tumors (ACTs), the genetic study of familial forms, and more recently, the development of genomic studies, have also recently allowed new insight into tumorigenesis. This review will describe the current body of knowledge on the development and growth of the adrenal cortex and the pathophysiology of cancer of the adrenal cortex.

outer zona glomerulosa (mineralocorticoids), the middle zona fasciculata (glucocorticoids), and the inner zona reticularis (androgens)—produce specific steroid hormones (Figure 1). The first description of the structure of the adrenal gland was made by Arnold J in 1866 and Evelyn H-M in 1927 (6, 91).

Function of the different cell layers of the adrenal cortex Aldosterone is involved in maintaining intravascular volume and electrolyte balance in mammals. In humans, deficiency of aldosterone results in hypotension, hyponatremia, and hyperkalemia (Table 1). Conversely, excessive secretion of aldosterone can induce hypertension, hypokaliemia, cardiac fibrosis, and heart failure (108, 224). Cortisol is necessary for glucose homeostasis and the mobilization of energy stores. Cortisol deficiency can result in hypoglycemia and lack of * Correspondence

Adrenocortical Development Structure and function of the adrenal gland in adult The adult adrenal is made up of two distinct parts, the medulla and the cortex. The cortex consists of three distinct types of cell layers characterized by the expression of specific steroidogenic enzymes. Therefore, each cell layer—the

Volume 5, January 2015

to [email protected] U1016, Institut Cochin, Paris, France 2 Cnrs, UMR8104, Paris, France 3 Universit´ e Paris Descartes, Sorbonne Paris Cit´ e, France 4 Department of Endocrinology, Referral Center for Rare Adrenal Diseases, Assistance Publique Hˆ opitaux de Paris, Hˆ opital Cochin, Paris, France Published online, January 2015 (comprehensivephysiology.com) DOI: 10.1002/cphy.c140010 C American Physiological Society. Copyright 1 Inserm,

293

Adrenocortical Growth and Cancer

Comprehensive Physiology

Fetal adrenal (A)

Capsule

Adult adrenal (B) Capsule

Definitive zone Zone glomerulosa Transitional zone Zone fasciculata

Fetal zone

Zone reticularis

Medulla

Developing medulla

Figure 1 Comparison of fetal and adult adrenal. (A) Fetal adrenal gland histology. The fetal gland is composed of two types of tissue, the fetal zone and the definitive zone. The fetal zone constitutes more than 80% of the fetal gland. Under the capsule lies the definitive zone. (B) Adult adrenal gland histology. The adult adrenal is constituted by two distinct tissues, the outer cortex and the inner medulla. These two tissues have different cellular origin and produce corticosteroid and catecholamines, respectively. The cortex is composed of three distinct cell layers: the glomerulosa, fasciculata and reticularis. The adrenal gland is encapsulated. Originally published, with permission, by Nat Rev Endocrinol (236).

stress response, whereas an excess of cortisol can induce Cushing’s syndrome (Table 1). Dehydroepiandrosterone (DHEA) is secreted by the reticularis zone and is involved in adrenarche.

Steroidogenesis in the adrenal cortex All these hormones have a common primary precursor, cholesterol (Figure 2). The rate limiting step in Table 1

steroidogenesis is carried out by the steroidogenic acute regulatory protein (StAR) which translocates cholesterol from the outer to the inner mitochondrial membrane. This provides cholesterol for the initial step of steroidogenesis, the conversion to pregnenolone by cholesterol side-chain cleavage (CYP11A1). Aldosterone, cortisol, and DHEA synthesis all share this first step that results in the conversion of cholesterol to pregnenolone.

Adrenal Cortex Functions Zona glomerulosa

Zona fasciculata

Zona reticularis

Location

Outer

Middle

Inner

Proportion

15%

75%

10%

Stimulus

Angiotensin II, (ACTH, serum potassium)

ACTH

ACTH

Primary membrane receptor

Angiotensin II receptor

MC2R

MC2R

Specific enzyme activity

CYP11B2

CYP17, CYP11B1

CYP17

Hormone product

Mineralocorticoids (aldosterone)

Glucocorticoids (cortisol)

Sex steroid: DHEA and DHEAS

Function

Regulation of intravascular volume, electrolyte balance

Glucose homeostasis, mobilization of energy stores

adrenarche

Deficiency

Hyponatremia, hyperkalemia, hypotension

Hypoglycemia, lack of stress response

Excessive secretion

Hypertension, cardiac fibrosis, heart failure

Cushing’s syndrome

294

Virilization




Figure 2 Steroidogenic pathways in human adult adrenal cortex. The adrenal cortex produces zonespecific steroids due to specific steroidogenic enzyme expression. There are three distinct steroids: mineralocorticoids produced by zona glomerulosa, glucocorticoids synthesized by zona fasciculata, and androgen produced by zona reticularis. Cholesterol, which is the common precursor, is internalized by StAR protein in the inner mitochondrial membrane. Abbreviations: CYP11B2, aldosterone synthase; CYP17, 17-hydroxylase, CYP17, 17,20-lyase; CYP11B1, 11β-hydroxylase; DHEA, dehydroepiandrosterone; DHEAS, dehydroepiandrosterone sulfate; HSD3B2, type II 3β-hydroxysteroid dehydrogenase; CYP11A1, cholesterol side-chain cleveage; CYP21, 21-hydroxylase; 17βHSD, 17β-hydroxysteroid dehydrogenase; p450Aro, aromatase; StAR, steroidogenic acute regulatory protein; CS, corticosterone; DOC, deoxycortisol; DOCS, deoxycorticosterone; 18OHCS, 18-hydroxylase corticosterone.

HSD3B2 (type II 3β-hydroxysteroid dehydrogenase), which belongs to the short-chain dehydrogenase family, and three others, cytochrome P450, CYP21 (21-hydroxylase) and CYP11B2 (cytochrome P450, family 11, subfamily B, polypeptide 2 or also named aldosterone synthase), are involved in aldosterone synthesis. Pregnonolone passively diffuses into the endoplasmic reticulum and is converted to progesterone by HSD3B2. CYP11A1 and CYP11B2 are located in the inner mitochondrial membrane, while CYP21 is located in the endoplasmic reticulum. CYP21 hydroxylates progesterone to deoxycorticosterone. The final steps between deoxycorticosterone to aldosterone are carried by the same enzyme: CYP11B2. Deoxycorticosterone is converted to corticosterone by 11βhydroxylation. Finally, aldosterone synthesis is completed by 18β-hydroxylation and 18-oxydation (134). In the zona fasciculata, CYP17 (17α-hydroxylase) converts pregnenolone into 17α-hydroxypregnenolone (17OHPregnenolone), which is then converted to 17OHProgesterone by HSD3B2. Subsequently, 17OHProgesterone is converted to deoxycortisol by CYP21 and to cortisol by CYP11B1. In the zona reticulatis, 17OHPregnenolone is converted to DHEA by the CYP17 enzyme. The sulfo-transferase (SULT2A1) converts DHEA to DHEAS (DHEA sulfate) (265).


DHEA and androstenedione serve as substrates for sex steroid (testosterone and estradiol) synthesis in peripheral tissues. Functional zonation relies in part on the zone-specific expression of the different enzymes (264).

Adrenal development Adrenogonadal primordium (AGP) arise from the condensation of coelomic epithelium and/or intermediate mesoderm (Figure 3A) around the week 4 in humans and day 9 in mice (86, 343). The AGP is characterized by NR5A1 (Nuclear Receptor Subfamily 5, Group A, Member 1; or SF1: Steroidogenic Factor 1) expression (132, 216). Then, migration of germ cells in a part of the AGP allows for the differentiation of the gonadal and the adrenal primordium (fetal adrenal zone) (Figure 3B) (132). The specification of adrenal primordium from the AGP requires an upregulation of SF1 expression. Sf1 expression is activated by the interaction of Wt1 (Wilms tumor 1) and Cited2 (Cbp/P300-interacting transactivator, with Glu/Asp-Rich carboxy-terminal domain, 2) (326). Once separated from the AGP, a transcription complex containing the homeobox PKNOX1 (PBX/Knotted 1 Homeobox 1), Hox9b (homeobox gene 9b) and Pbx1 (pre-B-cell leukemia homeobox 1) is recruited to maintain Sf1 expression

295



Transversal section of embryo (fourth weeks in human, E9 in mouse)

(A)

Amniotic cavity

Neural tube

Notochord

Somites

Intermediate mesoderm

Dorsal aorta

Coelomic epithelium Yolk sac (B)

(1) Urogenital ridge

(2) Adrenogonadal primordium Adrenogonadal primordium (AGP) Kidney

Coelomic intermediate epithelium mesoderm

(3) Fetal adrenal

Adrenal primordium Gonadal primordium

(4) Adult adrenal

Fetal adrenal

Adult adrenal with medulla Neural crest cells

Kidney

Gonad

Germinal cells migration

Wt1, Wnt4

Pbx1, Cited2, Sf1, Dax1

Kidney

POMC-derived peptides Gonad Kidney

β-catenin shh

Details in panel C (C) Adrenal primordia/fetal zone

Human 8w

Migration of neural crest cell

Encapsulation

Formation of definitive cortex

Differentiation of zona fasciculata and zona glomerulosa

E11.5-12.5

Formation of zona reticularis

6-8 years

9w Birth

Mouse E10.5

Fetal zone regression

E14.5

- First pregmancy (female) - Puberty (male)

Figure 3

Development of adrenal gland from urogenital ridge to adult adrenal. (A) Transversal section of an embryo at four weeks in human or at embryonic day nine in mouse. (B) (1) The urogenital ridge corresponds to longitudinal elevation of the intermediate mesoderm. (2) The adrenogonadal primordium (AGP) is formed by condensation of coelomic epithelium and/or intermediate mesoderm. AGP separates into adrenal primordium and gonadal primordium in which germ cells accumulate. (3) Fetal adrenal is localized cranial to the kidney. (4) The adult adrenal gland is formed by fetal adrenal proliferation and differentiation in steroidogenic cells and by migration of chromaffin cells inner the cortex. Factors involved in each step have been annotated. (C) Adrenal gland organogenesis in human and mouse. At the eighth week of gestation in humans (E10.5 in mice), the adrenal primordial/fetal zone (grey cells) derives from the AGP. At the ninth week of gestation in humans (E11.5-12.5 in mice), chromaffin cells (red cells) colonize the inner layer of the fetal cortex to form the future medulla. At 14.5 days in mice, there is an encapsulation of the fetal zone by mesenchymal cells (blue cells) followed by the formation of definitive cells (orange cells). There is a proliferation of the fetal zone until the birth. At birth, the adrenal cortex undergoes profound structural modification: the definitive zone begins to differentiate in zona fasciculata (yellow cells) and zona glomerulosa (orange cells). The fetal zone regresses after birth in humans, while in mice the fetal zone persists until puberty for males and the first pregnancy in females. In humans, at the age of 6 to 8 years, the zona reticularis (green cells) is formed. Abbreviation: E, embryonic day. Adapted, with permission, from (127).

in the fetal zone through activation of a fetal zone-specific Sf1 enhancer (FAdE). Subsequently, Sf1 itself induces the activation of FAdE and the consequent expression of Sf1 (357). At week 9, the chromaffin cells migrate from the neural crest into the fetal zone where they will later form the medulla.

296

At the same time, there is an encapsulation of the gland by mesenchymal cells migrating from the area of the Bowman’s capsule. IGF2 (insulin growth factor 2) is expressed at high levels in the developing fetal adrenal and the IGF system is



considered as the most important controller of the fetal zone growth (155, 231, 232). At birth, IGF2 expression decreases dramatically and coincident with fetal zone regression. IGF2 appears to be expressed postnatally only in the adrenal capsule and the periphery of the cortex (16, 232). Moreover, it is believed that the capsule serves as a stem cell niche involved in the development of the definitive cortex (342). At this stage of development, steroidogenic cells are organized into two distinct components. Centrally localized the fetal zone contains large eosinophilic cells, while small steroidogenic cells with basophilic cytoplasm form the definitive cortex in the vicinity of the adrenal capsule. Subsequently, the transitional zone differentiates from the definitive cortex. This zone, localized between the definitive and the fetal zones, is composed of cells similar to that of the definitive zone (Figure 1). The cells of fetal zone are the principal source of steroid precursors (DHEA) used by placenta to produce estrogens (267). The proliferation of fetal adrenocortical cells is regulated by ACTH (adrenocorticotropic hormone) secreted by the fetal pituitary (adrenocorticotropic hormone) (231). ACTH might act on growth by regulating growth factors like insulinlike growth factor 2 (IGF2), fibroblast growth factor and epidermal growth factor (69, 232, 334). The fetal zone exists only during fetal life, hence its name. The fetal zone constitutes more than 80% of the fetal adrenal gland. Disorder in which ACTH signaling is impaired in the adrenal gland result in adrenal hypoplasia. In congenital malformations connected with the absence of pituitary gland, for example, anencephaly, development of the fetal zone is severely impaired (117, 308, 309). This same adrenal phenotype can be observed in patients with ACTH resistance (see below paragraph “Late phases of adrenocortical development”). However, the definitive zone appears normal in anencephalics despite the absence of ACTH stimulation indicating that the structural development of the definitive zone is independent of ACTH (117). Moreover, transplanted Pomc-/- adrenal glands under the kidney capsule of wild-type mice, rescues the functional as well as the structural adrenal defects (168). These finding suggest that ACTH is not required for the development of the definitive zone but is required for postnatal proliferation and maintenance of the adrenal structures. After birth major modifications of the adrenal structure occur. The weight of the adrenal glands decreases strikingly during the first few weeks of life. The size that is attained by the fetal glands just before birth is not achieved again until late in adolescence (266). There is a regression of the fetal zone by apoptosis that allows for the coalescence of the chromaffin cells to form a rudimentary medulla. Indeed, the medulla becomes mature only at the age of 12 to 18 months (72). The definitive zone starts to differentiate and proliferate into the zona fasciculata and zona glomerulosa at birth, which occurs simultaneously with the coalescence of chromaffin cells (169, 304). At the age of 6 to 8 years, the zona reticularis appears between the zona fasciculata and the adrenal medulla (231) at the same time as the occurrence of the adrenarche.



The adrenal development in mice follows a similar pattern as human development. The AGP arises from the coelomic epithelium/underlying mesonephric mesenchyme by embryonic day nine (132, 154). At embryonic day 10.5, the adrenal primordium separates from the AGP (132). At embryonic day 11.5 to 12.5, cells originating from the neural crest migrate to the adrenal primordium and differentiate into the neuroendocrine chromaffin cells (3), which will constitute the medulla. At embryonic day 14.5, there is an encapsulation followed by the formation of the definitive zone. After birth, multiple modifications occur. First, the definitive zone starts to differentiate into zona fasciculata and zona glomerulosa (174). A specific feature of the mouse adrenal cortex is the Xzone, a remnant of the fetal adrenal zone located between the medulla and the cortex (357). While the human fetal zone regresses at birth, the mouse fetal zone (X-zone) regresses during puberty in males or at the time of first pregnancy in females through apoptosis, involving activin signaling (26, 140) (Figure 3C).

Gene involved in the development of adrenal cortex Urogenital ridge Several genes are important for urogenital ridge development, such as Wilms’ tumor 1 (WT1) and the wingless-type MMTV integration site family, member 4 (WNT4) genes.

WT1 WT1 encodes a DNA (deoxyribonucleic acid) binding protein with four zinc finger rings. It was initially identified as a tumor suppressor gene mutated in Wilms’ tumor (childhood tumor of the kidney, nephroblastoma) (51, 109, 124, 254). The fundamental role of Wt1 in urogenital ridge development is demonstrated in mice with Wt1 defects. Wt1 mutant mice have kidney, gonadal, and adrenal aplasia (181, 237, 330). A recent study has described the role of Wt1 to maintain the undifferentiated state of the AGP. Wt1 seems to plays a major role in the adrenocortical development. It is a key factor to define AGP identity by inhibiting the steroidogenic differentiation process through blockage of adrenocortical steroidogenic cells into a progenitor state. Mice carrying an overexpression of Wt1 in AGP have smaller adrenals than wild-type mice, while no gonadal defects are observed (15). In humans, mutations in WT1 cause various organ defects such as WAGR syndrome (Wilms’ tumor, aniridia, genitorurinary malformation, mental retardation, OMIM 194072), disorders of the kidney and gonad development, or the Denys-Drash (OMIM 194080) (253) and Frasier syndrome (OMIM 136680) (17). However, no adrenal defects have been described in humans with the WT1 mutation (Table 2).

WNT4 The Wnt4 protein belongs to WNT (winglessrelated mouse mammary tumor virus integration site) secreted

297

298

Urogenital ridge

Table 2

Sf-1/SF-1

Wnt4/WNT4

Wt1/WT1

Gene (Mouse/ HUMAN)

Mouse

Human

Mouse

Human

Mouse

Species

Lethality, absence of gonad, splenic vascular, and ventromedial hypothalamic nucleus abnormalities Small gonads

SF-1 heterozygous (+/–)

Primary amenorrhoea, m¨ ullerian duct abnormalities, hypoplastic uterus, androgen excess

46 XX heterozygous mutations: E226G/R83C/L12P KO

46 XY complete gonadal dysgenesis

Disruption of testerone synthesis and male vasculature

Overexpression XY Duplication of 1p31-p35 region XY

Masculinized development characterize by development of Wolffian duct and loss of mullerian duct, testosterone synthesis

KO XX

Frasier syndrome: renal failure,streaks gonads, 46,XY complete gonadal dysgenesis, 46,XY DSD

Heterozygous mutations in intron 9, in exon 9: R390X/F392L

Lethal, failure of kidney, pituitary gland and mammary gland development

Denys-Drash syndrome: Urogenital disorders, renal failure, 46,XY DSD, Wilms’ tumor

Missense mutations in exon 8 or 9

KO

WAGR syndrome: Wilms’ tumor, aniridia, genitourinary anomalies, mental retardation

Fertile

Overexpression De novo chromosomal deletion 11p13

Lethal, failure of kidney and gonad development

Phenotype

KO

Mutation

Adrenal insufficiency, adrenal development and organization defects

Absence of adrenal gland

Normal

Not reported

Not reported

Normal structure with impaired steroid formation

Normal

Normal

Normal

Adrenal hypoplasia

Adrenal aplasia, hypoplasia

Adrenal phenotype

(27, 35)

(153, 157, 216, 217, 241, 282, 296)

(30, 31, 257)

(164)

(165)

(163, 325)

(48, 136, 306, 324)

(17, 229)

(119, 253)

(254)

(15)

(181, 237, 330)

Refs.

Mouse and human mutants with adrenal phenotype. Main genetic alterations and the associated phenotypes of the genes involved in mouse and human adrenocortical development

Adrenocortical Growth and Cancer Comprehensive Physiology



Fetal adrenal

Gli3/GLI3

Ctnnb1/ CTNNB1

Homozygous Autosomique dominant

Human

β-catenin activating mutations

Pallister-hall syndrome: kidney malformation

Pallister-hall syndrome

Not reported

KO β-catenin (fl/fl; Sf1/Cre high)

Constitutive activation of β-catenin in adrenal cortex

Embryonic lethality during gastrulation

46 XY complete gonadal dysgenesis

Xp21 duplication KO

Hypogonadotropic, hypogonadism

Sex reversal dependent on genetic background

XY mouse transgene Many mutations

Male infertility: reduced testicular weight with arrest of germ cells production

Cardiac malformations

Brain and cardiac malformations

Impaired differentiation of gonad and kidney

KO

Mouse

Human

Mouse

Human

Mouse

Heterogygous missense mutations or short deletions or frameshifts

Human

Dax1/DAX1

KO

Mouse

Cited2/ CITED2

KO

Primary ovarian insufficiency

46 XX—many mutations

Mouse

Disorders of sex development

46 XY—many mutations

Pbx1/PBX1

Human

Adrenal hypoplasia, aplasia

Absence of adrenal gland

Identified in ACC and ACA with wnt/β-catenin pathway activation

Adrenal hyperplasia and malignant tumors (old mice)

Adrenal aplasia, diminution of adrenocortical precursor proliferation

Not reported

Cytomegalic adrenal hypoplasia, persistence of fetal zone, adrenal insufficiency

Not reported

No regression of the X zone

Normal

Adrenal agenesis

Adrenal agenesis

Normal in most cases; Adrenal insufficiency (only for heterozygous R255L mutation)

Normal in most cases; Adrenal insufficiency (only for heterozygous G35E, homozygous R92Q mutations)

(166)

(38)

(continued)

(37, 105, 135, 225, 313, 320)

(25)

(175)

(125)

(18)

(162, 256)

(310)

(65, 226, 352)

(305, 346)

(14)

(287)

(2, 212, 338)

(1, 21, 32, 70, 92, 131, 179, 180, 207, 212, 220, 258, 276, 338)

Comprehensive Physiology Adrenocortical Growth and Cancer

299

300

Pc1/PC1

Pomc/ POMC

Acd/ACD

KO

Heterozygous mutation G483A

Human

Heterozygous or homogygous mutations

Human

Mouse

KO

Mouse

Spontaneous autosomal recessive

Heterozygous missense mutations

Human

Mouse

KO

Mouse

Many mutations

Human

Cdkn1c/ CDKN1C

KO Shh (fl/fl; SF-1/Cre+)

Mouse

Shh/SHH

Mutation

Species

Gene (Mouse/ HUMAN)

(Continued)

Late phases

Table 2

Obesity, impaired glucose homeostasis, small intestinal dysfunction, hypogonadotropic hypogonadism

Severe growth defect, ACTH deficiency, impaired processing of proinsulin

Obesity, red hair pigmentation (not constant)

Obesity, altered pigmentation

Perinatal lethality, retarded growth, skin hyperpigmentation, poorly developed pelage, hydronephrosis, hypogonadism, skeletal defects

IMAGe syndrome

Abdominal muscle defects, cleft palate, bone ossification defects, renal medullary dysplasia, cytomegaly

Holoprosencephaly, developmental delay, feeding difficulties,epilepsy, instability of temperature, heart rate and respiration endocrine disorders (diabete insipidus, hypogonadism, tyroid hypoplasia, growth hormone deficiency)

Not reported

Phenotype

Adrenal insufficiency

Normal

Secondary adrenal insufficiency

Adrenal hypopasia, secondary adrenal insufficiency

Adrenal dysplasia and insufficiency

Adrenal hypoplasia

Adrenal hyperplasia

Adrenal hypoplasia

Severe hypoplasia, cortex desorganized

Adrenal phenotype

(160)

(272)

(63, 93, 182, 183, 230)

(66, 168)

(22)

(5)

(354)

(23, 85, 196, 278)

(58)

Refs.

Adrenocortical Growth and Cancer Comprehensive Physiology



Nnt/NNT

Mcm4/ MCM4

Star/STAR

Mrap/MRAP

Mc2r/MC2R

Tpit/TPIT

KO

Homozygous or compound heterozygosity

Human

Homozygous: p.Pro24ArgfsX4

Mouse

Human

Hypomorphic allele of Mcm4 in Mcm3+/- mice

KO

Homozygous: R192C/R188C

Human

Mouse

KO

Homozygous mutation

Human

Mouse

KO

Autosomal recessive mutation: S74I

Human

Mouse

KO

Homozygous mutation: S128F

Human

Mouse

KO

Mouse

Familial glucocorticoid deficiency

Glucose intolerance and reduced insulin secretion

Familial glucocorticoid deficiency

In mice, homozygosity for a disrupted Mcm4allele (Mcm4–/–) caused preimplantation lethality

Familial glucocorticoid deficiency type III

Female external genitalia

Familial glucocorticoid deficiency type II

Obesity

Familial glucocorticoid deficiency type I

Hypoglycemia upon prolonged fasting, high levels of ACTH, unresponsiveness to ACTH, unaltered body length

Primary adrenal insufficiency

Zona fasciculata desorganized and reduced corticosterone level


abnormal morphology with steroidogenic cells displaced by nonsteroidogenic, GATA-4- and Gli1-positive cells


Adrenal hypoplasia, adrenal insufficiency


Normal

Primary adrenal insufficiency, adrenal hypoplasia

Adrenal hypoplasia, low levels of aldosterone and corticosterone

Secondary adrenal insufficiency

Secondary adrenal insufficiency, adrenal hypoplasia

(228)

(102, 228, 322)

(150)

(235)

(54)

(234)

(7)

(62)

(57)

(190)

Comprehensive Physiology Adrenocortical Growth and Cancer

301


proteins, which play an important role in development (50, 327). This protein binds to the frizzled receptor and leads to the activation of β-catenin and its target genes. Wnt4 gene Knockdown (KO) mice show an absence of kidney development due to a lack of mesenchymal to epithelial transformation, which is necessary for nephron development (306). Due to the absence of kidneys, mice died 24 h after birth (Table 2). In addition, Wnt4 is essential for pituitary gland (324) and mammary gland (48) development. Moreover, mice with deletion of the Wnt4 gene also have adrenal defects and the XX Wnt4-null mice show a masculinized development characterized by the presence of the Wolffian duct, male vasculature and the loss of mullerian ducts. This phenotype is due to aberrant expression of Cyp17 and testosterone production in the gonads of the female, which is responsible for the masculinization of the embryo (163, 325). Inversely, Wnt4-transgenic XY mice carrying a gain-offunction for Wnt4 show disruption of testicular vasculature and diminished testosterone synthesis (165). Wnt4-mutant mice show a decrease in the aldosterone synthesis with a decrease of cells expressing the Cyp11b2 gene and ectopic expression of cells with adrenal phenotype in the gonads of the female (136). These data indicate that Wnt4 seems to have a role in the migration and/or sorting of the specific adreno/gonadal progenitors. In humans, a patient carrying a duplication of WNT4 resulting in WNT4 overexpression shows a 46, XY complete gonadal dysgenesis. XX female patients with a WNT4 mutation present an absence of vagina and uterus as well as kidney defects, though no adrenal alteration is observed (30,31, 257) (Table 2).

Adrenogonadal primordium

SF1 SF1 belongs to the superfamily of nuclear receptors and is also called NR5A1 (nuclear receptor subfamily 5, group A, member 1) or Ad4BP (Ad4 binding protein). It contains a zinc finger DNA-binding domain (DBD) in its N-terminal region that enables binding to the promoter of target genes. In its C terminal region, SF1 contains the ligand binding domain, but SF1 has no known ligand so it is an orphan receptor (126). SF1 is a transcriptional regulator of several genes involved in the hypothalamic-pituitary-steroidogenic axis. SF1 was first identified as the regulator of the promoter of the cytochrome P450 (145, 239) and other steroidogenic enzymes (185). Generally, SF1 is expressed in steroidogenic tissues of foetuses and adult animals (128, 133, 152, 154, 240). Hatano showed that Sf1 is expressed early in the AGP (132). Sf1 is expressed in adrenal cortical cells, testicular Leydig cells and ovarian theca and granulosa cells (152, 284, 315). The expression pattern of Sf1 suggests that it plays a role in the hypothalamic-pituitary-steroidogenic axis. β-catenin can activate SF1 (122, 147), and SF1 is crucial for gonad and adrenal development. Sf1 expression is essential to the proliferation of progenitor cells. Indeed, mice with Sf1 haploinsufficiency

302


present reduced adrenals (27, 35). Mice with a disruption of Sf1 show an absence of adrenals and gonads (216, 282, 296) as well as developmental abnormalities in terms of splenic vascular architecture (241) and in the ventromedial hypothalamic nucleus (153). Mice homozygously deficient for Sf1 die because of glucocorticoid and mineralocorticoid insufficiency (217). In humans, the first heterozygous loss-of-function SF1 mutation was observed in a patient with 46, XY complete gonadal dysgenesis and adrenal failure (1) (Table 2). This mutation occurred in the first zinc finger domain (G35E) and abolish DNA binding and thus SF1 transcriptional activity. Only one human subject has been described with a homozygous SF1 mutation (R92Q). This patient shows a 46, XY complete gonadal dysgenesis and adrenal function impairment (2). Unlike the G35E mutation, the R92Q mutation diminishes the transcriptional activity of SF1 but does not abolish it. This could explain that only the homozygous carrier of the R92Q mutation has adrenal defects in contrast with its heterozygous relatives. This observation reveals the importance of SF1 in development. Another heterozygous mutation of SF1 was observed in a girl with a missense mutation (R255L) that diminishes the transcriptional activity. No defect of gonadal development was observed, in contrast with adrenal insufficiency (32). This observation suggests that SF1 has a role in male gonadal development but not in female gonadal development. By contrast, SF1 plays a role in both sexes in adrenal development. However, mutations reported later provided new insights into the role of SF1 in development (Table 2). Indeed, an XY patient with 46, XY complete gonadal dysgenesis shows no adrenal function defect. This patient presented a 8pb deletion in SF1 (68). The mutated protein acts like a dominant negative mutant on the normal allele. This new mutation has a different impact on transcriptional activity of SF1 in adrenals than in gonads, as it may alter transcription only in the gonads. Similarly, a SF1 mutation observed in a patient with gonadal dysgenesis or primary ovarian insufficiency was not associated with adrenal failure (70, 131, 179, 207, 212, 220, 259, 276, 344). Overall, these data suggests that in human development, SF1 haploinsufficiency has more effect on gonadal development than adrenal development.

PBX1 PBX1 (Pre-B-cell-leukemia) is a transcription factor belonging to the TALE (three amino acid loop extension) family (49) and interacting with the HOX (homeobox) genes (161). Pbx1 KO mice show defects in adrenal development (287) (Table 2) and have a decreased Sf1 expression. Indeed, Pbx1 regulates Sf1 expression (357). In humans, no PBX1 mutations have been found in patients with adrenal defects (97). CITED2 CITED2 is a cofactor of the transcriptional activator p300/CBP (29) and others, for whom it can modulate their transcriptional activity (45, 318). Cited2 KO mouse show



adrenal aplasia and cardiac and brain defects (14) (Table 2). The effect of Cited2 on development is explained by its interaction with Wt1 in the regulation of the expression of Sf1 (326). In humans, no CITED2 mutation have been found in patients with defects in adrenal development (97).

DAX1 (NR0B1) DAX1 (dosage-sensitive sex reversal (DSS), adrenal hypoplasia critical (AHC) region, on chromosome X, gene 1) or NR0B1 (Nuclear receptor subfamily 0, group B, member 1) is a transcription factor of the nuclear receptor family (OMIM 300473). DAX1 negatively regulates the transcriptional activity of SF1 and other genes (159, 186, 188, 244, 281). DAX1 represses steroidogenesis in adrenocortical cells at different levels (187, 353). DAX1 mutations abolish its negative regulator function due to mislocalization of the DAX1 protein. Indeed, mutated DAX1 is no longer located in the nucleus (159, 186, 199). XY Dax1 KO mice show an absence of the X-zone regression and little diminution of the P450 side-chain cleavage enzyme expression (65, 352). The phenotype of the lack of X-zone regression is similar to the phenotype of AHC in humans, but these mice also have normal adult zones. These results suggest that in mice, Dax1 induces the regression of the X-zone but is not required for the adult zone development nor steroidogenesis (Table 2). In addition, Dax1 plays a role in male gonadal development. The XY KO mice present with small testis compared to the wild-type mice and an arrest of germ cell synthesis after 14 days (226, 352). Mice with overexpression of Dax1 present a sex reversal (310). Dax1 antagonizes the effect of the Sry gene. The double mutant (heterozygous for Sf1 and KO for Dax1) shows antagonist function of Dax1 and Sf1 in steroidogenesis. Indeed, surprisingly, the mice do not present a more severe adrenal deficiency, but on the contrary, there is a rescue of the adrenal steroidogenesis (12). This suggests that Dax1 and Sf1 have antagonist roles in steroidogenesis. Indeed, Sf1 stimulates the expression of genes whereas Dax1 inhibits Sf1-mediated transactivation through protein-protein interaction (159, 242, 351). In human, mutations of DAX1 gene (DSS/AHC/Xchromosome gene-1; NR0B1) cause an X-linked disease (Table 2), the cytomegalic form of adrenal hypoplasia congenita (AHC) (256). X-linked AHC (OMIM 300200) is characterized by a hypoplastic adrenal gland constituted by an absence of the adult zone and a disorganized fetal zone with enlarged eosinophilic cells. The patients display primary adrenal insufficiency during infancy characterized by decreased glucocorticoid and mineralocorticoid production and a hypogonadotropic hypogonadism. In humans, a large number of DAX1 mutations have been reported (65, 162, 256). Duplication of DAX1 leads to dosage-sensitive 46, XY complete gonadal dysgenesis (18). Fetal adrenal

Wnt/β-catenin signaling Wnt/ß-catenin signaling plays an important role in development. β-catenin can be a



coactivator for multiple nuclear receptors, like SF1 (39, 122, 165). Null mice for ß-catenin died during embryonic development due to abnormal ectoderm development during gastrulation (125). Mice with inactivation of β-catenin, specifically in the adrenal cortex, show adrenal aplasia and diminution of the proliferation of progenitor cells (175). In humans, constitutive somatic activating mutations of β-catenin have been found in ACTs (10, 313, 314, 320). This suggests that β-catenin is a major regulator of adrenocortical cell proliferation.

Hedgehog signaling The hedgehog signaling contains three ligands: sonic hedgehog (SHH), desert hedgehog (DHH), and Indian hedgehog (IHH). The activation of hedgehog signaling prevents the cleavage of GLI Krüppel family member 3 (GLI3) (337). GLI3 acts as a transcriptional activator. Human mutations in SHH are associated with adrenal hypoplasia (23, 85, 196, 278). Mutations in GLI3 have been found to be associated with adrenal insufficiency in PallisterHall syndrome (166). The mutations result in truncated protein, which act as a transcriptional repressor (295). Mice with Gli3 mutations show a similar phenotype to that of Pallister-Hall syndrome with adrenal aplasia (38). Inactivation of Shh in the adrenal cortex leads to multiple defects: hypoplasia, disorganization of histological structure, and defects in the encapsulation of the medulla (58).

The adrenocortical dysplasia gene Adrenocortical dysplasia (Acd) corresponds to a spontaneous autosomal recessive mouse mutant (22). The Acd mice show Acd and hypofunction. These mice also present other organ features derived from the urogenital ridge. Male Acd mutants show a reduced number of germ cells in the seminiferous tubules and are infertile (170). Additionally, Acd mutant mice are smaller than their wild-type littermates, show skin hyperpigmentation and skeletal defects, and have a shorter life. Histologically, the X-zone failed to develop, whereas the medulla is unaffected. The cortical cells and nuclei size are also increased. Hormonal studies show a low corticosterone level in female mice and elevated ACTH levels in both sexes.

How is Acd implicated in adrenal development? The Acd gene has been cloned and identified as a telomeric protector. Telomeres situated at the extremity of chromosomes are made of telomeric repeats. Failure in telomere protection is well known to be involved in tumorigenesis induction. The Acd gene corresponds to the mouse ortholog of the human ACD (originally named PTOP, TINT1, PIP1 and TPP1) (170), which belongs to the shelterin complex. ACD regulates telomerase recruitment and activity (148, 208, 350). ACD do not bind directly to the telomeric repeats, but instead help the recruitment of other shelterin proteins to the telomeric repeats (142, 345). The mice that are double mutant for Acd and Tp53 (tumor protein p53) offer new insights into the role of Acd. Tp53

303


loss in Acd mutant mice rescues the Acd (87). This is in keeping with previous results in mouse embryonic fibroblasts in which loss of Acd induced cell senescence through the Tp53 pathway (123, 142, 345). Other studies show that Tp53 loss rescues the caudal truncation in Acd null mice. Acd null mice present an increased apoptosis and no decrease in proliferation (332). These results show that Acd induces cell senescence by the Tp53 pathway, but also that double mutant mice for Acd and Tp53 display more carcinomas than Tp53 null mice. This demonstrates that Acd might also be implicated more generally in tumorigenesis by regulating telomere protection (87).

IMAGe syndrome IMAGe syndrome (OMIM 300290) is a rare disorder corresponding to the association of Intrauterine growth retardation, Metaphyseal dysplasia, AHC, and Genital alterations (24, 206, 251, 317, 331). Due to an overlap between Acd and Dax1 mutant mice and the features of IMAGe syndrome, it was hypothesized that the ACD mutation or DAX1 could be involved in IMAGe syndrome. The human ACD gene was sequenced IMAGe syndrome patients, but no mutation of the ACD gene was found (151). Moreover, no mutations of DAX1 have been found (331). More recently, an exome sequence allowed the identification of mutations of CDKN1C (Cyclin-dependent kinase inhibitor 1C [P57, Kip2)] in patients with IMAGe syndrome (5). The mutations are considered to be activating mutations. This gene is located at 11p15, an imprinted region in keeping with an apparent inheritance of the disease from the mother. Interestingly, this gene has also been implicated in Beckwith-Wiedemann syndrome in which overgrowth and adrenal tumors can be observed. In Beckwith-Wiedemann syndrome, mutations inactivate CDKN1C (see paragraph “Genetic alteration in adrenocortical carcinomas: from familial syndromes to sporadic ACC/Beckwith-Wiedemann Syndrome—IGF2 gene and locus 11p15”).

Late phases of adrenocortical development Pituitary-derived factors are very important for adrenal development. Anencephalic foetuses show, in absence of ACTH, that the fetal zone of the adrenal gland fails to develop. Hypophysectomy leads to adrenal atrophy. Conversely, excessive chronic stimulation of the adrenal cortex by ACTH leads to Cushing’s syndrome. CRH (corticotropin-releasing hormone) secreted by hypothalamus binds to pituitary corticotrophs expressing CRH receptor1. The pituitary gland synthesizes POMC (pro-opio-melanocortin), which is the precursor of ACTH. ACTH stimulates adrenal development by binding to the MC2R (melanocortin-receptor 2).

Pomc-derived peptides are essential for postnatal development At birth, there is no difference in size and adrenal structure between Pomc-null and wild-type mice, whereas from those first postnatal weeks to adulthood, the adrenal size of mutants becomes smaller than those of wild-type mice (168), with no distinct zona fasciculata and

304


zona glomerulosa and an absence of corticosterone secretion (66). Pomc seem not necessary for the prenatal development of adrenals but might be necessary for postnatal adrenal development (168). Indeed, transplantation of adrenals from Pomcnull mice in adrenalectomized wild-type littermates leads to normal and functional adrenal gland.

Pomc-derived peptides are involved proliferation and the differentiation

in

the

ACTH Coll et al. show that treatment of Pomc-mutant mice with ACTH restores adrenal size, cortical architecture and corticosterone secretion (66). ACTH seems to be sufficient for adrenal development. Others POMC-derived peptides Others studies provide evidence for Pomc-derived peptides other than ACTH acting on proliferation and differentiation of adrenal cells. Multiples studies describe the mitogenic activity of POMC-derived peptides other than ACTH (88-90, 94, 213). Moreover, they also observe that adrenal secretory protease, a serine protease which is responsible for the cleavage of Pomc, is upregulated in the outer adrenal cortex after unilateral adrenalectomy, a zone implicated in the renewal of adrenal cells thanks to stem cells (33)

Human genetic diseases Defects of POMC biosynthesis Krude et al. described in 1998 the first two cases of POMC mutations (182) (OMIM 176830). The two patients presented with hypoglycemia and neonatal jaundice. They were later diagnosed with ACTH deficiency which was associated with early onset obesity and red hair (182). In 2003, the same group described three additional cases with similar phenotypes (183). The red hair is not a systematic feature as some cases have been described without red hair (63, 93, 230). Mutations in the prohormone convertase 1 (PC1) gene induce disruption of prohormone processing, including POMC. Patients with mutated PC1 present adrenal insufficiency, early-onset obesity, impaired glucose homeostasis, small intestinal dysfunction, and hypogonadotropic hypogonadism (160). Mutations in genes involved in pituitary development result in ACTH and POMC-derived peptides deficiency (OMIM 613038; 262600; 221750; 262700; 182230; 300123). Mutations in TPIT transcription factor (also named TBX19—T-box 19) have been found in patients with ACTH deficiency (OMIM 604614). TPITs activate POMC gene expression and might have a role in the development of the pituitary gland (190). ACTH resistance ACTH resistance or familial glucocorticoid deficiency (FGD) correspond to an autosomal recessive disorder characterized by symptoms of cortisol deficiency and increased ACTH with absence of mineralocorticoid deficiency (61, 227). ACTH resistance is due to mutation in the



MC2R gene (OMIM 607397), which encodes the receptor for ACTH (FGD type 1, OMIM 202200) (62), or in the MRAP gene (234), which encodes the MC2R accessory protein (FGD type 2,OMIM 607398). The MRAP protein is required for the correct trafficking of the ACTH receptor to the cell surface. More than 50% of affected patients do not carry a mutation either in MC2R or MRAP and are classified as FGD type 3 (OMIM 609197) (233). Some patients with FDG type 3 present a mutation in the STAR gene. The STAR gene is essential for the transport of cholesterol into mitochondria for synthesis of all steroid hormones. Mutations in the STAR gene disturb cholesterol transport, leading to nonclassic lipoid congenital adrenal hyperplasia (13) and very low levels of adrenal steroids, which is responsible for the diagnosis of FGD type 3 (235). Mutations of MCM4 (Minichromosome Maintenance Complex Component 4) gene and NNT (Nicotinamide Nucleotide Transhydrogenase) gene have recently been found in patients with FGD syndrome (150, 228). Patients and mice with a mutation in the MCM4/Mcm4 gene (150) show adrenal failure whereas the precise role of this gene on the adrenal needs to be clarified. Mice mutated for the Nnt gene, an antioxidant defense gene, present a slightly disorganized zona fasciculata with increased apoptosis compared to their wild-type littermates (228).

Renewal of adrenocortical cells Regenerative capacity of the adrenal gland The observation of undifferentiated cells proliferating and repopulating the organ is further supported by experiments assessing the regenerative potential of the adrenal gland. In experiments of enucleation, corresponding to removal of the inner section of the gland and leaving the capsule and the subcapsular region, the cortex regenerates. The regenerated cortex has a correct cortical zonation and normal steroidogenic function (245, 252, 255, 299). This experiment supports an essential role of the capsule/subcapsule region in adrenocortical growth maintenance. The presence of undifferentiated cells has been shown in multiple mammalian species. Histological study in the arctic seal (46) showed in the periphery of the adrenal cortex cluster of rounded large cells with features of less-differentiated cells. In mice adrenal, BrdU pulse chase and proliferating cell nuclear antigen (PCNA) staining is detected in peripheral cells of the cortex (288). In the unilateral adrenalectomy experiment, which leads to compensatory growth of the contralateral adrenal, labeling for PCNA was increased in cells adjacent to the capsule (27). These observations suggests the existence of stem cells in the peripheral part of the adrenal cortex

Stem cells and adrenal cortex development To understand the process of adrenal development and regeneration from the stem cell, multiple studies have investigated



the lineage between the capsule, the fetal cortex, and the definitive cortex (174, 342). Analysis of Shh pathway shows its importance for adrenal gland development and maintenance (58, 149, 176). Lineage tracing experiments have shown (1) that Gli1(+) and Sf1(−) cells of the capsule differentiate into cells of the cortex and (2) that Shh(+) and Sf1(+) progenitor cells of the subcapsular region have been shown to differentiate into Sf1(+)/Cyp11b2(+) cells of the zona glomerulosa and Sf1(+)/Cyp11b1(+) cells of the zona fasciculata (149, 176). It is unclear if Gli(+) cells residing in the capsule give rise to Shh(+) cells of the subcapsular region. These studies demonstrate that cells from the capsular and subcapsular regions give rise to the definitive cortex by centripetal movement. Centripetal migration has also been supported by a recent study; lineage-tracing experiments using Cyp11b2-Cre (causes recombination) and GFP (Green Fluorescent Protein) show that the zona glomerulosa cells give rise to the zona fasciculata cells. There is a direct lineage conversion without passage through an undifferentiated state (101) (Figure 4). This study shows that Sf1 deletion in zona glomerulosa cells (Cyp11b2-Cre/Sf1 lox/lox) lead to the absence of zona glomerulosa development while functional zona fasciculata are still formed. This result implies the existence of other mechanisms of zona fasciculata cell formation. As argued in the zonal model, it is possible that each zone develops and is maintained somewhat independently. Moreover, specific progenitor cells from the subcapsular region could differentiate directly in zona fasciculata cells without previously differentiating in zona glomerulosa cells. Another possibility for the source of progenitor cells is the adrenal X-zone, a juxtamedullary zone found in rodents and originating from the fetal zone, which could contribute to zona fasciculata cells (26, 140, 197, 283, 357, 358). Finally, it might be possible that zona fasciculata cells are maintained by self duplication (Figure 4).

Regulators of adrenal stem cell maintenance, proliferation, and differentiation Their principal role is the regulation of NR5A1 (SF1) expression.

Wnt/β-catenin Several studies showed the importance of β-catenin in the maintenance of multiple organs (143, 184, 209). In the adrenal, there is an activation of the Wnt/β-catenin signaling pathway in the subcapsular region (175). Moreover, β-catenin is essential for development and maintenance of the definitive cortex. The cre-lox system was used to abolish β-catenin only in cells expressing Sf1. In a case of total loss of β-catenin with a high expressing Sf1 transgene, an adrenal aplasia is observed. This provides evidence that activation of Wnt/β-catenin is required for adrenal development. This aplasia might be due to a decreased proliferation of the definitive zone, demonstrated by a diminution of BrdU (5-bromo-2deoxyuridine) incorporation. In the case of incomplete loss

305



Sf1(+) Cyp11b1(+)

Self-duplication

Zona fasciculata

Progenitor cells Sf1(+) Cyp11b2(+)

X-zone progenitors

Zona glomerulosa

Zonal model

Capsule Subcapsule

Alternative pathway

Specific progenitors

Major pathway

X-zone Medulla

Figure 4 Model of adrenal development. Subcapsular progenitor cells (dark grey) give rise to definitive adrenal cells by centripedal differentiation (major pathway) based on works by (58, 101, 149, 176). Some alternative pathways could participate or are activated to maintain the zona fasciculata in certain conditions. Blue: capsular cells; dark-gray: progenitor cells; orange: zona glomerulosa cells; yellow: zona fasciculata cells; light-gray: X-zone cells; white: medulla cells.

of β-catenin expression in all cells expressing Sf1 using a low expressing Sf1 transgene, the adrenal cortex forms, but the cortex becomes progressively thinner and has a decreased steroidogenic activity. The formation of the adrenal might be due to the presence of Sf1 and β-catenin, but the progressive thinning of the cortex might be due to a loss of progenitor cells. It seems, then, that β-catenin has a role in the maintenance of progenitor cells (175).

DAX1 (NR0B1) DAX1 plays an essential role in the inhibition of SF1-mediated steroidogenesis (71, 159, 188). Dax1 is expressed in the subcapsular region like β-catenin (174). β-catenin and Sf1 bind to the Dax1 promoter and activate its transcription. The glucocorticoid receptor (Gr or Nr3c1— nuclear receptor subfamily 3, group C, member 1) is also able to activate the Dax1 promoter and synergizes with Sf1. Gr and Sf1 are part of the same complex on the Dax1 promoter and ACTH stimulation disrupts the formation of this complex. The expression of Dax1 is decreased and it removes the inhibition of Sf1 mediated steroidogenesis so that Sf1 progenitor cells can respond to ACTH (121). Sf1 progenitors undergo differentiation. Another role of Dax1 has been shown in the mice embryonic stem cells. Dax1 seems to maintain the pluripotency of stem cells whereas loss of Dax1 induces differentiation (171, 172). A recent study by Scheys and coll., confirms this role in adrenal cells. They showed that young mice with loss of Dax1 present an enhanced steroidogenesis and subcapsular adrenocortical proliferation. As these mice age, they exhibit altered subcapsular proliferation and steroidogenesis, which can be explained by depletion of stem/progenitor cells. These data reveal that both deficient-Dax1 mice and patients with X-linked AHC exhibit adrenal failure that is consistent

306

with adrenocortical subcapsular progenitor cell depletion and argue for a significant role of Dax1 in maintenance of these cells (285).

TCF21 (POD1, Capsulin, or Epicardin) TCF21 (transcription factor 21) is a bHLH (basic helix-loop-helix) transcription factor which plays an important role in the development of numerous tissues (260). Tcf21 is expressed in the urogenital ridge and has a crucial role in the development of the gonads and adrenals (73, 174, 215, 260, 316). Tcf21 represses the transcriptional activity of Sf1 and Tcf21-deficient mice showed an increase of Sf1-expressing cells in the gonads and in the adrenals (73, 174, 316). In a recent study, Wood et al. found also that Tcf21-expressing cells give rise to steroidogenic cortical cells and nonsteroidogenic capsular cells in the adrenal before the capsule formation, and give rise only to nonsteroidogenic stromal cells after the capsule formation (341).

Adrenocortical Cancer ACTs can be classified as benign adrenal adenomas (ACA) and malignant ACCs, which are typically unilateral. Bilateral tumors of the adrenal cortex are rare and usually benign. ACC is a rare tumor with an estimated incidence between one to two cases per million and per year in adults in North America and Europe. The prevalence has been estimated between 4 and 12 per million (118). As it is for many rare tumors, the incidence is difficult to determine and the true numbers might be higher than the current estimations. For instance, the prevalence of adrenal incidentalomas range in the general population from 1% in subjects younger than



Table 3


The Weiss Score Weight of criteria

Histological criteria

0

1

Nuclear grade∗

1 and 2

3 and 4

Mitoses

≤5 for 50 fields ×400

≥6 for 50 fields ×400

Atypical mitoses

No

Yes

Clear cells

>25%

≤25%

Diffuse architecture

≤33% surface

>33% surface

Confluent necrosis

No

Yes

Venous invasion

No

Yes

Sinusoidal invasion

No

Yes

Capsular infiltration

No

Yes

The presence of three or more criteria highly correlates with malignacy (333). ∗ According to Fuhrman criteria (103).

30 years to 7% in subjects older than 70 years. In patients with adrenal incidentaloma selected for surgery, the frequency of ACC is of course higher (3%-10%) (218, 221). In children, the incidence of ACC is considered to be ten times lower as it is in adults, except in South Brazil where there is a higher incidence of pediatric ACC. This high incidence is explained by a specific germline TP53 mutation. On the primary tumors without distant metastasis there is not a single pathological feature which allows to diagnose a malignant adrenal cortical tumor. Combinations of various histological parameters allow to establish a “score” for a given tumor that has developed. The most widely used is the Weiss score, comprised of nine different items (193) (Table 3). Each item is given a value of one when it is present and zero when it is absent. The score is obtained by summing the values of each individual item. It is assumed that a score equal to or above three is most likely associated with a malignant tumor. Other approaches based on microscopic features analysis have been developed but have been less widely used and are therefore less validated than the Weiss score. The study of familial ACT has been very important in the understanding of the genetics of sporadic tumors. ACC is among the most aggressive endocrine tumors with a negative prognosis. Morbidity and mortality can be secondary to steroid hormone excess and/or tumor growth and metastases. The mechanisms of ACC development are only partially known. The study of rare genetic syndromes responsible for familial ACC has been instrumental in making initial progress in this field (204). It has allowed for the study of specific gene and loci that play an important role in ACC development. More recently, the development of genomics stimulated research in the field at the pan-genomic level (8).


Genetic alteration in adrenocortical carcinomas: From familial syndromes to sporadic ACC Li-Fraumeni syndrome—TP53 and locus 17p13 Li-Fraumeni syndrome and Li-Fraumeni-like syndrome Described in 1969 by two epidemiologists named Frederick Li and Joseph Fraumeni (200, 201), Li-Fraumeni syndrome (LFS—OMIM 151623) is an autosomal dominant disorder. This syndrome refers to the susceptibility of developing breast cancer, soft tissue sarcomas, brain tumors, osteosarcoma, leukemia, and adrenocortical carcinoma. Cancers of skin, colon and pancreas have also been reported in LFS. Chompret Criteria have been defined for clinical diagnosis of Li-Fraumeni syndrome: (i) a tumor belonging to the LFS tumor spectrum, before the age of 46 years. This means any of the following malignancies: soft tissue sarcoma, osteosarcoma, premenopausal breast cancer, brain tumor, adrenal cortical carcinoma, leukemia, or lung cancer—and at least one first-degree or second-degree family member with an LFSrelated tumor (except breast cancer if the individual has breast cancer) before the age of 56 years or with multiple tumors. Or (2) a person with multiple tumors (except multiple breast tumors), two of which belonging to the LFS tumor spectrum and the first of which occurred before age 46 or (iii) a person who is diagnosed with ACC or a tumor in the choroid plexus (a membrane around the brain), regardless of family history (40, 59, 319). Families presenting incomplete features of LFS are referred to as having Li-Fraumeni-like syndrome. Germline mutations in the TP53 gene, located on 17p13, are present in 70% of families with Li-Fraumeni syndrome. In a majority of cancer types, acquired somatic mutations of

307



this tumor suppressor gene have been identified (53). Its gene is the most frequently mutated across all cancers (53, 144). ACC is a less frequent manifestation of LFS, developing in 3% to 10% of patients (40, 141, 201). While the prevalence of germline TP53 mutations in apparently sporadic ACT is low (3% and 6%) (139, 269), this proportion is significantly higher in children (50%-80%) (328, 335). These data show that TP53 genetic testing should be done in any child with apparently sporadic ACC but also discussed in adults younger than 46 (59, 60).

TP53 somatic alteration in sporadic adrenocortical cancers TP53 was first considered in the pathophysiology of ACC because of Li-Fraumeni syndrome. In adults, somatic mutations of TP53 are found in about a third of sporadic ACC cases (139, 205, 247, 269, 274, 298). Most of the mutations are located in four hot spot regions within exons five and eight (247, 274). Interestingly, these mutations are usually observed in larger and more advanced tumors. In ACC, loss of heterozygosity (LOH) at the 17p13 locus is observed in >80% of cases (111, 348) and less than 30% in adrenocortical adenoma (ACA).

TP53 in pediatric ACT In North America and Europe, 50 to 80% of children with sporadic ACC have a germline mutation of TP53 (328, 335). In Southern Brazil, the incidence of pediatric ACCs is 10 times higher than the rest of the world. A specific germline mutation in the tetramerization domain of the TP53 gene (R337H) has been found in almost all cases (192, 277). The impact of this specific mutation on the function of p53 protein may be pH dependant (80). The R337H mutation in the TP53 gene is found in only 13% of Brazilian adults with ACTs and comes with a poor prognosis (192). Recently, in Southern Brazil, this germline mutation

has also been associated with pediatric plexus carcinoma and osteosarcoma (291), and, in adults, can significantly increase the risk of breast cancer (11, 110). It was initially believed that this mutation, which has a low penetrance, specifically predisposes to ACC development in childhood, but now it is well recognized that this mutation is also associated with classical LFS (74). Recently, the results of a neonatal screening in Paranà state (Southern Brazil) for the TP53 R337R mutation and surveillance for early detection of childhood ACTs of 171649 newborns were published. This study is the first neonatal genomic DNA testing to select children for surveillance for a specific malignancy and showed the high efficacy of this surveillance program in detecting ACTs of low weight and volume without clinical signs (75).

Beckwith-Wiedemann Syndrome—IGF2 gene and locus 11p15

Beckwith-Wiedemann

Syndrome BeckwithWiedemann syndrome (BWS—OMIM 130650) is a pediatric overgrowth disorder and has an estimated incidence of one in 13,000 live births. BWS causes macrosomia, macroglossia, organomegaly, and the development of embryonic tumors (Wilms’ tumor, hepatoblastoma, rhabdomyosarcoma, and ACC). Approximately 85% of reported BWS cases are sporadic, while the remaining 15% are familial. BWS is caused in 90% of cases by an alteration in the expression of genes located at 11p15 (202,203). This locus at 11p15 (137) contains paternally expressed genes such as IGF2 which promote growth and maternally expressed genes such as H19 imprinted, maternally expressed transcript (H19), and cyclin-dependent kinase inhibitor C (CDKN1C or p57/kip2), which restrain growth (Figure 5).

Normal adrenal IGF2

IGF2

IGF2

IGF2

IGF2 IGF1R

IGF1R IGF2

IGF2

IGF2 IGF2

Paternal allele

Paternal allele

Maternal allele CDKN1C (p57kip2)

IGF2

H19

Paternal allele CDKN1C (p57kip2)

IGF2

H19 Paternal isodisomy

Figure 5

Alterations of 11p15 locus and IGF2 overexpression in ACC. The imprinted 11p15 locus contains the CDKN1C (p57kip2), IGF2, and H19 genes. In a normal adrenal (on the left), only the paternal allele of the IGF2 gene is expressed, whereas only the maternal alleles of CDKN1C and H19 are expressed. Paternal isodisomy is usually observed in adrenal cancers (on the right) with loss of the maternal allele at 11p15. This leads to the overexpression of IGF2 and decreased expression of CDKN1C and H19.

308



In BWS, various genetic and epigenetic alterations in the imprinting of the 11p15 locus lead to overexpression of IGF2 as well as to the low expression of CDKN1C and H19 (79, 189). Several mechanisms may explain IGF2 overexpression. Chromosome rearrangements are rare (1%-3% of cases) (36, 79). The most frequent explanation is loss of the maternal allele with duplication of the paternal allele (paternal isodisomy). More rarely, a loss of imprinting occurs, leading to IGF2 expression by both parental genes (79, 113, 246, 268). Approximately 5% to 10% of sporadic BWS cases and 40% of familial BWS cases are due to an inactivating mutation in CDKN1C gene. Mice lacking Cdkn1c have several abnormalities also seen in patients with BWS, as the adrenal cortical hyperplasia (354). The most frequent adrenal tumors are adrenal cysts and ACA, which represent 28% and 8% of the benign tumors in BWS, respectively. Less than 1% of children with BWS will develop an ACC, which represent 7% of overall malignant tumors in this syndrome (191).

IGF2 in ACC The insulin-like growth factors system is involved in the development of the adrenal cortex, and its role in ACC was initially considered because of BeckwithWiedemann syndrome. Many studies have demonstrated that IGF2 is strongly overexpressed in 90% of ACC cases and could be used as a diagnosis marker of ACC (42, 111-113, 156, 232). Several mechanisms may explain IGF2 overexpression in ACC. The most frequent is loss of the maternal allele and duplication of the paternal allele (paternal isodisomy). More rarely, a loss of imprinting occurs, leading to IGF2 expression by both parental genes (113, 246, 268). Three different transgenic mice models with overexpression of IGF2 (ranging from 2- to 87-fold) in the adrenal cortex do not develop adrenal tumors over a time span of 14 months even though the IGF signaling pathway was activated (84, 135). However, in both studies, IGF2 overexpression could accelerate tumor progression in the context of an activated Wnt/β-catenin pathway. These results suggest that IGF2 overexpression alone is not sufficient and that a second or multiple alteration is necessary for adrenocortical tumorigenesis.

Familial adenomatous polyposis and Wnt/β-catenin pathway

Familial adenomatous polyposis The Wnt pathway regulates several cellular processes; abnormalities of this pathway have been described in the development of several cancers (56, 64, 195), including colorectal cancer and those associated with familial adenomatous polyposis (FAP— OMIM 175100) syndrome. FAP is caused by mutations in the adenomatous polyposis coli (APC gene, located in 5q21), leading to a nonfunctional version of the APC protein. FAP syndrome is an autosomaldominant disorder and patients with FAP will develop colon polyps and have an increased risk of colorectal cancer and a



predisposition to various extracolonic manifestations, hepatoblastomas, gastrointestinal polyps, gastroduodenal tumors, and endocrine tumors such as thyroid tumors and ACTs (222). Benign and malignant ACTs were observed in FAP patients (28, 34, 107, 146, 222, 243, 249, 292, 301, 323, 336) with abnormal cytoplasmic and nuclear β-catenin localization on immunohistochemistry, revealing an activation of the Wnt/β-catenin pathway. In most ACTs from FAP, second-hit mutations or LOH of the normal APC allele were identified (34, 107, 146). Yamakita and coll. (347) suggested that second-hit mutations are not always found in ACT from FAP. Because most of the previous genetic data on ACTs in patients with FAP are not available, we cannot rule out some unrelated sporadic adrenal disease.

Wnt/β-catenin pathway in sporadic adrenocortical cancers The regulation of β-catenin accumulation in the cytoplasm, with subsequent translocation into the nucleus, is the central intracellular event regulating the canonical Wnt pathway. In the absence of Wnt stimulation of its receptor, the AXIN-adenomatous polyposis coli (APC)-glycogen synthase kinase 3 β (GSK-3β) complex binds and phosphorylates β-catenin, resulting in its ubiquitylation and degradation by proteosomes (173) (Figure 6). When the Wnt ligand activates intracellular signaling, β-catenin enters the nucleus and interacts with the lymphoid enhancer-binding factor 1/T cell-specific transcription factor (LEF/TCF) family of transcription factors. This activates transcription of Wnt target genes. Immunohistochemistry can be used to study β-catenin protein localization as a marker of Wnt pathway activation. When the pathway is not activated, β-catenin is localized at the cell membrane. After activation by an extracellular ligand or a genetic alteration, β-catenin is visible in the cytoplasm and/or the nucleus. Mutations of some genes leading to aberrant stimulation of Wnt-signaling have been described in several types of sporadic tumors (114). In ACC, β-catenin delocalization can be observed as consistent with an abnormal activation of the Wnt signaling pathway (105, 320). In a subset of these tumors, this can be explained by activating mutations of β-catenin. In patients with FAP and ACC, biallelic inactivation of APC in ACC can activate the Wnt signaling pathway. By contrast, alterations of the APC gene are not observed in sporadic ACC (105, 107). Recently, AXIN1 and AXIN2 gene were analyzed and no alterations were found, suggesting that these genes do not play a role in ACC tumorigenesis and Wnt/β-catenin pathway activation (120). In a recent study on a large cohort of ACC, a potential new tumor suppressor gene related to the Wnt/β-catenin pathway, ZNRF3 (Zinc And Ring Finger 3), was revealed to be the most frequently altered gene (10). This gene encodes a cell surface transmembrane E3 ubiquitin ligase that acts as a negative feedback regulator of Wnt/β-catenin signaling by promoting the degradation of

309



Absence of ligand

Presence of ligand Wnt

Wnt Wnt

Frizzled

LRP

Cadherin

Frizzled

LRP

β-catenin α-catenin AXIN DSH AXIN

GSK3β

WTX

APC

β-catenin

DSH

WTX

P

GSK3β APC

β-catenin degradation

β-catenin β-catenin

Proteasome β-catenin

β-catenin LEF/TCF Target genes repressed

Target genes activated

Figure 6

The Wnt signaling pathway. Left: In the absence of Wnt ligand, β-catenin is low, owing to degradation by the ubiquitin-proteasome system after phosphorylation by the GSK3β-APC-AXIN-WTX complex. Right: Stimulation by Wnt ligand leads to the inactivation of the degradation complex, which leads to the stabilization of β-catenin in the cytoplasm. After translocation to the nucleus, β-catenin stimulates expression of target genes after interaction with TCF/LEF. Mutations of β-catenin abolish phosphorylation of β-catenin, which leads to its accumulation by preventing its degradation by the ubiquitin-proteasome system.

the LRP6 (low density lipoprotein receptor-related protein 6) and Frizzled receptors (129). It remains to be demonstrated if ZNRF3 alterations or other components of the Wnt signaling pathway could take part in the activation of this pathway and contribute to the pathogenesis of ACC. In two transgenic mice models, constitutive β-catenin activation induces adrenal hyperplasia and promotes adrenal cancer development (25, 135).

MEN 1 syndrome—Menin gene and locus 11q13

Multiple endocrine neoplasia 1 Multiple endocrine neoplasia 1 (MEN1; OMIM 131100) is an autosomal dominant syndrome, caused by inactivating mutations in the MEN1 gene, located in 11q13. This gene, thought to be a tumor suppressor gene, encodes the Menin protein whose exact function is unknown. Because Menin protein is located in the nucleus, it could play a role in the cell cycle, DNA replication or gene transcription. MEN1 syndrome is characterized by a risk of developing pituitary, pancreatic and parathyroid tumors. In 20% of cases, these patients develop ACTs, frequently a nonfunctional ACA and more rarely an adrenocortical carcinoma; in less than 1%, pheochromocytomas were found (104, 178, 223, 290). MEN1 and 11q13 in ACC LOH at 11q13 are observed in more than 90% of informative ACC and only 20% of ACAs

310

(138, 178, 290). Mice with heterozygous inactivation of Men1 gene developed multiple endocrine tumors including adrenocortical carcinoma in one fifth of cases and less frequently pheochromocytomas (130). In previous studies, only rare ACC cases with mutation of the MEN1 gene were identified suggesting that another tumor suppressor gene located on the long arm of the chromosome 11 is involved in ACC formation (138, 289, 290, 359). However a recent study on a large cohort of ACCs (n = 121) suggests that mutations in MEN1 are not uncommon (7% of cases) (10), but the correlation with LOH at 11q13 remains to be demonstrated.

Lynch syndrome Lynch syndrome (LS—OMIM 120435), also called hereditary nonpolyposis colorectal cancer (HNPCC), was originally described by Warthin in 1913 (339) and later in 1966 by Lynch (219). Lynch syndrome is an inherited disorder that increases the risk of many types of cancer, particularly colorectal cancer. LS is caused by germline mutations in DNA mismatchrepair (MMR) genes MLH1 (mutL homolog 1), MSH2 (mutS homolog 2), MSH6 (mutS homolog 6), and PMS2 (postmeiotic segregation increased 2). People with Lynch syndrome also have an increased risk of cancers of the endometrium, ovary, thyroid, lung, small intestine, liver, central nervous system, skin, and adrenal cortex.



Karamurzin et al. reported four cases of ACC in patients with Lynch syndrome (167) and recently, Raymond et al. studied a large cohort of ACC (n = 94) and identified three patients (3.2%) with a family history suggestive of LS (270). Mutations in the MMR gene were found in the three families. Patients with ACC and a personal or family history of LS tumors could be considered for genetic risk assessment.

Carney complex Carney complex (CNC—OMIM 160980) was described in 1985 (52). The most frequent manifestations of CNC are lentiginosis, myxomas, and ACTH-independent Cushing’s syndrome due to primary pigmented nodular adrenocortical disease. Recently, two cases of ACC have been reported in CNC patients with germline PRKAR1A (protein kinase, cAMP-dependent, regulatory, type I, and alpha) mutations (4, 238).

New molecular markers of adrenocortical tumors Gene expression and pathways altered In clinical practice, ACTs are classified according to their secretion and malignancy status. Several studies (Table 4) have shown that the classification of tumors based on their transcriptome leads to two distinct groups, corresponding to ACCs and ACAs independently of the secretion (76, 78, 95, 96, 115, 116, 194, 300, 302, 321, 329, 340). A large number of genes are differentially expressed in ACC versus ACA (Table 5).

Cell cycle regulators in ACCs In most tissues, the majority of genes which are altered in tumorigenesis are involved in cell proliferation and cell cycle. Some cyclin genes and their partners were dysregulated in ACC (78, 115, 312, 321). Cyclin E1 (CCNE1), Cyclin E2 (CCNE2), and other genes involved in G1/S transition, such as cell division protein kinase 2 and 4 (CDK2 and CDK4), were overexpressed in ACC (43, 312). The G2/M transition is also dysregulated with overexpression of various genes, Cyclin B2 (CCNB2), cell division protein kinase 7 (CDK7), the cell division control 2 (CDC2), cell division cycle 25 homolog B (CDC25B) genes, ubiquitin C (UBC), Mdm2 p53-binding protein homologue (MDM2), and the topoisomerase II alpha (TOP2A) gene (312). Others genes involved in the control of cell cycle were overexpressed, such as Cyclin B1 (CCNB1) and Cyclin A2 involved in G2/M and S/G2 transitions, respectively (9, 78). Downregulation of Steroidogenec genes in ACC: Loss of differentiation Genes involved in steroidogenesis are globally downregulated in ACC compared to ACA. DeFraipont and colleagues identified a cluster with 14 genes



downregulated in ACC, some involved in steroidogenesis (76), StAR; cytochrome P450, family 11, subfamily A, polypeptide 1 (CYP11A1); hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 1 (HSD3B1); CYP11B1; cytochrome P450, family 21, subfamily A, polypeptide 2 (CYP21A2); and cytochrome P450, family 17, subfamily A, polypeptide 1 (CYP17A1); cAMP responsive element modulator (CREM), retinoblastoma 1 (RB1); protein phosphatase, Mg2+/Mn2+ dependent, 1A (PPM1A); nonmetastatic cells 1, protein (NM23A) (NME1); transforming growth factor, beta receptor III (TGFBR3); S100 calcium binding protein B (S100B); glypican 3 (GPC3); and inhibin, alpha (INHA). The tumors reclusterized with the expression profiles of these steroidogenesis cluster genes separated in two groups. Eighty-one percent of the tumors in the group with low expression were ACC, and 93% in the group with high expression were ACA. In the microarray study by de Reyniès et al., several steroidogenic genes, the melanocortin 2 receptor or ACTH receptor (MC2R), cytochrome P450, family 11, subfamily B, polypeptide 1 (CYP11B1); hydroxy-delta5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 2 (HSD3B2); and aldo-keto reductase family 1, member B1 (aldose reductase) (AKR1B1) are downregulated in ACC (78, 198, 261). MC2R gene, located at 18p11.2, produces a seven transmembrane G-protein coupled receptor. It belongs to a family with five members. Loss of allele at the MC2R locus has been reported in ACC but not in ACA. Moreover, in nonsecreting ACAs and in ACC, MC2R expression is decreased (273, 275), while MC2R expression is upregulated in cortisolsecreting ACAs. It is likely that the decreased expression of MC2R in ACC could take part in the downregulation of genes involved in steroidogenesis, the dedifferentiation of these aggressive tumors and dysregulation of the cAMP pathway that plays an important role in the physiology of the adrenal cortex (280).

IGF2 pathway: A role in ACC? The IGF signaling pathway plays an important role in cell proliferation and participates in the development of several tumors. IGF2 involvement in ACC was initially considered because of BeckwithWiedemann syndrome (BWS). Various studies that used global gene expression analysis confirmed the initial observation before the transcriptomic area: IGF2 is the gene most overexpressed in ACC compared to ACA (44, 76, 78, 115, 116, 302). DeFraipont and colleagues identified a cluster of eight genes which are upregulated in ACC. This cluster, named the IGF2-cluster, contains two growth factors (IGF2 and TGFB2), two fibroblast growth factor receptors (FGFR1 and FGFR4), the macrophage stimulating 1 receptor (MST1R), the TGFβ receptor type I (TGFBR1), KCNQ1 overlapping transcript 1 (KCNQ1OT1 or LIT1—located in the IGF2 locus) and glyceraldehyde-3-phosphate dehydrogenase (76). Tumors are separated into two groups when reclusterized with the genes of this IGF2-cluster. Ninety percent of tumors in groups with low expression were adenomas and 75% of tumors in the group that hit high expression were carcinomas.

311


Table 4


Adrenocortical Genomic Studies Samples

Genomic studies

ACC

ACA

NA

Informations

Giordano et al. 2003 (116)

11

4

3

91 genes were overexpressed (more than threefold) in ACC vs. NA and ACA including IGF2 (insulin-like growth factor 2), SPP (osteopontin) and STK15 (serine threonine kinase 15). These genes could predict Malignancy.

DeFraipont et al. 2005 (76)

24

33

Two clusters of genes, the IGF2 cluster (eight genes including IGF2, TGFB2, FGFR1, FGFR4 . . . ) and the steroidogenesis cluster (14 genes including genes encoding steroidogenic enzymes as STAR, CYP11A, HSD3B1, CYP11B1, CYP21A2, and CYP17), predict malignancy. A set of 14 genes predicts metastatic recurrence.

Velazquez-Fernandez et al. 2005 (329)

7

13

Unsupervised classification separates ACC from ACA. 571 genes show more than twofold expression difference in ACC vs. ACA. The 2 most significant differentially upregulated genes were USP4 (ubiquitin-specific protease 4) and UFD1L (ubiquitin fusion degradation 1-like).

Slater et al. 2006 (300)

10

10

21 genes show expression difference in ACC vs. ACA in cluding IGF2 whose is overexpressed in ACC.

Lombardi et al. 2006 (211)

2

2

ACC showed overexpression of HSPD1 (Heat Shock 60 kDa Protein 1 or HSP60), CCND1 (cyclin D1) and TOP1 [topoisomerase (DNA) I] compared to ACA. The expression of JUN (Jun proto-oncogene) was downregulated in the ACC.

Fernandez-Ranvier et al. 2008a (96)

11

43

25 genes located on chromosome 11q13 are downregulated in ACC vs. ACA. Six of these genes (SERPING1, MRPL48, TM7SF2, DDB1, NDUFS8, and PRDX5) were good diagnostic markers for distinguishing ACC from ACA.

Fernandez-Ranvier et al. 2008b (95)

11

74

15 genes were downregulated and 22 were upregulated in ACC vs. ACA. Five of these genes (IL13RA2, HTR2B, CCNB2, RARRES2, and SLC16A9) were good diagnostic markers for distinguishing ACC from ACA.

de Reynies et al. 2009 (78)

34

58

Clustering analysis discriminates ACC from ACA, and reveals two subtypes of ACC associated with different outcome. RT-PCR based disease-free predictor (DLGAP5-PINK1) and survival predictor (BUB1B-PINK1) are proposed.

Giordano et al. 2009 (115)

33

22

10

879 genes were upregulated and 1011 were downregulated in ACC vs. ACA including including IGF2, SPP1, TOP2A, ENC1, and H19. Clustering analysis reveals two groups of ACC, associated with different outcome and different mitotic count.

Laurell et al. 2009 (194)

11

17

4

Clustering analysis discriminates ACC from ACA (with an upregulation of IGF2 and a downregulation of ALDH1A1 in ACC), and reveals two subtypes of ACC associated with different outcome.

Soon et al. 2009 (302)

12

16

T¨ omb¨ ol et al. 2009 (321)

4

8

4

301 were found to be downregulated, whereas 302 genes were upregulated (including IGF2, TOP2A, CCNB2, CDC2, and CDC25) in ACC.

Soon et al. 2009 (303)

22

27

6

The miRNome discriminates ACC from ACA and 23 microRNAs were found to be significantly differentially expressed between ACC and ACA. Downregulation of miR-195 and upregulation of miR-483-5p in were significantly associated with poorer disease-specific survival.

Tombol et al. 2009 (321)

4

8

4

Six miRs with significantly different expression were found. miR-184 and miR-503 showed significantly higher, whereas miR-511 and miR-214 showed significantly lower expression in ACC. By measuring expression of miR-511 and miR-503, ACC could be distinguished from ACA.

Transcriptome

177 genes show expression difference in ACC vs. ACA. IGF2, MAD2L1, and CCNB1 were significantly higher in ACCs compared with ACAs while ABLIM1, NAV3, SEPT4, and RPRM were significantly lower.

miRNA studies

312



Table 4


(Continued) Samples

Genomic studies

ACC

ACA

NA

Informations

Patterson et al. 2011 (250)

10

26

21

The miRNome discriminates ACC from ACA. 5 miRNAs (including miR-483-5p) had higher expression and 18 miRNAs had lower expression in ACC. MiR-483-5p expression alone could accurately distinguish between ACA and ACC.

Schmitz et al. 2011 (286)

4

9

4

The miRNome discriminates ACC from ACA. 248 miRNAs show expression difference in ACC vs. ACA. Low expression of miR-675 and/or miR-335 is associated with malignancy.

Ozata et al. 2011 (248)

22

26

The miRNome discriminates ACC from ACA. 72 miRNAs show expression difference in ACC vs ACA. High expression of miR-503, miR-1202, and/or miR-1275 is associated with a poor prognosis.

Chabre et al. 2013 (55)

12

6

12 miRNAs show expression difference in ACC vs. ACA. 29 miRNAs show expression difference between aggressive ACC (metastatic or recurring within 3 years) and nonaggressive ACC (nonrecurring after 3 years). Combinations of these miRNAs discriminate ACC from

Assi´ e et al. 2014 (10)

45

3

miR-483 (located within intron 2 of the IGF2 locus) was overexpressed in ACC. Consensus clustering identified three stable tumor clusters. One of them was characterized by the upregulation of 11 miRNAs belonging to the miRNA-506-514 cluster (Xq27.3) and by the downregulation of 38 miRNAs belonging to the imprinted DLK1-MEG3 cluster (14q32.2).

Chromosomal alteration (CGH and SNP) Kjellman et al. 1996 (177)

8

14

There was a relationship between the number of genetic aberrations detected using CGH and both tumor size and malignancy. Recurrent losses of chromosomal regions 2, 11q, and 17p and gains at chromosomes 4 and 5 were identified in ACC.

Zhao et al. 1999 (356)

12

23

CGH analysis show that alterations are more frequent in ACC with a recurent losses of 1p21–31, 2q, 3p, 3q, 6q, 9p, and 11q14-qter, as well as gains and amplifications of 5q12, 9q32-qter, 12q, and 20q.

Dohna et al. 2000 (83)

14

8

ACC have specific gains of chromosome 7, 14, or 19 compare to ACA and high-level amplifications are found exclusively in ACC.

Zhao et al. 2002 (355)

5

4

Putative role of SAS/CDK4 and MDM2 coamplification (12q) in the progression of adrenocortical tumours.

Sidhu et al. 2002 (297)

13

18

In ACC, the most common gains were on chromosome 5, 12, 19, and 4 and losses at 1p, 17p, 22q, and 11q.

Stephan et al. 2008 (307)

25

Several recurrent gains (5, 7, 12, 16q, and 20) and losses (1, 3p, 10q, 11, 14q, 15q, 17, and 22q) are identified in ACC. Several isolated CGH probes scattered among the genome are associated with survival. The combination of these probes identifies three groups

Szabo et al 2010 (312)

4

Several recurrent gains (5, 7, 12, and 19q) are identified in ACC.

Barreau et al. 2012 (20)

52

86

A larger proportion of the genome is altered in ACC vs ACA. A qPCR-based diagnostic tool is proposed. The chromosome alterations also contain prognostic information.

Ronchi et al. (279)

22

24

A larger part of the genome is altered in ACC vs. ACA in terms of copy number alterations, but also in terms of loss of heterozygosity. A specific pattern is associated with survival.

De Martino et al. 2013 (77)

40

Several recurrent gains (5, 7, 12, 19, and 20) and losses (1 and 22) are reported. Recurrent amplification of CDK4 and deletion of CDKN2A and CDKN2B are identified.

Assi´ e et al. 2014 (10)

121

Several recurrent gains (4, 5, 7, 8, 12, 16, 19, and 20) and losses (1p and 22). Recurrent amplification (TERT and CDK4) and homozygous deletions (CDKN2A, RB1, and ZNRF3). (continued)


313


Table 4


(Continued) Samples

Genomic studies

ACC

ACA

NA

Informations

Rechache et al. 2012 (271)

20

48

19

Methylome discriminates ACC vs. ACA. In their intergenic regions, ACC are globally hypomethylated. 52 hypermethylated and downregulated genes in ACC are identified.

Fonseca et al. 2012 (99)

15

27

6

212 CpG islands in the promoter regions are significantly hypermethylated in ACC vs. ACA. For 6 genes selected among these 212, expression is low in ACC.

Barreau et al. 2013 (19)

51

84

Methylome

Focusing on the CpG islands of genes promoter regions, methylome reveals two subtypes of ACC, one with hypermethylation, the other without. This hypermethylation is associated with a poor prognosis. The transcriptome/methylation correlation shows 1741 genes.

Exome sequencing Assi´ e et al. 2014 (10)

45

Four genes were significantly enriched for mutations: CTNNB1, TP53, DAXX, and MEN1

Genomic studies compare profiles of adrenocortical carcinomas, adrenocortical adenomas, and for few, normal adrenals (NA). ACC, adrenocortical carcinoma; ACA, adrenocortical adenoma.

Overexpressed IGF2 is thought to act in a paracrine manner through the insulin-like growth factor 1 receptor (IGF1R), sustaining tumor and cell proliferation (42, 210, 300). It appears that the IGF1 receptor, which mediates the trophic effects of IGF2, is expressed at the same level in benign and malignant tumors (42). Regarding other cell types, Logie and colleagues showed in the ACC cell line H295R that the IGF2 effect on proliferation is dependent on IGF1R (210). In ACC, the expression of some IGF-binding proteins, which modulate the effects of effects of IGF1 and IGF2, is altered (41, 78, 115, 300). In mice models, though, overexpression of IGF2 alone had no impact and a mild effect in combination with active β-catenin [(84, 135), and paragraph “Genetic alteration in adrenocortical carcinomas: from familial syndromes to sporadic ACC/Beckwith-Wiedemann Syndrome—IGF2 gene and locus 11p15”]. The IGF system is a therapeutic approach in human ACC, and IGF1 receptor antagonists are currently being tested in clinical trials.

Wnt signaling pathway in ACCs Several observations suggest activation of the Wnt pathway as a major alteration in ACC pathogenesis. First, as mentioned previously (paragraph “Genetic alteration in adrenocortical carcinomas: from familial syndromes to sporadic ACC/FAP and Wnt/β-catenin pathway”), β-catenin delocalization can be observed in ACC, explained in part by activating mutations of β-catenin (105, 320). Secondly, microarray analyses showed activation of the Wnt/β-catenin pathway in ACC with upexpression of several transcriptional targets: baculoviral IAP repeat-containing 5

314

(BIRC5), ectodermal-neural cortex 1 (ENC1), pituitary tumortransforming 1 (PTTG1), and twist homolog 1 (TWIST1) (76, 78, 115, 300, 329). Studies in vitro and in vivo suggest Wnt/βcatenin signaling pathway inactivation as a promising therapeutic target in ACC. The Wnt/β-catenin inactivation pathway in H295R cells by PKF115-584 or a sh-RNA targeted βcatenin mRNA decreased the percentage of cells in S-phase and increased the percentage of apoptotic cells (81, 106) and associated with a complete absence of tumor growth in a xenograft model (106).

Other growth factors and pathways Several other growth factors signaling pathways are potentially involved in tumorigenesis. For example, fibroblast growth factor receptors genes, FGFR1 and FGFR4, were overexpressed (76, 78, 115, 300, 329) and could participate in ACC development, but functional relevance remains to be determined. A metaanalysis of ACT transcriptome described the retinoic acid signaling as a potentially relevant pathway (312). Alterations in the expression of some genes of this pathway—RXRA (retinoid X receptor, alpha), ALDH1A1 (aldehyde dehydrogenase 1 family, member A1) and ALDH1A3 (aldehyde dehydrogenase 1 family, member A3)—that were described in several microarray studies (78, 115, 116, 194, 302, 329) lead to a decrease in both retinoic acids production and their action. Retinoids are involved in several cancers, and are used in cancer therapy. 9-cis retinoic acid (9-cisRA) is a specific ligand for both the retinoid acid receptors (RARs) and retinoid X receptors (294). 9-cisRA is able to decrease steroid secretion and cell proliferation of the ACC cell line H295 and reduced



Table 5


Adrenocortical Carcinoma Signature Gene symbol

Gene title

Up in Carcinoma vs. Adenoma Growth factors and receptors

Cell cycle

DNA replication

IGF2

Insulin-like growth factor 2 (somatomedin A)

FGFR1

Fibroblast growth factor receptor 1

FGFR4

Fibroblast growth factor receptor 4

CCNA2

Cyclin A2

CCNB1

Cyclin B1

CCNB2

Cyclin B2

CCNE1

Cyclin E1

CDC2

Cell division cycle 2, G1 to S and G2 to M

CDC23

Cell division cycle 23 homolog

CDC25B

Cell division cycle 25 homolog B

CDC25C

Cell division cycle 25 homolog C

CDK2

Cyclin-dependent kinase 2

CDK4


CDK7


PTTG1

Pituitary tumor-transforming 1

UBE2C

Ubiquitin-conjugating enzyme E2C

RRM2

Ribonucleotide reductase M2 polypeptide

MLFIIP

MLF1 interacting protein

PRC1

Protein regulator of cytokinesis 1

TPX2

TPX2, microtubule-associated, homolog

TOP2A

Topoisomerase (DNA) II alpha 170 kDa

Down in Carcinoma vs. Adenoma Steroidogenesis

Metabolism and transport

CYP11A1

Cytochrome P450, family 11, subfamily A, polypeptide 1

CYP11B1

Cytochrome P450, family 11, subfamily B, polypeptide 1

CYP17A1


CYP21A2


HSD3B1

Hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 1

HSD3B2

Hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 2

STAR

Steroidogenic acute regulatory protein

APOC1

Apolipoprotein C-I

PLTP

Phospholipid transfer protein

SREBF1

Sterol regulatory element binding transcription factor 1

B4GALT6

UDP-Gal:betaGlcNAc beta 1,4- galactosyltransferase, polypeptide 6

MAN1A1

Mannosidase, alpha, class 1A, member 1

Adrenocortical carcinomas (ACC) differ from adrenocortical adenomas (ACA) by their increased expression of genes involved in growth, cell cycle, and DNA replication and by their decreased expression of genes involved in steroidogeneis and metabolism. Adapted from (261).


315


tumor growth in an in vivo xenograft model (98, 311). Targeting this pathway could represent a` new candidate in the treatment of ACC and other secreting ACTs.

Subgroups of ACCs identifies by transcriptome Two transcriptomic studies identified two distinct groups of ACC (78, 115), named C1A (with poor prognosis) and C1B (with better prognosis) in the study by de Reynies et al. (78). In both studies, overall survival (OS) differed significantly between the two groups (Table 4). In the poor-outcome group, overexpressed genes were mainly involved in cell cycle and transcription. The good-outcome group was enriched by genes involving cell metabolism and intracellular transport. Moreover, by unsupervised clustering transcriptome analysis, three different subgroups were identified in the poor-outcome group (263), two of them being associated with p53 or βcatenin alterations, respectively. This alteration had a major influence on tumor biology. Indeed, global expression of p53 and β-catenin target genes were altered in these subgroups respectively (263). More recently, some somatic mutations, loss of the retinoblastoma protein (pRb) and allele loss were identified at the RB1 locus in an ACC cohort (262). RB1 is a well-known gatekeeper tumor suppressor gene, whose loss or inactivation leads to uncontrolled cell proliferation (47). RB1 genetic and pRb protein expression alterations were only associated with the poor-outcome ACC group. As a consequence, 10% of the poor-outcome ACCs were carriers of a somatic RB1 mutation. In a similar way, 27% of the poor prognosis ACCs were found with a pRb loss. By contrast with TP53 and CTNNB1 [catenin (cadherin-associated protein), beta 1] abnormalities, RB1 alterations were not found with a mutually exclusive pattern. Some ACCs with RB1 alterations simultaneously had a TP53 alteration, which might suggest the necessity to inactivate in the same tumor the p53 and pRb pathways. Cooperation between these two pathways has been demonstrated in different human cancers (67, 293).

Malignancy and survival predictors Several studies showed the prediction of the recurrence (or the Disease-Free Survival) and the prediction of specific death (or OS). De Reynies et al. (78) developed and proposed two molecular predictors based on the expression of three genes evaluated by quantitative PCR (polymerase chain reaction), with one predicting recurrence of an ACT and the other predicting OS rates in ACC (Table 4). These markers have been validated by another team (100). MicroRNA expression MicroRNAs (miR) are small noncoding double strand RNA molecules (around 20-24 nucleotides) that are involved in regulation of gene expression by a posttranscriptional process (158, 349). MicroRNAs can bind the nontranslated 3’ regions (UTR: untranslated region) of target mRNA molecules and can induce their degradation or the inhibition of translation.

316


MicroRNAs regulate several cellular processes (differentiation, proliferation, and apoptosis) and some of these miR are dysregulate in tumors and may be good biomarkers for cancer diagnosis and prognosis (214). Seven studies (six in adult and one in pediatric, Table 4) have focused on the miR expression profile in unilateral ACTs (55, 82, 248, 250, 286, 303, 321) and showed differentially the expression of several miR between ACC and ACA. Soon and coll. (303) examined the expression profile of 847 miRNAs in 27 adenomas, 22 adrenocortical carcinomas, and 6 normal adrenal tissues adjacent to the tumors. The miRNome discriminates ACC from ACA. 23 miR were found differentially expressed between ACA and ACC. Upregulation of miR-483-5p and downregulation of miR-195 were significantly associated with poor prognosis in adrenocortical carcinoma. Tombol et al. (321) analyzed expression of 368 miR in four of each sample type (normal adrenal, nonsecreting adenomas, secreting adenomas and adrenocortical carcinomas). In this analysis, 14 miRs have significant differences and were analyzed by quantitative qPCR in an extended cohort of samples (10 normal adrenals, 10 nonsecreting ACA, 9 secreting ACA, and 7 ACC). The difference was only confirmed for 6 of the 14 miR (miR-184, miR-210, miR-214, miR-375, miR-503, and miR-511) and 3 were able to identify the ACC (miR-184, miR-503, and miR-511). Combination of the miR-511 and miR-503 expressions, by calculating the difference between dCT-miR511 and dCTmiR503, identified ACCs from ACAs with 100% of sensitivity and 80% of specificity. Patterson and colleagues (250) used a miRNA microarray on 10 ACC, 26 ACA, and 21 normal adrenals. The authors showed that the miRNome discriminates ACC from ACA. Three miR (miR-100, miR-125b, and miR-195) were significantly downregulated, and one (miR-483-5p) was upregulated in ACC compared to ACA. The miR-483 locus is within the IGF2 locus and their expressions are correlated. MiR-483-5p expression was evaluated by quantitative PCR on an independent cohort (35 ACA and two locoregional ACC recurrences and 29 ACC metastases) and the difference between ACA and ACC was confirmed. Schmitz and colleagues (286) analyzed miRNA profiles in four ACC, nine ACA, and four normal adrenals. The miRnome discriminates ACC from ACA. One hundred and fifty-nine of 667 miR analyzed were upregulated and 35 were downregulated in ACC as compared to ACA. In particular, three miR downregulated in ACC (miR-675, miR-139-3p, and miR-335) were confirmed by quantitative PCR in an independent cohort of 15 ACC. ¨ Ozata et al. (248) analyzed 903 miR expression on 22 ACC, 26 ACA, and 4 normal adrenals. The miRNome discriminates ACC from ACA and 72 miR show expression difference between two groups. In particular, four were upregulated (miR-483-3p, miR-483-5p, miR-210, and miR-21) and three downregulated (miR-195, miR-497, and miR-1974) in ACC and were validated by quantitative PCR analyses. Inhibition of miR-483-3p or miR-483-5p and overexpression of



miR-195 or miR-497 reduced human adrenocortical H295R cells proliferation. Moreover, height expression of miR-503, miR-1202, and miR-1275 is associated with a poor prognosis. Chabre et al. (55) analyzed 1900 miR in 12 ACC and 6 ACA. 12 miR shown difference expression between ACC and ACA, and 29 miR between aggressive ACC and nonaggressive ACC (nonrecurring after 3 years). Combinations of these miRs discriminate ACC from ACA and aggressive ACC from nonaggressive ACC. Among these miR, miR-485-5p and miR-195 can be identified in the serum. The circulating miRs have a diagnostic and prognostic value. Finally, Doghman et al. (82) studied miR expression on pediatric ACTs. In this study, 26 miR were found significantly differentially expressed. Two miR (miR-99a and miR-100), which are downregulated, are predicted to target components of insulin like growth factor receptor 1 (IGFR1), mammalian target of rapamycin (mTor) and raptor signaling. By blocking mTor signaling in both in vitro and in vivo xenograft models, ACT growth could be inhibited. These results suggest that mTor inhibitor could be used in ACC therapy. All these studies show several miR differentially expressed between ACC and ACA and could be used to predict survival (Table 4). In several studies, two identical miR were differentially expressed between ACC and ACA; the miR195 is downregulated while the miR-483-5p is upregulated (55, 248, 250, 303). This last miR (miR-483-5p) is localized in the IGF2 locus, and its expression is correlated with IGF2 expression. Because it is very cumbersome to identify the real mRNA target(s) of the miR, the exact role of these deregulations of expression in the pathology remains to be determined.

Chromosome alterations Several studies (20, 83, 177, 297, 307, 312, 355, 356), using conventional comparative genomic hybridization (CGH) or CGH array (Table 4), identified many chromosome alterations in ACC, including a majority of gains, mainly in chromosomes 5 and 12, and fewer losses, including chromosome 1p. Chromosomal alterations also contain prognostic information both for predicting recurrence and specific death (20, 307) (Table 4). However, no single alteration can provide accurate information, and a large combination of alterations is required for ACC prognostication, making it necessary to use chips to get the information. Barreau et al. proposed to summarize the prognostic information to the measurement of six loci by quantitative PCR. The sensitivity and specificity were 100% and 80% respectively on an independent validation cohort. De Martino et al reported in a cohort of 40 ACC several recurrent gains (chromosome 5, 7, 12, 19, and 20) and losses (1, 22) (77). Recurrent amplification of CDK4 and deletion of CDKN2A (cyclin-dependent kinase inhibitor 2A) and CDKN2B (cyclin-dependent kinase inhibitor 2B) are also identified in this study.



Ronchi et al. investigated 24 ACA and 22 ACC by single nucleotide polymorphism (SNP) arrays (279). SNP profiling, including the most altered chomosomes (1, 5, 7, and 12), may differentiate malignant from benign ACTs. A larger part of the genome is altered in ACC versus ACA in terms of copy number alterations as well as LOH. The total number of LOH significantly correlated with tumor size. In a recent study, somatic copy number alterations were profiled by SNP arrays in a large cohort of ACC cases (n = 121) (10). Chromosomes 4, 5, 7, 8, 12, 16, 19, and 20 were significantly gained, whereas chromosome arm 1p and chromosome 22 showed significant deletion. Moreover, recurrent amplifications of TERT (Telomerase reverse transcriptase— 5p15.33) and CDK4 (12q14) and homozygous deletions of CDKN2A (9p21.3), RB1 (13q14), and ZNRF3 (22q12.1) were identified.

Methylome Three studies have explore the DNA methylation profiling in ACTs (19, 99, 271). Rechache and colleagues (271) analyzed 485000 individual CpG (a majority in intergenic regions) on 20 ACC, 48 ACA and 19 normal adrenals. They demonstrated that methylome could distinguish between ACC and ACA; ACC cases were globally hypomethylated (in intragenic regions), but the CpG islands in promoter regions of genes were hypermethyled. 52 hypermethylated and downregulated genes in ACC were identified, including RARRES2, SLC16A9, and GATA6. The following two studies (19, 99) focused on DNA methylation levels in CpG islands from promoter regions and analyze 27600 CpG. Fonseca and colleagues (99) studied 15 ACC, 27 ACA and six normal adrenals. 212 CpG islands in the promoter regions are significantly hypermethylated in ACC as compared to ACA. Six genes among these 212 (CDKN2A, GATA4, DLEC1, HDAC10, PYCARD, and SCGB3A1/HIN1) were also dowregulated in ACC. Treatment with 5-aza-20-deoxycytidine (a cytosine methylation inhibitor) of human adrenocrotical cell line (H295R) leads to increased expression of these genes. Barreau et al. analyzed the methylation patterns of CpG islands in promoter regions of 51 ACC and 84 ACA (19) using the same chip as Fonseca and colleagues. Methylation was higher in ACC than in ACA and unsupervised clustering identified two groups of ACC, one with hypermethylation, evoking a CpG island methylator phenotype (CIMP), and the other one without hypermethylation. The hypermethylated ACC were subdivided into two groups with different levels of methylation (CIMP-high and CIMP-low). The identified methylation statuses were validated in 15 carcinomas by MS-MLPA. Hypermethylation was also associated with a poor-prognosis (Table 4). The transcriptome/methylation correlation shows 1741 genes (among 12250) negatively correlated (including H19, PLAGL1, G0S1, and NDRG2).

317



Conclusion To understand the process of adrenal development and regeneration from the stem cell, multiple studies have investigated the lineage between the capsule, the fetal cortex, and the definitive cortex. The strongest current hypothesis regarding the location of the stem/progenitor cells is that they are located in the subcapsular region. These cells give rise to the zona glomerula cells which, in turn, give rise to the zona fasciculata cells. Knowledge gained from the study of the inherited syndromes that increase ACC risk, coupled with the recent advances in the fasting moving tools of genomics, have been important to progress in our understanding of ACC. It is now clear that ACC harbor molecular features (mRNA/miRNA expression, chromosomic alterations, and methylation) reflecting their malignancy potential and their prognosis. Several genes and signaling pathways involved in adrenal development are also found altered in ACC (IGF2, SF1, and Wnt/β-catenin). Genomic studies of these alterations are progressing and will help to develop new molecular tools for ACTs classification. Stem/progenitor cells have a robust proliferation potential and are involved in many cancers. But, what is the role of these stem/progenitor cells in the development of adrenal cancer? Further analyses are needed to gain insights into roles of stem/progenitor cells in adrenocrotical tumors. The identification of signaling pathways playing an important role in ACC development might in the future to develop new targeted therapies that are dramatically needed for this aggressive cancer.

References 1. 2.

3. 4.

5.

6. 7.

8. 9.

318

Achermann JC, Ito M, Ito M, Hindmarsh PC, Jameson JL. A mutation in the gene encoding steroidogenic factor-1 causes XY sex reversal and adrenal failure in humans. Nat Genet 22: 125-126, 1999. Achermann JC, Ozisik G, Ito M, Orun UA, Harmanci K, Gurakan B, Jameson JL. Gonadal determination and adrenal development are regulated by the orphan nuclear receptor steroidogenic factor-1, in a dose-dependent manner. J Clin Endocrinol Metab 87: 1829-1833, 2002. Anderson DJ and Axel R. A bipotential neuroendocrine precursor whose choice of cell fate is determined by NGF and glucocorticoids. Cell 47: 1079-1090, 1986. Anselmo J, Medeiros S, Carneiro V, Greene E, Levy I, Nesterova M, Lyssikatos C, Horvath A, Carney JA, Stratakis CA. A large family with Carney complex caused by the S147G PRKAR1A mutation shows a unique spectrum of disease including adrenocortical cancer. J Clin Endocrinol Metab 97: 351-359, 2012. Arboleda VA, Lee H, Parnaik R, Fleming A, Banerjee A, Ferraz-deSouza B, Delot EC, Rodriguez-Fernandez IA, Braslavsky D, Bergada I, Dell’Angelica EC, Nelson SF, Martinez-Agosto JA, Achermann JC, Vilain E. Mutations in the PCNA-binding domain of CDKN1C cause IMAGe syndrome. Nat Genet 44: 788-792, 2012. Arnold J. Ein Beitrag zur feineren Struktur und dem Chemismus der Nebennieren. Virchow Arch Patholog Anatomie Physiol Klin Med 35: 64-107, 1866. Asai M, Ramachandrappa S, Joachim M, Shen Y, Zhang R, Nuthalapati N, Ramanathan V, Strochlic DE, Ferket P, Linhart K, Ho C, Novoselova TV, Garg S, Ridderstrale M, Marcus C, Hirschhorn JN, Keogh JM, O’Rahilly S, Chan LF, Clark AJ, Farooqi IS, Majzoub JA. Loss of function of the melanocortin 2 receptor accessory protein 2 is associated with mammalian obesity. Science 341: 275-278, 2013. Assie G, Giordano TJ, Bertherat J. Gene expression profiling in adrenocortical neoplasia. Mol Cell Endocrinol 351: 111-117, 2012. Assie G, Guillaud-Bataille M, Ragazzon B, Bertagna X, Bertherat J, Clauser E. The pathophysiology, diagnosis and prognosis of

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22. 23.

24.

25.

26.

adrenocortical tumors revisited by transcriptome analyses. Trends Endocrinol Metab 21: 325-334, 2010. Assie G, Letouze E, Fassnacht M, Jouinot A, Luscap W, Barreau O, Omeiri H, Rodriguez S, Perlemoine K, Rene-Corail F, Elarouci N, Sbiera S, Kroiss M, Allolio B, Waldmann J, Quinkler M, Mannelli M, Mantero F, Papathomas T, De Krijger R, Tabarin A, Kerlan V, Baudin E, Tissier F, Dousset B, Groussin L, Amar L, Clauser E, Bertagna X, Ragazzon B, Beuschlein F, Libe R, de Reynies A, Bertherat J. Integrated genomic characterization of adrenocortical carcinoma. Nat Genet 46: 607-612, 2014. Assumpcao JG, Seidinger AL, Mastellaro MJ, Ribeiro RC, Zambetti GP, Ganti R, Srivastava K, Shurtleff S, Pei D, Zeferino LC, Dufloth RM, Brandalise SR, Yunes JA. Association of the germline TP53 R337H mutation with breast cancer in southern Brazil. BMC Cancer 8: 357, 2008. Babu PS, Bavers DL, Beuschlein F, Shah S, Jeffs B, Jameson JL, Hammer GD. Interaction between Dax-1 and steroidogenic factor-1 in vivo: Increased adrenal responsiveness to ACTH in the absence of Dax-1. Endocrinology 143: 665-673, 2002. Baker BY, Lin L, Kim CJ, Raza J, Smith CP, Miller WL, Achermann JC. Nonclassic congenital lipoid adrenal hyperplasia: A new disorder of the steroidogenic acute regulatory protein with very late presentation and normal male genitalia. J Clin Endocrinol Metab 91: 4781-4785, 2006. Bamforth SD, Braganca J, Eloranta JJ, Murdoch JN, Marques FI, Kranc KR, Farza H, Henderson DJ, Hurst HC, Bhattacharya S. Cardiac malformations, adrenal agenesis, neural crest defects and exencephaly in mice lacking Cited2, a new Tfap2 co-activator. Nat Genet 29: 469-474, 2001. Bandiera R, Vidal VP, Motamedi FJ, Clarkson M, Sahut-Barnola I, von Gise A, Pu WT, Hohenstein P, Martinez A, Schedl A. WT1 maintains adrenal-gonadal primordium identity and marks a population of AGP-like progenitors within the adrenal gland. Dev Cell 27: 5-18, 2013. Baquedano MS, Berensztein E, Saraco N, Dorn GV, de Davila MT, Rivarola MA, Belgorosky A. Expression of the IGF system in human adrenal tissues from early infancy to late puberty: Implications for the development of adrenarche. Pediatr Res 58: 451-458, 2005. Barbaux S, Niaudet P, Gubler MC, Grunfeld JP, Jaubert F, Kuttenn F, Fekete CN, Souleyreau-Therville N, Thibaud E, Fellous M, McElreavey K. Donor splice-site mutations in WT1 are responsible for Frasier syndrome. Nat Genet 17: 467-470, 1997. Bardoni B, Zanaria E, Guioli S, Floridia G, Worley KC, Tonini G, Ferrante E, Chiumello G, McCabe ER, Fraccaro M, et al. A dosage sensitive locus at chromosome Xp21 is involved in male to female sex reversal. Nat Genet 7: 497-501, 1994. Barreau O, Assie G, Wilmot-Roussel H, Ragazzon B, Baudry C, Perlemoine K, Rene-Corail F, Bertagna X, Dousset B, Hamzaoui N, Tissier F, de Reynies A, Bertherat J. Identification of a CpG island methylator phenotype in adrenocortical carcinomas. J Clin Endocrinol Metab 98: E174-184, 2013. Barreau O, de Reynies A, Wilmot-Roussel H, Guillaud-Bataille M, Auzan C, Rene-Corail F, Tissier F, Dousset B, Bertagna X, Bertherat J, Clauser E, Assie G. Clinical and pathophysiological implications of chromosomal alterations in adrenocortical tumors: An integrated genomic approach. J Clin Endocrinol Metab 97: E301-311, 2012. Bashamboo A, Ferraz-de-Souza B, Lourenco D, Lin L, Sebire NJ, Montjean D, Bignon-Topalovic J, Mandelbaum J, Siffroi JP, ChristinMaitre S, Radhakrishna U, Rouba H, Ravel C, Seeler J, Achermann JC, McElreavey K. Human male infertility associated with mutations in NR5A1 encoding steroidogenic factor 1. Am J Hum Genet 87: 505512, 2010. Beamer WG, Sweet HO, Bronson RT, Shire JG, Orth DN, Davisson MT. Adrenocortical dysplasia: A mouse model system for adrenocortical insufficiency. J Endocrinol 141: 33-43, 1994. Bendavid C, Dubourg C, Gicquel I, Pasquier L, Saugier-Veber P, Durou MR, Jaillard S, Frebourg T, Haddad BR, Henry C, Odent S, David V. Molecular evaluation of foetuses with holoprosencephaly shows high incidence of microdeletions in the HPE genes. Hum Genet 119: 1-8, 2006. Bergada I, Del Rey G, Lapunzina P, Bergada C, Fellous M, Copelli S. Familial occurrence of the IMAGe association: Additional clinical variants and a proposed mode of inheritance. J Clin Endocrinol Metab 90: 3186-3190, 2005. Berthon A, Sahut-Barnola I, Lambert-Langlais S, de Joussineau C, Damon-Soubeyrand C, Louiset E, Taketo MM, Tissier F, Bertherat J, Lefrancois-Martinez AM, Martinez A, Val P. Constitutive beta-catenin activation induces adrenal hyperplasia and promotes adrenal cancer development. Hum Mol Genet 19: 1561-1576, 2010. Beuschlein F, Looyenga BD, Bleasdale SE, Mutch C, Bavers DL, Parlow AF, Nilson JH, Hammer GD. Activin induces x-zone apoptosis that inhibits luteinizing hormone-dependent adrenocortical tumor formation in inhibin-deficient mice. Mol Cell Biol 23: 3951-3964, 2003.



27.

28. 29. 30.

31. 32.

33.

34.

35.

36.

37.

38. 39.

40.

41.

42.

43.

44.

45.

46. 47.

Beuschlein F, Mutch C, Bavers DL, Ulrich-Lai YM, Engeland WC, Keegan C, Hammer GD. Steroidogenic factor-1 is essential for compensatory adrenal growth following unilateral adrenalectomy. Endocrinology 143: 3122-3135, 2002. Beuschlein F, Reincke M, Koniger M, D’Orazio D, Dobbie Z, Rump LC. Cortisol producing adrenal adenoma–a new manifestation of Gardner’s syndrome. Endocr Res 26: 783-790, 2000. Bhattacharya S, Michels CL, Leung MK, Arany ZP, Kung AL, Livingston DM. Functional role of p35srj, a novel p300/CBP binding protein, during transactivation by HIF-1. Genes Dev 13: 64-75, 1999. Biason-Lauber A, De Filippo G, Konrad D, Scarano G, Nazzaro A, Schoenle EJ. WNT4 deficiency–a clinical phenotype distinct from the classic Mayer-Rokitansky-Kuster-Hauser syndrome: A case report. Hum Reprod 22: 224-229, 2007. Biason-Lauber A, Konrad D, Navratil F, Schoenle EJ. A WNT4 mutation associated with Mullerian-duct regression and virilization in a 46,XX woman. N Engl J Med 351: 792-798, 2004. Biason-Lauber A, Schoenle EJ. Apparently normal ovarian differentiation in a prepubertal girl with transcriptionally inactive steroidogenic factor 1 (NR5A1/SF-1) and adrenocortical insufficiency. Am J Hum Genet 67: 1563-1568, 2000. Bicknell AB, Lomthaisong K, Woods RJ, Hutchinson EG, Bennett HP, Gladwell RT, Lowry PJ. Characterization of a serine protease that cleaves pro-gamma-melanotropin at the adrenal to stimulate growth. Cell 105: 903-912, 2001. Blaker H, Sutter C, Kadmon M, Otto HF, Von Knebel-Doeberitz M, Gebert J, Helmke BM. Analysis of somatic APC mutations in rare extracolonic tumors of patients with familial adenomatous polyposis coli. Gene Chromosome Canc 41: 93-98, 2004. Bland ML, Jamieson CA, Akana SF, Bornstein SR, Eisenhofer G, Dallman MF, Ingraham HA. Haploinsufficiency of steroidogenic factor-1 in mice disrupts adrenal development leading to an impaired stress response. Proc Natl Acad Sci U S A 97: 14488-14493, 2000. Bliek J, Snijder S, Maas SM, Polstra A, van der Lip K, Alders M, Knegt AC, Mannens MM. Phenotypic discordance upon paternal or maternal transmission of duplications of the 11p15 imprinted regions. Eur J Med Genet 52: 404-408, 2009. Bonnet S, Gaujoux S, Launay P, Baudry C, Chokri I, Ragazzon B, Libe R, Rene-Corail F, Audebourg A, Vacher-Lavenu MC, Groussin L, Bertagna X, Dousset B, Bertherat J, Tissier F. Wnt/beta-catenin pathway activation in adrenocortical adenomas is frequently due to somatic CTNNB1-activating mutations, which are associated with larger and nonsecreting tumors: A study in cortisol-secreting and -nonsecreting tumors. J Clin Endocrinol Metab 96: E419-426, 2011. Bose J, Grotewold L, Ruther U. Pallister-Hall syndrome phenotype in mice mutant for Gli3. Hum Mol Genet 11: 1129-1135, 2002. Botrugno OA, Fayard E, Annicotte JS, Haby C, Brennan T, Wendling O, Tanaka T, Kodama T, Thomas W, Auwerx J, Schoonjans K. Synergy between LRH-1 and beta-catenin induces G1 cyclinmediated cell proliferation. Mol Cell 15: 499-509, 2004. Bougeard G, Sesboue R, Baert-Desurmont S, Vasseur S, Martin C, Tinat J, Brugieres L, Chompret A, de Paillerets BB, Stoppa-Lyonnet D, Bonaiti-Pellie C, Frebourg T. Molecular basis of the Li-Fraumeni syndrome: An update from the French LFS families. J Med Genet 45: 535-538, 2008. Boulle N, Baudin E, Gicquel C, Logie A, Bertherat J, Penfornis A, Bertagna X, Luton JP, Schlumberger M, Le Bouc Y. Evaluation of plasma insulin-like growth factor binding protein-2 as a marker for adrenocortical tumors. Eur J Endocrinol 144: 29-36, 2001. Boulle N, Logie A, Gicquel C, Perin L, Le Bouc Y. Increased levels of insulin-like growth factor II (IGF-II) and IGF-binding protein-2 are associated with malignancy in sporadic adrenocortical tumors. J Clin Endocrinol Metab 83: 1713-1720, 1998. Bourcigaux N, Gaston V, Logie A, Bertagna X, Le Bouc Y, Gicquel C. High expression of cyclin E and G1 CDK and loss of function of p57KIP2 are involved in proliferation of malignant sporadic adrenocortical tumors. J Clin Endocrinol Metab 85: 322-330, 2000. Bourdeau I, Antonini SR, Lacroix A, Kirschner LS, Matyakhina L, Lorang D, Libutti SK, Stratakis CA. Gene array analysis of macronodular adrenal hyperplasia confirms clinical heterogeneity and identifies several candidate genes as molecular mediators. Oncogene 23: 1575-1585, 2004. Braganca J, Swingler T, Marques FI, Jones T, Eloranta JJ, Hurst HC, Shioda T, Bhattacharya S. Human CREB-binding protein/p300interacting transactivator with ED-rich tail (CITED) 4, a new member of the CITED family, functions as a co-activator for transcription factor AP-2. J Biol Chem 277: 8559-8565, 2002. Bragulla H, Hirschberg RM, Schlotfeldt U, Stede M, Budras KD. On the structure of the adrenal gland of the common seal (Phoca vitulina vitulina). Anat Histol Embryol 33: 263-272, 2004. Bremner R and Zacksenhaus E. Cyclins, Cdks, E2f, Skp2, and more at the first international RB Tumor Suppressor Meeting. Cancer Res 70: 6114-6118, 2010.



48. Brisken C, Heineman A, Chavarria T, Elenbaas B, Tan J, Dey SK, McMahon JA, McMahon AP, Weinberg RA. Essential function of Wnt-4 in mammary gland development downstream of progesterone signaling. Genes Dev 14: 650-654, 2000. 49. Burglin TR. Analysis of TALE superclass homeobox genes (MEIS, PBC, KNOX, Iroquois, TGIF) reveals a novel domain conserved between plants and animals. Nucleic Acids Res 25: 4173-4180, 1997. 50. Cadigan KM, Nusse R. Wnt signaling: A common theme in animal development. Genes Dev 11: 3286-3305, 1997. 51. Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH, et al. Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms’ tumor locus. Cell 60: 509-520, 1990. 52. Carney JA, Gordon H, Carpenter PC, Shenoy BV, Go VL. The complex of myxomas, spotty pigmentation, and endocrine overactivity. Medicine (Baltimore) 64: 270-283, 1985. 53. Caron de Fromentel C, Soussi T. TP53 tumor suppressor gene: A model for investigating human mutagenesis. Gene Chromosome Canc 4: 1-15, 1992. 54. Caron KM, Soo SC, Wetsel WC, Stocco DM, Clark BJ, Parker KL. Targeted disruption of the mouse gene encoding steroidogenic acute regulatory protein provides insights into congenital lipoid adrenal hyperplasia. Proc Natl Acad Sci U S A 94: 11540-11545, 1997. 55. Chabre O, Libe R, Assie G, Barreau O, Bertherat J, Bertagna X, Feige JJ, Cherradi N. Serum miR-483-5p and miR-195 are predictive of recurrence risk in adrenocortical cancer patients. Endocr Relat Cancer 20: 579-594, 2013. 56. Chiang JM, Chou YH, Chen TC, Ng KF, Lin JL. Nuclear beta-catenin expression is closely related to ulcerative growth of colorectal carcinoma. Br J Cancer 86: 1124-1129, 2002. 57. Chida D, Nakagawa S, Nagai S, Sagara H, Katsumata H, Imaki T, Suzuki H, Mitani F, Ogishima T, Shimizu C, Kotaki H, Kakuta S, Sudo K, Koike T, Kubo M, Iwakura Y. Melanocortin 2 receptor is required for adrenal gland development, steroidogenesis, and neonatal gluconeogenesis. Proc Natl Acad Sci U S A 104: 18205-18210, 2007. 58. Ching S, Vilain E. Targeted disruption of Sonic Hedgehog in the mouse adrenal leads to adrenocortical hypoplasia. Genesis 47: 628-637, 2009. 59. Chompret A, Abel A, Stoppa-Lyonnet D, Brugieres L, Pages S, Feunteun J, Bonaiti-Pellie C. Sensitivity and predictive value of criteria for p53 germline mutation screening. J Med Genet 38: 43-47, 2001. 60. Chompret A, Brugieres L, Ronsin M, Gardes M, Dessarps-Freichey F, Abel A, Hua D, Ligot L, Dondon MG, Bressac-de Paillerets B, Frebourg T, Lemerle J, Bonaiti-Pellie C, Feunteun J. P53 germline mutations in childhood cancers and cancer risk for carrier individuals. Br J Cancer 82: 1932-1937, 2000. 61. Clark AJ, Chan LF, Chung TT, Metherell LA. The genetics of familial glucocorticoid deficiency. Best Pract Res Clin Endocrinol Metab 23: 159-165, 2009. 62. Clark AJ, McLoughlin L, Grossman A. Familial glucocorticoid deficiency associated with point mutation in the adrenocorticotropin receptor. Lancet 341: 461-462, 1993. 63. Clement K, Dubern B, Mencarelli M, Czernichow P, Ito S, Wakamatsu K, Barsh GS, Vaisse C, Leger J. Unexpected endocrine features and normal pigmentation in a young adult patient carrying a novel homozygous mutation in the POMC gene. J Clin Endocrinol Metab 93: 4955-4962, 2008. 64. Clements WM, Wang J, Sarnaik A, Kim OJ, MacDonald J, FenoglioPreiser C, Groden J, Lowy AM. beta-Catenin mutation is a frequent cause of Wnt pathway activation in gastric cancer. Cancer Res 62: 3503-3506, 2002. 65. Clipsham R, McCabe ER. DAX1 and its network partners: Exploring complexity in development. Mol Genet Metab 80: 81-120, 2003. 66. Coll AP, Challis BG, Yeo GS, Snell K, Piper SJ, Halsall D, Thresher RR, O’Rahilly S. The effects of proopiomelanocortin deficiency on murine adrenal development and responsiveness to adrenocorticotropin. Endocrinology 145: 4721-4727, 2004. 67. Conkrite K, Sundby M, Mu D, Mukai S, MacPherson D. Cooperation between Rb and Arf in suppressing mouse retinoblastoma. J Clin Invest 122: 1726-1733, 2012. 68. Correa FH, Gomes MB. Diabetic pregnancy: Outpatient follow-up in a Brazilian University Hospital. Arq Bras Endocrinol Metabol 48: 499504, 2004. 69. Coulter CL. Fetal adrenal development: Insight gained from adrenal tumors. Trends Endocrinol Metab 16: 235-242, 2005. 70. Coutant R, Mallet D, Lahlou N, Bouhours-Nouet N, Guichet A, Coupris L, Croue A, Morel Y. Heterozygous mutation of steroidogenic factor-1 in 46,XY subjects may mimic partial androgen insensitivity syndrome. J Clin Endocrinol Metab 92: 2868-2873, 2007. 71. Crawford PA, Dorn C, Sadovsky Y, Milbrandt J. Nuclear receptor DAX-1 recruits nuclear receptor corepressor N-CoR to steroidogenic factor 1. Mol Cell Biol 18: 2949-2956, 1998.

319


72.

73. 74. 75.

76.

77.

78.

79. 80.

81. 82.

83.

84.

85.

86. 87.

88. 89. 90.

320

Crowder RE. The development of the adrenal gland in man, with special reference to origin and ultimate location of cell types and evidence in favor of the “cell migration” theory. Contemp Embryol 251: 195-209, 1957. Cui S, Ross A, Stallings N, Parker KL, Capel B, Quaggin SE. Disrupted gonadogenesis and male-to-female sex reversal in Pod1 knockout mice. Development 131: 4095-4105, 2004. Custodio G, Komechen H, Figueiredo FR, Fachin ND, Pianovski MA, Figueiredo BC. Molecular epidemiology of adrenocortical tumors in southern Brazil. Mol Cell Endocrinol 351: 44-51, 2012. Custodio G, Parise GA, Kiesel Filho N, Komechen H, Sabbaga CC, Rosati R, Grisa L, Parise IZ, Pianovski MA, Fiori CM, Ledesma JA, Barbosa JR, Figueiredo FR, Sade ER, Ibanez H, Arram SB, Stinghen ST, Mengarelli LR, Figueiredo MM, Carvalho DC, Avilla SG, Woiski TD, Poncio LC, Lima GF, Pontarolo R, Lalli E, Zhou Y, Zambetti GP, Ribeiro RC, Figueiredo BC. Impact of neonatal screening and surveillance for the TP53 R337H mutation on early detection of childhood adrenocortical tumors. J Clin Oncol 31: 2619-2626, 2013. de Fraipont F, El Atifi M, Cherradi N, Le Moigne G, Defaye G, Houlgatte R, Bertherat J, Bertagna X, Plouin PF, Baudin E, Berger F, Gicquel C, Chabre O, Feige JJ. Gene expression profiling of human adrenocortical tumors using complementary deoxyribonucleic Acid microarrays identifies several candidate genes as markers of malignancy. J Clin Endocrinol Metab 90: 1819-1829, 2005. De Martino MC, Al Ghuzlan A, Aubert S, Assie G, Scoazec JY, Leboulleux S, Do Cao C, Libe R, Nozieres C, Lombes M, Pattou F, Borson-Chazot F, Hescot S, Mazoyer C, Young J, Borget I, Colao A, Pivonello R, Soria JC, Bertherat J, Schlumberger M, Lacroix L, Baudin E. Molecular screening for a personalized treatment approach in advanced adrenocortical cancer. J Clin Endocrinol Metab 98: 40804088, 2013. de Reynies A, Assie G, Rickman DS, Tissier F, Groussin L, Rene-Corail F, Dousset B, Bertagna X, Clauser E, Bertherat J. Gene expression profiling reveals a new classification of adrenocortical tumors and identifies molecular predictors of malignancy and survival. J Clin Oncol 27: 1108-1115, 2009. Demars J, Gicquel C. Epigenetic and genetic disturbance of the imprinted 11p15 region in Beckwith-Wiedemann and Silver-Russell syndromes. Clin Genet 81: 350-361, 2012. DiGiammarino EL, Lee AS, Cadwell C, Zhang W, Bothner B, Ribeiro RC, Zambetti G, Kriwacki RW. A novel mechanism of tumorigenesis involving pH-dependent destabilization of a mutant p53 tetramer. Nat Struct Biol 9: 12-16, 2002. Doghman M, Cazareth J, Lalli E. The T cell factor/beta-catenin antagonist PKF115-584 inhibits proliferation of adrenocortical carcinoma cells. J Clin Endocrinol Metab 93: 3222-3225, 2008. Doghman M, El Wakil A, Cardinaud B, Thomas E, Wang J, Zhao W, Peralta-Del Valle MH, Figueiredo BC, Zambetti GP, Lalli E. Regulation of insulin-like growth factor-mammalian target of rapamycin signaling by microRNA in childhood adrenocortical tumors. Cancer Res 70: 4666-4675, 2010. Dohna M, Reincke M, Mincheva A, Allolio B, Solinas-Toldo S, Lichter P. Adrenocortical carcinoma is characterized by a high frequency of chromosomal gains and high-level amplifications. Genes Chromosomes Cancer 28: 145-152, 2000. Drelon C, Berthon A, Ragazzon B, Tissier F, Bandiera R, SahutBarnola I, de Joussineau C, Batisse-Lignier M, Lefrancois-Martinez AM, Bertherat J, Martinez A, Val P. Analysis of the role of Igf2 in adrenal tumour development in transgenic mouse models. PLoS One 7: e44171, 2012. Dubourg C, Lazaro L, Pasquier L, Bendavid C, Blayau M, Le Duff F, Durou MR, Odent S, David V. Molecular screening of SHH, ZIC2, SIX3, and TGIF genes in patients with features of holoprosencephaly spectrum: Mutation review and genotype-phenotype correlations. Hum Mutat 24: 43-51, 2004. Else T, Hammer GD. Genetic analysis of adrenal absence: Agenesis and aplasia. Trends Endocrinol Metab 16: 458-468, 2005. Else T, Trovato A, Kim AC, Wu Y, Ferguson DO, Kuick RD, Lucas PC, Hammer GD. Genetic p53 deficiency partially rescues the adrenocortical dysplasia phenotype at the expense of increased tumorigenesis. Cancer Cell 15: 465-476, 2009. Estivariz FE, Carino M, Lowry PJ, Jackson S. Further evidence that Nterminal pro-opiomelanocortin peptides are involved in adrenal mitogenesis. J Endocrinol 116: 201-206, 1988. Estivariz FE, Iturriza F, McLean C, Hope J, Lowry PJ. Stimulation of adrenal mitogenesis by N-terminal proopiocortin peptides. Nature 297: 419-422, 1982. Estivariz FE, Morano MI, Carino M, Jackson S, Lowry PJ. Adrenal regeneration in the rat is mediated by mitogenic N-terminal proopiomelanocortin peptides generated by changes in precursor processing in the anterior pituitary. J Endocrinol 116: 207-216, 1988.


91. Evelyn HM. A transitory zone in the adrenal cortex which shows age and sex relationships. Am J Anat 40: 251-293, 1927. 92. Fabbri HC, de Andrade JG, Soardi FC, de Calais FL, Petroli RJ, MacielGuerra AT, Guerra-Junior G, de Mello MP. The novel p.Cys65Tyr mutation in NR5A1 gene in three 46,XY siblings with normal testosterone levels and their mother with primary ovarian insufficiency. BMC Med Genet 15: 7, 2014. 93. Farooqi IS, Drop S, Clements A, Keogh JM, Biernacka J, Lowenbein S, Challis BG, O’Rahilly S. Heterozygosity for a POMC-null mutation and increased obesity risk in humans. Diabetes 55: 2549-2553, 2006. 94. Fassnacht M, Hahner S, Hansen IA, Kreutzberger T, Zink M, Adermann K, Jakob F, Troppmair J, Allolio B. N-terminal proopiomelanocortin acts as a mitogen in adrenocortical tumor cells and decreases adrenal steroidogenesis. J Clin Endocrinol Metab 88: 2171-2179, 2003. 95. Fernandez-Ranvier GG, Weng J, Yeh RF, Khanafshar E, Suh I, Barker C, Duh QY, Clark OH, Kebebew E. Identification of biomarkers of adrenocortical carcinoma using genomewide gene expression profiling. Arch Surg 143: 841-846; discussion 846, 2008. 96. Fernandez-Ranvier GG, Weng J, Yeh RF, Shibru D, Khafnashar E, Chung KW, Hwang J, Duh QY, Clark OH, Kebebew E. Candidate diagnostic markers and tumor suppressor genes for adrenocortical carcinoma by expression profile of genes on chromosome 11q13. World J Surg 32: 873-881, 2008. 97. Ferraz-de-Souza B, Martin F, Mallet D, Hudson-Davies RE, Cogram P, Lin L, Gerrelli D, Beuschlein F, Morel Y, Huebner A, Achermann JC. CBP/p300-interacting transactivator, with Glu/Asp-rich C-terminal domain, 2, and pre-B-cell leukemia transcription factor 1 in human adrenal development and disease. J Clin Endocrinol Metab 94: 678683, 2009. 98. Ferruzzi P, Ceni E, Tarocchi M, Grappone C, Milani S, Galli A, Fiorelli G, Serio M, Mannelli M. Thiazolidinediones inhibit growth and invasiveness of the human adrenocortical cancer cell line H295R. J Clin Endocrinol Metab 90: 1332-1339, 2005. 99. Fonseca AL, Kugelberg J, Starker LF, Scholl U, Choi M, Hellman P, Akerstrom G, Westin G, Lifton RP, Bjorklund P, Carling T. Comprehensive DNA methylation analysis of benign and malignant adrenocortical tumors. Genes Chromosomes Cancer 51: 949-960, 2012. 100. Fragoso MC, Almeida MQ, Mazzuco TL, Mariani BM, Brito LP, Goncalves TC, Alencar GA, Lima Lde O, Faria AM, Bourdeau I, Lucon AM, Freire DS, Latronico AC, Mendonca BB, Lacroix A, Lerario AM. Combined expression of BUB1B, DLGAP5, and PINK1 as predictors of poor outcome in adrenocortical tumors: Validation in a Brazilian cohort of adult and pediatric patients. Eur J Endocrinol 166: 61-67, 2012. 101. Freedman BD, Kempna PB, Carlone DL, Shah MS, Guagliardo NA, Barrett PQ, Gomez-Sanchez CE, Majzoub JA, Breault DT. Adrenocortical zonation results from lineage conversion of differentiated zona glomerulosa cells. Dev Cell 26: 666-673, 2013. 102. Freeman H, Shimomura K, Cox RD, Ashcroft FM. Nicotinamide nucleotide transhydrogenase: A link between insulin secretion, glucose metabolism and oxidative stress. Biochem Soc Trans 34: 806-810, 2006. 103. Fuhrman SA, Lasky LC, Limas C. Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol 6: 655-663, 1982. 104. Gatta-Cherifi B, Chabre O, Murat A, Niccoli P, Cardot-Bauters C, Rohmer V, Young J, Delemer B, Du Boullay H, Verger MF, Kuhn JM, Sadoul JL, Ruszniewski P, Beckers A, Monsaingeon M, Baudin E, Goudet P, Tabarin A. Adrenal involvement in MEN1. Analysis of 715 cases from the Groupe d’etude des Tumeurs Endocrines database. Eur J Endocrinol 166: 269-279, 2012. 105. Gaujoux S, Grabar S, Fassnacht M, Ragazzon B, Launay P, Libe R, Chokri I, Audebourg A, Royer B, Sbiera S, Vacher-Lavenu MC, Dousset B, Bertagna X, Allolio B, Bertherat J, Tissier F. beta-catenin activation is associated with specific clinical and pathologic characteristics and a poor outcome in adrenocortical carcinoma. Clin Cancer Res 17: 328336, 2011. 106. Gaujoux S, Hantel C, Launay P, Bonnet S, Perlemoine K, Lefevre L, Guillaud-Bataille M, Beuschlein F, Tissier F, Bertherat J, RizkRabin M, Ragazzon B. Silencing mutated beta-catenin inhibits cell proliferation and stimulates apoptosis in the adrenocortical cancer cell line H295R. PLoS One 8: e55743, 2013. 107. Gaujoux S, Pinson S, Gimenez-Roqueplo AP, Amar L, Ragazzon B, Launay P, Meatchi T, Libe R, Bertagna X, Audebourg A, ZucmanRossi J, Tissier F, Bertherat J. Inactivation of the APC gene is constant in adrenocortical tumors from patients with familial adenomatous polyposis but not frequent in sporadic adrenocortical cancers. Clin Cancer Res 16: 5133-5141, 2010. 108. Gekle M, Grossmann C. Actions of aldosterone in the cardiovascular system: The good, the bad, and the ugly? Pflugers Arch 458: 231-246, 2009.



109. Gessler M, Poustka A, Cavenee W, Neve RL, Orkin SH, Bruns GA. Homozygous deletion in Wilms tumours of a zinc-finger gene identified by chromosome jumping. Nature 343: 774-778, 1990. 110. Giacomazzi J, Koehler-Santos P, Palmero EI, Graudenz MS, Rivero LF, Lima E, Putten AC, Hainaut P, Camey SA, Michelli RD, Neto CS, Fitarelli-Kiehl M, Geyer G, Meurer L, Geiger A, Azevedo MB, da Silva VD, Ashton-Prolla P. A TP53 founder mutation, p.R337H, is associated with phyllodes breast tumors in Brazil. Virchows Arch 463: 17-22, 2013. 111. Gicquel C, Bertagna X, Gaston V, Coste J, Louvel A, Baudin E, Bertherat J, Chapuis Y, Duclos JM, Schlumberger M, Plouin PF, Luton JP, Le Bouc Y. Molecular markers and long-term recurrences in a large cohort of patients with sporadic adrenocortical tumors. Cancer Res 61: 6762-6767, 2001. 112. Gicquel C, Bertagna X, Schneid H, Francillard-Leblond M, Luton JP, Girard F, Le Bouc Y. Rearrangements at the 11p15 locus and overexpression of insulin-like growth factor-II gene in sporadic adrenocortical tumors. J Clin Endocrinol Metab 78: 1444-1453, 1994. 113. Gicquel C, Raffin-Sanson ML, Gaston V, Bertagna X, Plouin PF, Schlumberger M, Louvel A, Luton JP, Le Bouc Y. Structural and functional abnormalities at 11p15 are associated with the malignant phenotype in sporadic adrenocortical tumors: Study on a series of 82 tumors. J Clin Endocrinol Metab 82: 2559-2565, 1997. 114. Giles RH, van Es JH, Clevers H. Caught up in a Wnt storm: Wnt signaling in cancer. Biochim Biophys Acta 1653: 1-24, 2003. 115. Giordano TJ, Kuick R, Else T, Gauger PG, Vinco M, Bauersfeld J, Sanders D, Thomas DG, Doherty G, Hammer G. Molecular classification and prognostication of adrenocortical tumors by transcriptome profiling. Clin Cancer Res 15: 668-676, 2009. 116. Giordano TJ, Thomas DG, Kuick R, Lizyness M, Misek DE, Smith AL, Sanders D, Aljundi RT, Gauger PG, Thompson NW, Taylor JM, Hanash SM. Distinct transcriptional profiles of adrenocortical tumors uncovered by DNA microarray analysis. Am J Pathol 162: 521-531, 2003. 117. Gray ES, Abramovich DR. Morphologic features of the anencephalic adrenal gland in early pregnancy. Am J Obstet Gynecol 137: 491-495, 1980. 118. Grumbach MM, Biller BM, Braunstein GD, Campbell KK, Carney JA, Godley PA, Harris EL, Lee JK, Oertel YC, Posner MC, Schlechte JA, Wieand HS. Management of the clinically inapparent adrenal mass (“incidentaloma”). Ann Intern Med 138: 424-429, 2003. 119. Guaragna MS, Lutaif AC, Piveta CS, Belangero VM, Maciel-Guerra AT, Guerra G, Jr, De Mello MP. Two distinct WT1 mutations identified in patients and relatives with isolated nephrotic proteinuria. Biochem Biophys Res Commun 441: 371-376, 2013. 120. Guimier A, Ragazzon B, Assie G, Tissier F, Dousset B, Bertherat J, Gaujoux S. AXIN genetic analysis in adrenocortical carcinomas updated. J Endocrinol Invest 36: 1000-1003, 2013. 121. Gummow BM, Scheys JO, Cancelli VR, Hammer GD. Reciprocal regulation of a glucocorticoid receptor-steroidogenic factor-1 transcription complex on the Dax-1 promoter by glucocorticoids and adrenocorticotropic hormone in the adrenal cortex. Mol Endocrinol 20: 2711-2723, 2006. 122. Gummow BM, Winnay JN, Hammer GD. Convergence of Wnt signaling and steroidogenic factor-1 (SF-1) on transcription of the rat inhibin alpha gene. J Biol Chem 278: 26572-26579, 2003. 123. Guo X, Deng Y, Lin Y, Cosme-Blanco W, Chan S, He H, Yuan G, Brown EJ, Chang S. Dysfunctional telomeres activate an ATM-ATRdependent DNA damage response to suppress tumorigenesis. EMBO J 26: 4709-4719, 2007. 124. Haber DA, Buckler AJ, Glaser T, Call KM, Pelletier J, Sohn RL, Douglass EC, Housman DE. An internal deletion within an 11p13 zinc finger gene contributes to the development of Wilms’ tumor. Cell 61: 1257-1269, 1990. 125. Haegel H, Larue L, Ohsugi M, Fedorov L, Herrenknecht K, Kemler R. Lack of beta-catenin affects mouse development at gastrulation. Development 121: 3529-3537, 1995. 126. Hammer GD, Ingraham HA. Steroidogenic factor-1: Its role in endocrine organ development and differentiation. Front Neuroendocrinol 20: 199-223, 1999. 127. Hammer GD, Parker KL, Schimmer BP. Minireview: Transcriptional regulation of adrenocortical development. Endocrinology 146: 10181024, 2005. 128. Hanley NA, Rainey WE, Wilson DI, Ball SG, Parker KL. Expression profiles of SF-1, DAX1, and CYP17 in the human fetal adrenal gland: Potential interactions in gene regulation. Mol Endocrinol 15: 57-68, 2001. 129. Hao HX, Xie Y, Zhang Y, Charlat O, Oster E, Avello M, Lei H, Mickanin C, Liu D, Ruffner H, Mao X, Ma Q, Zamponi R, Bouwmeester T, Finan PM, Kirschner MW, Porter JA, Serluca FC, Cong F. ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner. Nature 485: 195-200, 2012.



130. Harding B, Lemos MC, Reed AA, Walls GV, Jeyabalan J, Bowl MR, Tateossian H, Sullivan N, Hough T, Fraser WD, Ansorge O, Cheeseman MT, Thakker RV. Multiple endocrine neoplasia type 1 knockout mice develop parathyroid, pancreatic, pituitary and adrenal tumours with hypercalcaemia, hypophosphataemia and hypercorticosteronaemia. Endocr Relat Cancer 16: 1313-1327, 2009. 131. Hasegawa T, Fukami M, Sato N, Katsumata N, Sasaki G, Fukutani K, Morohashi K, Ogata T. Testicular dysgenesis without adrenal insufficiency in a 46,XY patient with a heterozygous inactive mutation of steroidogenic factor-1. J Clin Endocrinol Metab 89: 5930-5935, 2004. 132. Hatano O, Takakusu A, Nomura M, Morohashi K. Identical origin of adrenal cortex and gonad revealed by expression profiles of Ad4BP/SF1. Genes Cells 1: 663-671, 1996. 133. Hatano O, Takayama K, Imai T, Waterman MR, Takakusu A, Omura T, Morohashi K. Sex-dependent expression of a transcription factor, Ad4BP, regulating steroidogenic P-450 genes in the gonads during prenatal and postnatal rat development. Development 120: 2787-2797, 1994. 134. Hattangady NG, Olala LO, Bollag WB, Rainey WE. Acute and chronic regulation of aldosterone production. Mol Cell Endocrinol 350: 151162, 2012. 135. Heaton JH, Wood MA, Kim AC, Lima LO, Barlaskar FM, Almeida MQ, Fragoso MC, Kuick R, Lerario AM, Simon DP, Soares IC, Starnes E, Thomas DG, Latronico AC, Giordano TJ, Hammer GD. Progression to adrenocortical tumorigenesis in mice and humans through insulinlike growth factor 2 and beta-catenin. Am J Pathol 181: 1017-1033, 2012. 136. Heikkila M, Peltoketo H, Leppaluoto J, Ilves M, Vuolteenaho O, Vainio S. Wnt-4 deficiency alters mouse adrenal cortex function, reducing aldosterone production. Endocrinology 143: 4358-4365, 2002. 137. Henry I, Jeanpierre M, Couillin P, Barichard F, Serre JL, Journel H, Lamouroux A, Turleau C, de Grouchy J, Junien C. Molecular definition of the 11p15.5 region involved in Beckwith-Wiedemann syndrome and probably in predisposition to adrenocortical carcinoma. Hum Genet 81: 273-277, 1989. 138. Heppner C, Reincke M, Agarwal SK, Mora P, Allolio B, Burns AL, Spiegel AM, Marx SJ. MEN1 gene analysis in sporadic adrenocortical neoplasms. J Clin Endocrinol Metab 84: 216-219, 1999. 139. Herrmann LJ, Heinze B, Fassnacht M, Willenberg HS, Quinkler M, Reisch N, Zink M, Allolio B, Hahner S. TP53 germline mutations in adult patients with adrenocortical carcinoma. J Clin Endocrinol Metab 97: E476-485, 2012. 140. Hershkovitz L, Beuschlein F, Klammer S, Krup M, Weinstein Y. Adrenal 20alpha-hydroxysteroid dehydrogenase in the mouse catabolizes progesterone and 11-deoxycorticosterone and is restricted to the X-zone. Endocrinology 148: 976-988, 2007. 141. Hisada M, Garber JE, Fung CY, Fraumeni JF, Jr, Li FP. Multiple primary cancers in families with Li-Fraumeni syndrome. J Natl Cancer Inst 90: 606-611, 1998. 142. Hockemeyer D, Palm W, Else T, Daniels JP, Takai KK, Ye JZ, Keegan CE, de Lange T, Hammer GD. Telomere protection by mammalian Pot1 requires interaction with Tpp1. Nat Struct Mol Biol 14: 754-761, 2007. 143. Holland JD, Klaus A, Garratt AN, Birchmeier W. Wnt signaling in stem and cancer stem cells. Curr Opin Cell Biol 25: 254-264, 2013. 144. Hollstein M, Sidransky D, Vogelstein B, Harris CC. p53 mutations in human cancers. Science 253: 49-53, 1991. 145. Honda S, Morohashi K, Nomura M, Takeya H, Kitajima M, Omura T. Ad4BP regulating steroidogenic P-450 gene is a member of steroid hormone receptor superfamily. J Biol Chem 268: 7494-7502, 1993. 146. Hosogi H, Nagayama S, Kanamoto N, Yoshizawa A, Suzuki T, Nakao K, Sakai Y. Biallelic APC inactivation was responsible for functional adrenocortical adenoma in familial adenomatous polyposis with novel germline mutation of the APC gene: Report of a case. Jpn J Clin Oncol 39: 837-846, 2009. 147. Hossain A, Saunders GF. Synergistic cooperation between the betacatenin signaling pathway and steroidogenic factor 1 in the activation of the Mullerian inhibiting substance type II receptor. J Biol Chem 278: 26511-26516, 2003. 148. Houghtaling BR, Cuttonaro L, Chang W, Smith S. A dynamic molecular link between the telomere length regulator TRF1 and the chromosome end protector TRF2. Curr Biol 14: 1621-1631, 2004. 149. Huang CC, Miyagawa S, Matsumaru D, Parker KL, Yao HH. Progenitor cell expansion and organ size of mouse adrenal is regulated by sonic hedgehog. Endocrinology 151: 1119-1128, 2010. 150. Hughes CR, Guasti L, Meimaridou E, Chuang CH, Schimenti JC, King PJ, Costigan C, Clark AJ, Metherell LA. MCM4 mutation causes adrenal failure, short stature, and natural killer cell deficiency in humans. J Clin Invest 122: 814-820, 2012. 151. Hutz JE, Krause AS, Achermann JC, Vilain E, Tauber M, Lecointre C, McCabe ER, Hammer GD, Keegan CE. IMAGe association and

321


152.

153. 154. 155. 156. 157.

158. 159. 160.

161. 162. 163.

164.

165.

166. 167.

168.

169. 170.

171. 172. 173. 174.

175.

322

congenital adrenal hypoplasia: No disease-causing mutations found in the ACD gene. Mol Genet Metab 88: 66-70, 2006. Ikeda Y, Lala DS, Luo X, Kim E, Moisan MP, Parker KL. Characterization of the mouse FTZ-F1 gene, which encodes a key regulator of steroid hydroxylase gene expression. Mol Endocrinol 7: 852-860, 1993. Ikeda Y, Luo X, Abbud R, Nilson JH, Parker KL. The nuclear receptor steroidogenic factor 1 is essential for the formation of the ventromedial hypothalamic nucleus. Mol Endocrinol 9: 478-486, 1995. Ikeda Y, Shen WH, Ingraham HA, Parker KL. Developmental expression of mouse steroidogenic factor-1, an essential regulator of the steroid hydroxylases. Mol Endocrinol 8: 654-662, 1994. Ilvesmaki V, Blum WF, Voutilainen R. Insulin-like growth factor-II in human fetal adrenals: Regulation by ACTH, protein kinase C and growth factors. J Endocrinol 137: 533-542, 1993. Ilvesmaki V, Blum WF, Voutilainen R. Insulin-like growth factor binding proteins in the human adrenal gland. Mol Cell Endocrinol 97: 71-79, 1993. Ingraham HA, Lala DS, Ikeda Y, Luo X, Shen WH, Nachtigal MW, Abbud R, Nilson JH, Parker KL. The nuclear receptor steroidogenic factor 1 acts at multiple levels of the reproductive axis. Genes Dev 8: 2302-2312, 1994. Inui M, Martello G, Piccolo S. MicroRNA control of signal transduction. Nat Rev Mol Cell Biol 11: 252-263, 2010. Ito M, Yu R, Jameson JL. DAX-1 inhibits SF-1-mediated transactivation via a carboxy-terminal domain that is deleted in adrenal hypoplasia congenita. Mol Cell Biol 17: 1476-1483, 1997. Jackson RS, Creemers JW, Ohagi S, Raffin-Sanson ML, Sanders L, Montague CT, Hutton JC, O’Rahilly S. Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nat Genet 16: 303-306, 1997. Jacobs Y, Schnabel CA, Cleary ML. Trimeric association of Hox and TALE homeodomain proteins mediates Hoxb2 hindbrain enhancer activity. Mol Cell Biol 19: 5134-5142, 1999. Jadhav U, Harris RM, Jameson JL. Hypogonadotropic hypogonadism in subjects with DAX1 mutations. Mol Cell Endocrinol 346: 65-73, 2011. Jeays-Ward K, Hoyle C, Brennan J, Dandonneau M, Alldus G, Capel B, Swain A. Endothelial and steroidogenic cell migration are regulated by WNT4 in the developing mammalian gonad. Development 130: 3663-3670, 2003. Jordan BK, Mohammed M, Ching ST, Delot E, Chen XN, Dewing P, Swain A, Rao PN, Elejalde BR, Vilain E. Up-regulation of WNT-4 signaling and dosage-sensitive sex reversal in humans. Am J Hum Genet 68: 1102-1109, 2001. Jordan BK, Shen JH, Olaso R, Ingraham HA, Vilain E. Wnt4 overexpression disrupts normal testicular vasculature and inhibits testosterone synthesis by repressing steroidogenic factor 1/beta-catenin synergy. Proc Natl Acad Sci U S A 100: 10866-10871, 2003. Kang S, Graham JM, Jr, Olney AH, Biesecker LG. GLI3 frameshift mutations cause autosomal dominant Pallister-Hall syndrome. Nat Genet 15: 266-268, 1997. Karamurzin Y, Zeng Z, Stadler ZK, Zhang L, Ouansafi I, Al-Ahmadie HA, Sempoux C, Saltz LB, Soslow RA, O’Reilly EM, Paty PB, Coit DG, Shia J, Klimstra DS. Unusual DNA mismatch repair-deficient tumors in Lynch syndrome: A report of new cases and review of the literature. Hum Pathol 43: 1677-1687, 2012. Karpac J, Ostwald D, Bui S, Hunnewell P, Shankar M, Hochgeschwender U. Development, maintenance, and function of the adrenal gland in early postnatal proopiomelanocortin-null mutant mice. Endocrinology 146: 2555-2562, 2005. Keegan CE, Hammer GD. Recent insights into organogenesis of the adrenal cortex. Trends Endocrinol Metab 13: 200-208, 2002. Keegan CE, Hutz JE, Else T, Adamska M, Shah SP, Kent AE, Howes JM, Beamer WG, Hammer GD. Urogenital and caudal dysgenesis in adrenocortical dysplasia (acd) mice is caused by a splicing mutation in a novel telomeric regulator. Hum Mol Genet 14: 113-123, 2005. Kelly VR, Xu B, Kuick R, Koenig RJ, Hammer GD. Dax1 up-regulates Oct4 expression in mouse embryonic stem cells via LRH-1 and SRA. Mol Endocrinol 24: 2281-2291, 2010. Khalfallah O, Rouleau M, Barbry P, Bardoni B, Lalli E. Dax-1 knockdown in mouse embryonic stem cells induces loss of pluripotency and multilineage differentiation. Stem Cells 27: 1529-1537, 2009. Kikuchi A. Tumor formation by genetic mutations in the components of the Wnt signaling pathway. Cancer Sci 94: 225-229, 2003. Kim AC, Barlaskar FM, Heaton JH, Else T, Kelly VR, Krill KT, Scheys JO, Simon DP, Trovato A, Yang WH, Hammer GD. In search of adrenocortical stem and progenitor cells. Endocr Rev 30: 241-263, 2009. Kim AC, Reuter AL, Zubair M, Else T, Serecky K, Bingham NC, Lavery GG, Parker KL, Hammer GD. Targeted disruption of betacatenin in Sf1-expressing cells impairs development and maintenance of the adrenal cortex. Development 135: 2593-2602, 2008.


176. King P, Paul A, Laufer E. Shh signaling regulates adrenocortical development and identifies progenitors of steroidogenic lineages. Proc Natl Acad Sci U S A 106: 21185-21190, 2009. 177. Kjellman M, Kallioniemi OP, Karhu R, Hoog A, Farnebo LO, Auer G, Larsson C, Backdahl M. Genetic aberrations in adrenocortical tumors detected using comparative genomic hybridization correlate with tumor size and malignancy. Cancer Res 56: 4219-4223, 1996. 178. Kjellman M, Roshani L, Teh BT, Kallioniemi OP, Hoog A, Gray S, Farnebo LO, Holst M, Backdahl M, Larsson C. Genotyping of adrenocortical tumors: Very frequent deletions of the MEN1 locus in 11q13 and of a 1-centimorgan region in 2p16. J Clin Endocrinol Metab 84: 730-735, 1999. 179. Kohler B, Lin L, Ferraz-de-Souza B, Wieacker P, Heidemann P, Schroder V, Biebermann H, Schnabel D, Gruters A, Achermann JC. Five novel mutations in steroidogenic factor 1 (SF1, NR5A1) in 46,XY patients with severe underandrogenization but without adrenal insufficiency. Hum Mutat 29: 59-64, 2008. 180. Kohler B, Lin L, Mazen I, Cetindag C, Biebermann H, Akkurt I, Rossi R, Hiort O, Gruters A, Achermann JC. The spectrum of phenotypes associated with mutations in steroidogenic factor 1 (SF-1, NR5A1, Ad4BP) includes severe penoscrotal hypospadias in 46,XY males without adrenal insufficiency. Eur J Endocrinol 161: 237-242, 2009. 181. Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R. WT-1 is required for early kidney development. Cell 74: 679-691, 1993. 182. Krude H, Biebermann H, Luck W, Horn R, Brabant G, Gruters A. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet 19: 155-157, 1998. 183. Krude H, Biebermann H, Schnabel D, Tansek MZ, Theunissen P, Mullis PE, Gruters A. Obesity due to proopiomelanocortin deficiency: Three new cases and treatment trials with thyroid hormone and ACTH4-10. J Clin Endocrinol Metab 88: 4633-4640, 2003. 184. Kuhl SJ, Kuhl M. On the role of Wnt/beta-catenin signaling in stem cells. Biochim Biophys Acta 1830: 2297-2306, 2013. 185. Lala DS, Rice DA, Parker KL. Steroidogenic factor I, a key regulator of steroidogenic enzyme expression, is the mouse homolog of fushi tarazu-factor I. Mol Endocrinol 6: 1249-1258, 1992. 186. Lalli E, Bardoni B, Zazopoulos E, Wurtz JM, Strom TM, Moras D, Sassone-Corsi P. A transcriptional silencing domain in DAX-1 whose mutation causes adrenal hypoplasia congenita. Mol Endocrinol 11: 1950-1960, 1997. 187. Lalli E, Melner MH, Stocco DM, Sassone-Corsi P. DAX-1 blocks steroid production at multiple levels. Endocrinology 139: 4237-4243, 1998. 188. Lalli E, Sassone-Corsi P. DAX-1, an unusual orphan receptor at the crossroads of steroidogenic function and sexual differentiation. Mol Endocrinol 17: 1445-1453, 2003. 189. Lam WW, Hatada I, Ohishi S, Mukai T, Joyce JA, Cole TR, Donnai D, Reik W, Schofield PN, Maher ER. Analysis of germline CDKN1C (p57KIP2) mutations in familial and sporadic Beckwith-Wiedemann syndrome (BWS) provides a novel genotype-phenotype correlation. J Med Genet 36: 518-523, 1999. 190. Lamolet B, Pulichino AM, Lamonerie T, Gauthier Y, Brue T, Enjalbert A, Drouin J. A pituitary cell-restricted T box factor, Tpit, activates POMC transcription in cooperation with Pitx homeoproteins. Cell 104: 849-859, 2001. 191. Lapunzina P. Risk of tumorigenesis in overgrowth syndromes: A comprehensive review. Am J Med Genet C Semin Med Genet 137C: 53-71, 2005. 192. Latronico AC, Pinto EM, Domenice S, Fragoso MC, Martin RM, Zerbini MC, Lucon AM, Mendonca BB. An inherited mutation outside the highly conserved DNA-binding domain of the p53 tumor suppressor protein in children and adults with sporadic adrenocortical tumors. J Clin Endocrinol Metab 86: 4970-4973, 2001. 193. Lau SK, Weiss LM. The Weiss system for evaluating adrenocortical neoplasms: 25 years later. Hum Pathol 40: 757-768, 2009. 194. Laurell C, Velazquez-Fernandez D, Lindsten K, Juhlin C, Enberg U, Geli J, Hoog A, Kjellman M, Lundeberg J, Hamberger B, Larsson C, Nilsson P, Backdahl M. Transcriptional profiling enables molecular classification of adrenocortical tumours. Eur J Endocrinol 161: 141152, 2009. 195. Laurent-Puig P, Legoix P, Bluteau O, Belghiti J, Franco D, Binot F, Monges G, Thomas G, Bioulac-Sage P, Zucman-Rossi J. Genetic alterations associated with hepatocellular carcinomas define distinct pathways of hepatocarcinogenesis. Gastroenterology 120: 1763-1773, 2001. 196. Lazaro L, Dubourg C, Pasquier L, Le Duff F, Blayau M, Durou MR, de la Pintiere AT, Aguilella C, David V, Odent S. Phenotypic and molecular variability of the holoprosencephalic spectrum. Am J Med Genet A 129A: 21-24, 2004. 197. Lee FY, Faivre EJ, Suzawa M, Lontok E, Ebert D, Cai F, Belsham DD, Ingraham HA. Eliminating SF-1 (NR5A1) sumoylation in vivo results



198.

199. 200. 201. 202. 203. 204. 205.

206. 207.

208. 209. 210.

211.

212.

213. 214.

215. 216. 217. 218.

219. 220.

in ectopic hedgehog signaling and disruption of endocrine development. Dev Cell 21: 315-327, 2011. Lefrancois-Martinez AM, Bertherat J, Val P, Tournaire C, GalloPayet N, Hyndman D, Veyssiere G, Bertagna X, Jean C, Martinez A. Decreased expression of cyclic adenosine monophosphate-regulated aldose reductase (AKR1B1) is associated with malignancy in human sporadic adrenocortical tumors. J Clin Endocrinol Metab 89: 30103019, 2004. Lehmann SG, Lalli E, Sassone-Corsi P. X-linked adrenal hypoplasia congenita is caused by abnormal nuclear localization of the DAX-1 protein. Proc Natl Acad Sci U S A 99: 8225-8230, 2002. Li FP, Fraumeni JF, Jr. Soft-tissue sarcomas, breast cancer, and other neoplasms. A familial syndrome? Ann Intern Med 71: 747-752, 1969. Li FP, Fraumeni JF, Jr, Mulvihill JJ, Blattner WA, Dreyfus MG, Tucker MA, Miller RW. A cancer family syndrome in twenty-four kindreds. Cancer Res 48: 5358-5362, 1988. Li M, Squire JA, Weksberg R. Molecular genetics of BeckwithWiedemann syndrome. Curr Opin Pediatr 9: 623-629, 1997. Li M, Squire JA, Weksberg R. Molecular genetics of WiedemannBeckwith syndrome. Am J Med Genet 79: 253-259, 1998. Libe R, Bertherat J. Molecular genetics of adrenocortical tumours, from familial to sporadic diseases. Eur J Endocrinol 153: 477-487, 2005. Libe R, Groussin L, Tissier F, Elie C, Rene-Corail F, Fratticci A, Jullian E, Beck-Peccoz P, Bertagna X, Gicquel C, Bertherat J. Somatic TP53 mutations are relatively rare among adrenocortical cancers with the frequent 17p13 loss of heterozygosity. Clin Cancer Res 13: 844-850, 2007. Lienhardt A, Mas JC, Kalifa G, Chaussain JL, Tauber M. IMAGe association: Additional clinical features and evidence for recessive autosomal inheritance. Horm Res 57(Suppl 2): 71-78, 2002. Lin L, Philibert P, Ferraz-de-Souza B, Kelberman D, Homfray T, Albanese A, Molini V, Sebire NJ, Einaudi S, Conway GS, Hughes IA, Jameson JL, Sultan C, Dattani MT, Achermann JC. Heterozygous missense mutations in steroidogenic factor 1 (SF1/Ad4BP, NR5A1) are associated with 46,XY disorders of sex development with normal adrenal function. J Clin Endocrinol Metab 92: 991-999, 2007. Liu D, Safari A, O’Connor MS, Chan DW, Laegeler A, Qin J, Songyang Z. PTOP interacts with POT1 and regulates its localization to telomeres. Nat Cell Biol 6: 673-680, 2004. Logan CY, Nusse R. The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol 20: 781-810, 2004. Logie A, Boulle N, Gaston V, Perin L, Boudou P, Le Bouc Y, Gicquel C. Autocrine role of IGF-II in proliferation of human adrenocortical carcinoma NCI H295R cell line. J Mol Endocrinol 23: 23-32, 1999. Lombardi CP, Raffaelli M, Pani G, Maffione A, Princi P, Traini E, Galeotti T, Rossi ED, Fadda G, Bellantone R. Gene expression profiling of adrenal cortical tumors by cDNA macroarray analysis. Results of a preliminary study. Biomed Pharmacother 60: 186-190, 2006. Lourenco D, Brauner R, Lin L, De Perdigo A, Weryha G, Muresan M, Boudjenah R, Guerra-Junior G, Maciel-Guerra AT, Achermann JC, McElreavey K, Bashamboo A. Mutations in NR5A1 associated with ovarian insufficiency. N Engl J Med 360: 1200-1210, 2009. Lowry PJ, Silas L, McLean C, Linton EA, Estivariz FE. Pro-gammamelanocyte-stimulating hormone cleavage in adrenal gland undergoing compensatory growth. Nature 306: 70-73, 1983. Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, SweetCordero A, Ebert BL, Mak RH, Ferrando AA, Downing JR, Jacks T, Horvitz HR, Golub TR. MicroRNA expression profiles classify human cancers. Nature 435: 834-838, 2005. Lu J, Richardson JA, Olson EN. Capsulin: A novel bHLH transcription factor expressed in epicardial progenitors and mesenchyme of visceral organs. Mech Dev 73: 23-32, 1998. Luo X, Ikeda Y, Parker KL. A cell-specific nuclear receptor is essential for adrenal and gonadal development and sexual differentiation. Cell 77: 481-490, 1994. Luo X, Ikeda Y, Schlosser DA, Parker KL. Steroidogenic factor 1 is the essential transcript of the mouse Ftz-F1 gene. Mol Endocrinol 9: 1233-1239, 1995. Luton JP, Martinez M, Coste J, Bertherat J. Outcome in patients with adrenal incidentaloma selected for surgery: An analysis of 88 cases investigated in a single clinical center. Eur J Endocrinol 143: 111-117, 2000. Lynch HT, Shaw MW, Magnuson CW, Larsen AL, Krush AJ. Hereditary factors in cancer. Study of two large midwestern kindreds. Arch Intern Med 117: 206-212, 1966. Mallet D, Bretones P, Michel-Calemard L, Dijoud F, David M, Morel Y. Gonadal dysgenesis without adrenal insufficiency in a 46, XY patient heterozygous for the nonsense C16X mutation: A case of SF1 haploinsufficiency. J Clin Endocrinol Metab 89: 4829-4832, 2004.



221. Mantero F, Terzolo M, Arnaldi G, Osella G, Masini AM, Ali A, Giovagnetti M, Opocher G, Angeli A. A survey on adrenal incidentaloma in Italy. Study Group on Adrenal Tumors of the Italian Society of Endocrinology. J Clin Endocrinol Metab 85: 637-644, 2000. 222. Marchesa P, Fazio VW, Church JM, McGannon E. Adrenal masses in patients with familial adenomatous polyposis. Dis Colon Rectum 40: 1023-1028, 1997. 223. Marini F, Falchetti A, Luzi E, Tonelli F, Maria Luisa B. Multiple endocrine neoplasia type 1 (MEN1) syndrome. In: Riegert-Johnson DL, Boardman LA, Hefferon T, Roberts M, editors. Cancer Syndromes [Internet]. Bethesda (MD): National Center for Biotechnology Information, 2009. 224. Marney AM, Brown NJ. Aldosterone and end-organ damage. Clin Sci (Lond) 113: 267-278, 2007. 225. Masi G, Lavezzo E, Iacobone M, Favia G, Palu G, Barzon L. Investigation of BRAF and CTNNB1 activating mutations in adrenocortical tumors. J Endocrinol Invest 32: 597-600, 2009. 226. Meeks JJ, Weiss J, Jameson JL. Dax1 is required for testis determination. Nat Genet 34: 32-33, 2003. 227. Meimaridou E, Hughes CR, Kowalczyk J, Guasti L, Chapple JP, King PJ, Chan LF, Clark AJ, Metherell LA. Familial glucocorticoid deficiency: New genes and mechanisms. Mol Cell Endocrinol 371: 195200, 2013. 228. Meimaridou E, Kowalczyk J, Guasti L, Hughes CR, Wagner F, Frommolt P, Nurnberg P, Mann NP, Banerjee R, Saka HN, Chapple JP, King PJ, Clark AJ, Metherell LA. Mutations in NNT encoding nicotinamide nucleotide transhydrogenase cause familial glucocorticoid deficiency. Nat Genet 44: 740-742, 2012. 229. Melo KF, Martin RM, Costa EM, Carvalho FM, Jorge AA, Arnhold IJ, Mendonca BB. An unusual phenotype of Frasier syndrome due to IVS9 +4C>T mutation in the WT1 gene: Predominantly male ambiguous genitalia and absence of gonadal dysgenesis. J Clin Endocrinol Metab 87: 2500-2505, 2002. 230. Mendiratta MS, Yang Y, Balazs AE, Willis AS, Eng CM, Karaviti LP, Potocki L. Early onset obesity and adrenal insufficiency associated with a homozygous POMC mutation. Int J Pediatr Endocrinol 2011: 5, 2011. 231. Mesiano S, Jaffe RB. Developmental and functional biology of the primate fetal adrenal cortex. Endocr Rev 18: 378-403, 1997. 232. Mesiano S, Mellon SH, Jaffe RB. Mitogenic action, regulation, and localization of insulin-like growth factors in the human fetal adrenal gland. J Clin Endocrinol Metab 76: 968-976, 1993. 233. Metherell LA, Chan LF, Clark AJ. The genetics of ACTH resistance syndromes. Best Pract Res Clin Endocrinol Metab 20: 547-560, 2006. 234. Metherell LA, Chapple JP, Cooray S, David A, Becker C, Ruschendorf F, Naville D, Begeot M, Khoo B, Nurnberg P, Huebner A, Cheetham ME, Clark AJ. Mutations in MRAP, encoding a new interacting partner of the ACTH receptor, cause familial glucocorticoid deficiency type 2. Nat Genet 37: 166-170, 2005. 235. Metherell LA, Naville D, Halaby G, Begeot M, Huebner A, Nurnberg G, Nurnberg P, Green J, Tomlinson JW, Krone NP, Lin L, Racine M, Berney DM, Achermann JC, Arlt W, Clark AJ. Nonclassic lipoid congenital adrenal hyperplasia masquerading as familial glucocorticoid deficiency. J Clin Endocrinol Metab 94: 3865-3871, 2009. 236. Monticone S, Auchus RJ, Rainey WE. Adrenal disorders in pregnancy. Nat Rev Endocrinol 8: 668-678, 2012. 237. Moore AW, McInnes L, Kreidberg J, Hastie ND, Schedl A. YAC complementation shows a requirement for Wt1 in the development of epicardium, adrenal gland and throughout nephrogenesis. Development 126: 1845-1857, 1999. 238. Morin E, Mete O, Wasserman JD, Joshua AM, Asa SL, Ezzat S. Carney complex with adrenal cortical carcinoma. J Clin Endocrinol Metab 97: E202-206, 2012. 239. Morohashi K, Honda S, Inomata Y, Handa H, Omura T. A common trans-acting factor, Ad4-binding protein, to the promoters of steroidogenic P-450s. J Biol Chem 267: 17913-17919, 1992. 240. Morohashi K, Iida H, Nomura M, Hatano O, Honda S, Tsukiyama T, Niwa O, Hara T, Takakusu A, Shibata Y, et al. Functional difference between Ad4BP and ELP, and their distributions in steroidogenic tissues. Mol Endocrinol 8: 643-653, 1994. 241. Morohashi K, Tsuboi-Asai H, Matsushita S, Suda M, Nakashima M, Sasano H, Hataba Y, Li CL, Fukata J, Irie J, Watanabe T, Nagura H, Li E. Structural and functional abnormalities in the spleen of an mFtz-F1 gene-disrupted mouse. Blood 93: 1586-1594, 1999. 242. Nachtigal MW, Hirokawa Y, Enyeart-VanHouten DL, Flanagan JN, Hammer GD, Ingraham HA. Wilms’ tumor 1 and Dax-1 modulate the orphan nuclear receptor SF-1 in sex-specific gene expression. Cell 93: 445-454, 1998. 243. Naylor EW, Gardner EJ. Adrenal adenomas in a patient with Gardner’s syndrome. Clin Genet 20: 67-73, 1981. 244. Nedumaran B, Hong S, Xie YB, Kim YH, Seo WY, Lee MW, Lee CH, Koo SH, Choi HS. DAX-1 acts as a novel corepressor of orphan nuclear

323


245. 246. 247. 248.

249. 250. 251. 252. 253.

254. 255. 256. 257.

258.

259.

260.

261. 262.

263.

264. 265. 266. 267. 268. 269.

324

receptor HNF4alpha and negatively regulates gluconeogenic enzyme gene expression. J Biol Chem 284: 27511-27523, 2009. Nickerson PA, Brownie AC, Skelton FR. An electron microscopic study of the regenerating adrenal gland during the development of adrenal regeneration hypertension. Am J Pathol 57: 335-364, 1969. Ogawa O, Eccles MR, Szeto J, McNoe LA, Yun K, Maw MA, Smith PJ, Reeve AE. Relaxation of insulin-like growth factor II gene imprinting implicated in Wilms’ tumour. Nature 362: 749-751, 1993. Ohgaki H, Kleihues P, Heitz PU. p53 mutations in sporadic adrenocortical tumors. Int J Cancer 54: 408-410, 1993. Ozata DM, Caramuta S, Velazquez-Fernandez D, Akcakaya P, Xie H, Hoog A, Zedenius J, Backdahl M, Larsson C, Lui WO. The role of microRNA deregulation in the pathogenesis of adrenocortical carcinoma. Endocr Relat Cancer 18: 643-655, 2011. Painter TA, Jagelman DG. Adrenal adenomas and adrenal carcinomas in association with hereditary adenomatosis of the colon and rectum. Cancer 55: 2001-2004, 1985. Patterson EE, Holloway AK, Weng J, Fojo T, Kebebew E. MicroRNA profiling of adrenocortical tumors reveals miR-483 as a marker of malignancy. Cancer 117: 1630-1639, 2011. Pedreira CC, Savarirayan R, Zacharin MR. IMAGe syndrome: A complex disorder affecting growth, adrenal and gonadal function, and skeletal development. J Pediatr 144: 274-277, 2004. Pellegrino C, Ricci PD, Tongiani R. A quantitative cytochemical and physiological study of the rat adrenal cortex in hypertrophy after unilateral adrenalectomy. Exp Cell Res 31: 167-182, 1963. Pelletier J, Bruening W, Kashtan CE, Mauer SM, Manivel JC, Striegel JE, Houghton DC, Junien C, Habib R, Fouser L, et al. Germline mutations in the Wilms’ tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome. Cell 67: 437-447, 1991. Pelletier J, Bruening W, Li FP, Haber DA, Glaser T, Housman DE. WT1 mutations contribute to abnormal genital system development and hereditary Wilms’ tumour. Nature 353: 431-434, 1991. Perrone RD, Bengele HH, Alexander EA. Sodium retention after adrenal enucleation. Am J Physiol 250: E1-12, 1986. Phelan JK, McCabe ER. Mutations in NR0B1 (DAX1) and NR5A1 (SF1) responsible for adrenal hypoplasia congenita. Hum Mutat 18: 472-487, 2001. Philibert P, Biason-Lauber A, Rouzier R, Pienkowski C, Paris F, Konrad D, Schoenle E, Sultan C. Identification and functional analysis of a new WNT4 gene mutation among 28 adolescent girls with primary amenorrhea and mullerian duct abnormalities: A French collaborative study. J Clin Endocrinol Metab 93: 895-900, 2008. Philibert P, Leprieur E, Zenaty D, Thibaud E, Polak M, Frances AM, Lespinasse J, Raingeard I, Servant N, Audran F, Paris F, Sultan C. Steroidogenic factor-1 (SF-1) gene mutation as a frequent cause of primary amenorrhea in 46,XY female adolescents with low testosterone concentration. Reprod Biol Endocrinol 8: 28, 2010. Philibert P, Zenaty D, Lin L, Soskin S, Audran F, Leger J, Achermann JC, Sultan C. Mutational analysis of steroidogenic factor 1 (NR5a1) in 24 boys with bilateral anorchia: A French collaborative study. Hum Reprod 22: 3255-3261, 2007. Quaggin SE, Vanden Heuvel GB, Igarashi P. Pod-1, a mesodermspecific basic-helix-loop-helix protein expressed in mesenchymal and glomerular epithelial cells in the developing kidney. Mech Dev 71: 37-48, 1998. Ragazzon B, Assie G, Bertherat J. Transcriptome analysis of adrenocortical cancers: From molecular classification to the identification of new treatments. Endocr Relat Cancer 18: R15-27, 2011. Ragazzon B, Libe R, Assie G, Tissier F, Barreau O, Houdayer C, Perlemoine K, Audebourg A, Clauser E, Rene-Corail F, Bertagna X, Dousset B, Bertherat J, Groussin L. Mass-array screening of frequent mutations in cancers reveals RB1 alterations in aggressive adrenocortical carcinomas. Eur J Endocrinol 170: 385-391, 2014. Ragazzon B, Libe R, Gaujoux S, Assie G, Fratticci A, Launay P, Clauser E, Bertagna X, Tissier F, de Reynies A, Bertherat J. Transcriptome analysis reveals that p53 and {beta}-catenin alterations occur in a group of aggressive adrenocortical cancers. Cancer Res 70: 8276-8281, 2010. Rainey WE. Adrenal zonation: Clues from 11beta-hydroxylase and aldosterone synthase. Mol Cell Endocrinol 151: 151-160, 1999. Rainey WE, Nakamura Y. Regulation of the adrenal androgen biosynthesis. J Steroid Biochem Mol Biol 108: 281-286, 2008. Rainey WE, Rehman KS, Carr BR. Fetal and maternal adrenals in human pregnancy. Obstet Gynecol Clin North Am 31: 817-835, x, 2004. Rainey WE, Rehman KS, Carr BR. The human fetal adrenal: Making adrenal androgens for placental estrogens. Semin Reprod Med 22: 327336, 2004. Rainier S, Johnson LA, Dobry CJ, Ping AJ, Grundy PE, Feinberg AP. Relaxation of imprinted genes in human cancer. Nature 362: 747-749, 1993. Raymond VM, Else T, Everett JN, Long JM, Gruber SB, Hammer GD. Prevalence of germline TP53 mutations in a prospective series of


270.

271.

272.

273.

274.

275.

276.

277.

278.

279.

280.

281. 282.

283.

284. 285. 286.

287. 288. 289. 290.

unselected patients with adrenocortical carcinoma. J Clin Endocrinol Metab 98: E119-125, 2013. Raymond VM, Everett JN, Furtado LV, Gustafson SL, Jungbluth CR, Gruber SB, Hammer GD, Stoffel EM, Greenson JK, Giordano TJ, Else T. Adrenocortical carcinoma is a lynch syndrome-associated cancer. J Clin Oncol 31: 3012-3018, 2013. Rechache NS, Wang Y, Stevenson HS, Killian JK, Edelman DC, Merino M, Zhang L, Nilubol N, Stratakis CA, Meltzer PS, Kebebew E. DNA methylation profiling identifies global methylation differences and markers of adrenocortical tumors. J Clin Endocrinol Metab 97: E1004-E1013, 2012. Refaie S, Gagnon S, Gagnon H, Desjardins R, D’Anjou F, D’OrleansJuste P, Zhu X, Steiner DF, Seidah NG, Lazure C, Salzet M, Day R. Disruption of proprotein convertase 1/3 (PC1/3) expression in mice causes innate immune defects and uncontrolled cytokine secretion. J Biol Chem 287: 14703-14717, 2012. Reincke M, Beuschlein F, Lalli E, Arlt W, Vay S, Sassone-Corsi P, Allolio B. DAX-1 expression in human adrenocortical neoplasms: Implications for steroidogenesis. J Clin Endocrinol Metab 83: 2597-2600, 1998. Reincke M, Karl M, Travis WH, Mastorakos G, Allolio B, Linehan HM, Chrousos GP. p53 mutations in human adrenocortical neoplasms: Immunohistochemical and molecular studies. J Clin Endocrinol Metab 78: 790-794, 1994. Reincke M, Mora P, Beuschlein F, Arlt W, Chrousos GP, Allolio B. Deletion of the adrenocorticotropin receptor gene in human adrenocortical tumors: Implications for tumorigenesis. J Clin Endocrinol Metab 82: 3054-3058, 1997. Reuter AL, Goji K, Bingham NC, Matsuo M, Parker KL. A novel mutation in the accessory DNA-binding domain of human steroidogenic factor 1 causes XY gonadal dysgenesis without adrenal insufficiency. Eur J Endocrinol 157: 233-238, 2007. Ribeiro RC, Sandrini F, Figueiredo B, Zambetti GP, Michalkiewicz E, Lafferty AR, DeLacerda L, Rabin M, Cadwell C, Sampaio G, Cat I, Stratakis CA, Sandrini R. An inherited p53 mutation that contributes in a tissue-specific manner to pediatric adrenal cortical carcinoma. Proc Natl Acad Sci U S A 98: 9330-9335, 2001. Roessler E, Ward DE, Gaudenz K, Belloni E, Scherer SW, Donnai D, Siegel-Bartelt J, Tsui LC, Muenke M. Cytogenetic rearrangements involving the loss of the Sonic Hedgehog gene at 7q36 cause holoprosencephaly. Hum Genet 100: 172-181, 1997. Ronchi CL, Sbiera S, Leich E, Henzel K, Rosenwald A, Allolio B, Fassnacht M. Single nucleotide polymorphism array profiling of adrenocortical tumors–evidence for an adenoma carcinoma sequence? PLoS One 8: e73959, 2013. Rosenberg D, Groussin L, Jullian E, Perlemoine K, Medjane S, Louvel A, Bertagna X, Bertherat J. Transcription factor 3 ,5 -cyclic adenosine 5 -monophosphate-responsive element-binding protein (CREB) is decreased during human adrenal cortex tumorigenesis and fetal development. J Clin Endocrinol Metab 88: 3958-3965, 2003. Sablin EP, Woods A, Krylova IN, Hwang P, Ingraham HA, Fletterick RJ. The structure of corepressor Dax-1 bound to its target nuclear receptor LRH-1. Proc Natl Acad Sci U S A 105: 18390-18395, 2008. Sadovsky Y, Crawford PA, Woodson KG, Polish JA, Clements MA, Tourtellotte LM, Simburger K, Milbrandt J. Mice deficient in the orphan receptor steroidogenic factor 1 lack adrenal glands and gonads but express P450 side-chain-cleavage enzyme in the placenta and have normal embryonic serum levels of corticosteroids. Proc Natl Acad Sci U S A 92: 10939-10943, 1995. Sahut-Barnola I, de Joussineau C, Val P, Lambert-Langlais S, Damon C, Lefrancois-Martinez AM, Pointud JC, Marceau G, Sapin V, Tissier F, Ragazzon B, Bertherat J, Kirschner LS, Stratakis CA, Martinez A. Cushing’s syndrome and fetal features resurgence in adrenal cortexspecific Prkar1a knockout mice. PLoS Genet 6: e1000980, 2010. Sasano H, Shizawa S, Suzuki T, Takayama K, Fukaya T, Morohashi K, Nagura H. Ad4BP in the human adrenal cortex and its disorders. J Clin Endocrinol Metab 80: 2378-2380, 1995. Scheys JO, Heaton JH, Hammer GD. Evidence of adrenal failure in aging Dax1-deficient mice. Endocrinology 152: 3430-3439, 2011. Schmitz KJ, Helwig J, Bertram S, Sheu SY, Suttorp AC, Seggewiss J, Willscher E, Walz MK, Worm K, Schmid KW. Differential expression of microRNA-675, microRNA-139-3p and microRNA-335 in benign and malignant adrenocortical tumours. J Clin Pathol 64: 529-535, 2011. Schnabel CA, Selleri L, Cleary ML. Pbx1 is essential for adrenal development and urogenital differentiation. Genesis 37: 123-130, 2003. Schulte DM, Shapiro I, Reincke M, Beuschlein F. Expression and spatio-temporal distribution of differentiation and proliferation markers during mouse adrenal development. Gene Expr Patterns 7: 72-81, 2007. Schulte KM, Heinze M, Mengel M, Simon D, Scheuring S, Kohrer K, Roher HD. MEN I gene mutations in sporadic adrenal adenomas. Hum Genet 105: 603-610, 1999. Schulte KM, Mengel M, Heinze M, Simon D, Scheuring S, Kohrer K, Roher HD. Complete sequencing and messenger ribonucleic acid



291.

292.

293. 294.

295.

296.

297.

298.

299. 300.

301. 302.

303.

304.

305.

306. 307.

308. 309. 310. 311.

312.

expression analysis of the MEN I gene in adrenal cancer. J Clin Endocrinol Metab 85: 441-448, 2000. Seidinger AL, Mastellaro MJ, Paschoal Fortes F, Godoy Assumpcao J, Aparecida Cardinalli I, Aparecida Ganazza M, Correa Ribeiro R, Brandalise SR, Dos Santos Aguiar S, Yunes JA. Association of the highly prevalent TP53 R337H mutation with pediatric choroid plexus carcinoma and osteosarcoma in southeast Brazil. Cancer 117: 22282235, 2011. Seki M, Tanaka K, Kikuchi-Yanoshita R, Konishi M, Fukunari H, Iwama T, Miyaki M. Loss of normal allele of the APC gene in an adrenocortical carcinoma from a patient with familial adenomatous polyposis. Hum Genet 89: 298-300, 1992. Sherr CJ, McCormick F. The RB and p53 pathways in cancer. Cancer Cell 2: 103-112, 2002. Shimizu M, Takai K, Moriwaki H. Strategy and mechanism for the prevention of hepatocellular carcinoma: Phosphorylated retinoid X receptor alpha is a critical target for hepatocellular carcinoma chemoprevention. Cancer Sci 100: 369-374, 2009. Shin SH, Kogerman P, Lindstrom E, Toftgard R, Biesecker LG. GLI3 mutations in human disorders mimic Drosophila cubitus interruptus protein functions and localization. Proc Natl Acad Sci U S A 96: 28802884, 1999. Shinoda K, Lei H, Yoshii H, Nomura M, Nagano M, Shiba H, Sasaki H, Osawa Y, Ninomiya Y, Niwa O, et al. Developmental defects of the ventromedial hypothalamic nucleus and pituitary gonadotroph in the Ftz-F1 disrupted mice. Dev Dyn 204: 22-29, 1995. Sidhu S, Marsh DJ, Theodosopoulos G, Philips J, Bambach CP, Campbell P, Magarey CJ, Russell CF, Schulte KM, Roher HD, Delbridge L, Robinson BG. Comparative genomic hybridization analysis of adrenocortical tumors. J Clin Endocrinol Metab 87: 3467-3474, 2002. Sidhu S, Martin E, Gicquel C, Melki J, Clark SJ, Campbell P, Magarey CJ, Schulte KM, Roher HD, Delbridge L, Robinson BG. Mutation and methylation analysis of TP53 in adrenal carcinogenesis. Eur J Surg Oncol 31: 549-554, 2005. Skelton FR. Adrenal regeneration and adrenal-regeneration hypertension. Physiol Rev 39: 162-182, 1959. Slater EP, Diehl SM, Langer P, Samans B, Ramaswamy A, Zielke A, Bartsch DK. Analysis by cDNA microarrays of gene expression patterns of human adrenocortical tumors. Eur J Endocrinol 154: 587-598, 2006. Smith TG, Clark SK, Katz DE, Reznek RH, Phillips RK. Adrenal masses are associated with familial adenomatous polyposis. Dis Colon Rectum 43: 1739-1742, 2000. Soon PS, Gill AJ, Benn DE, Clarkson A, Robinson BG, McDonald KL, Sidhu SB. Microarray gene expression and immunohistochemistry analyses of adrenocortical tumors identify IGF2 and Ki-67 as useful in differentiating carcinomas from adenomas. Endocr Relat Cancer 16: 573-583, 2009. Soon PS, Tacon LJ, Gill AJ, Bambach CP, Sywak MS, Campbell PR, Yeh MW, Wong SG, Clifton-Bligh RJ, Robinson BG, Sidhu SB. miR-195 and miR-483-5p identified as predictors of poor prognosis in adrenocortical cancer. Clin Cancer Res 15: 7684-7692, 2009. Spencer SJ, Mesiano S, Lee JY, Jaffe RB. Proliferation and apoptosis in the human adrenal cortex during the fetal and perinatal periods: Implications for growth and remodeling. J Clin Endocrinol Metab 84: 1110-1115, 1999. Sperling S, Grimm CH, Dunkel I, Mebus S, Sperling HP, Ebner A, Galli R, Lehrach H, Fusch C, Berger F, Hammer S. Identification and functional analysis of CITED2 mutations in patients with congenital heart defects. Hum Mutat 26: 575-582, 2005. Stark K, Vainio S, Vassileva G, McMahon AP. Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature 372: 679-683, 1994. Stephan EA, Chung TH, Grant CS, Kim S, Von Hoff DD, Trent JM, Demeure MJ. Adrenocortical carcinoma survival rates correlated to genomic copy number variants. Mol Cancer Ther 7: 425-431, 2008. Sucheston ME, Cannon MS. Development of zonular patterns in the human adrenal gland. J Morphol 126: 477-491, 1968. Sucheston ME, Cannon MS. Microscopic comparison of the normal and anencephalic human adrenal gland with emphasis on the transientzone. Obstet Gynecol 35: 544-553, 1970. Swain A, Narvaez V, Burgoyne P, Camerino G, Lovell-Badge R. Dax1 antagonizes Sry action in mammalian sex determination. Nature 391: 761-767, 1998. Szabo DR, Baghy K, Szabo PM, Zsippai A, Marczell I, Nagy Z, Varga V, Eder K, Toth S, Buzas EI, Falus A, Kovalszky I, Patocs A, Racz K, Igaz P. Antitumoral effects of 9-cis retinoic acid in adrenocortical cancer. Cell Mol Life Sci 71: 917-932, 2013. Szabo PM, Tamasi V, Molnar V, Andrasfalvy M, Tombol Z, Farkas R, Kovesdi K, Patocs A, Toth M, Szalai C, Falus A, Racz K, Igaz P. Metaanalysis of adrenocortical tumour genomics data: Novel pathogenic pathways revealed. Oncogene 29: 3163-3172, 2010.



313. Tadjine M, Lampron A, Ouadi L, Bourdeau I. Frequent mutations of beta-catenin gene in sporadic secreting adrenocortical adenomas. Clin Endocrinol (Oxf) 68: 264-270, 2008. 314. Tadjine M, Lampron A, Ouadi L, Horvath A, Stratakis CA, Bourdeau I. Detection of somatic beta-catenin mutations in primary pigmented nodular adrenocortical disease. Clin Endocrinol (Oxf) 69: 367-373, 2008. 315. Takayama K, Sasano H, Fukaya T, Morohashi K, Suzuki T, Tamura M, Costa MJ, Yajima A. Immunohistochemical localization of Ad4binding protein with correlation to steroidogenic enzyme expression in cycling human ovaries and sex cord stromal tumors. J Clin Endocrinol Metab 80: 2815-2821, 1995. 316. Tamura M, Kanno Y, Chuma S, Saito T, Nakatsuji N. Pod-1/Capsulin shows a sex- and stage-dependent expression pattern in the mouse gonad development and represses expression of Ad4BP/SF-1. Mech Dev 102: 135-144, 2001. 317. Tan TY, Jameson JL, Campbell PE, Ekert PG, Zacharin M, Savarirayan R. Two sisters with IMAGe syndrome: Cytomegalic adrenal histopathology, support for autosomal recessive inheritance and literature review. Am J Med Genet A 140: 1778-1784, 2006. 318. Tien ES, Davis JW, Vanden Heuvel JP. Identification of the CREBbinding protein/p300-interacting protein CITED2 as a peroxisome proliferator-activated receptor alpha coregulator. J Biol Chem 279: 24053-24063, 2004. 319. Tinat J, Bougeard G, Baert-Desurmont S, Vasseur S, Martin C, Bouvignies E, Caron O, Bressac-de Paillerets B, Berthet P, Dugast C, BonaitiPellie C, Stoppa-Lyonnet D, Frebourg T. 2009 version of the Chompret criteria for Li Fraumeni syndrome. J Clin Oncol 27: e108-109; author reply e110, 2009. 320. Tissier F, Cavard C, Groussin L, Perlemoine K, Fumey G, Hagnere AM, Rene-Corail F, Jullian E, Gicquel C, Bertagna X, Vacher-Lavenu MC, Perret C, Bertherat J. Mutations of beta-catenin in adrenocortical tumors: Activation of the Wnt signaling pathway is a frequent event in both benign and malignant adrenocortical tumors. Cancer Res 65: 7622-7627, 2005. 321. Tombol Z, Szabo PM, Molnar V, Wiener Z, Tolgyesi G, Horanyi J, Riesz P, Reismann P, Patocs A, Liko I, Gaillard RC, Falus A, Racz K, Igaz P. Integrative molecular bioinformatics study of human adrenocortical tumors: microRNA, tissue-specific target prediction, and pathway analysis. Endocr Relat Cancer 16: 895-906, 2009. 322. Toye AA, Lippiat JD, Proks P, Shimomura K, Bentley L, Hugill A, Mijat V, Goldsworthy M, Moir L, Haynes A, Quarterman J, Freeman HC, Ashcroft FM, Cox RD. A genetic and physiological study of impaired glucose homeostasis control in C57BL/6J mice. Diabetologia 48: 675686, 2005. 323. Traill Z, Tuson J, Woodham C. Adrenal carcinoma in a patient with Gardner’s syndrome: Imaging findings. AJR Am J Roentgenol 165: 1460-1461, 1995. 324. Treier M, Gleiberman AS, O’Connell SM, Szeto DP, McMahon JA, McMahon AP, Rosenfeld MG. Multistep signaling requirements for pituitary organogenesis in vivo. Genes Dev 12: 1691-1704, 1998. 325. Vainio S, Heikkila M, Kispert A, Chin N, McMahon AP. Female development in mammals is regulated by Wnt-4 signalling. Nature 397: 405-409, 1999. 326. Val P, Martinez-Barbera JP, Swain A. Adrenal development is initiated by Cited2 and Wt1 through modulation of Sf-1 dosage. Development 134: 2349-2358, 2007. 327. van Amerongen R, Nusse R. Towards an integrated view of Wnt signaling in development. Development 136: 3205-3214, 2009. 328. Varley JM, McGown G, Thorncroft M, James LA, Margison GP, Forster G, Evans DG, Harris M, Kelsey AM, Birch JM. Are there low-penetrance TP53 Alleles? evidence from childhood adrenocortical tumors. Am J Hum Genet 65: 995-1006, 1999. 329. Velazquez-Fernandez D, Laurell C, Geli J, Hoog A, Odeberg J, Kjellman M, Lundeberg J, Hamberger B, Nilsson P, Backdahl M. Expression profiling of adrenocortical neoplasms suggests a molecular signature of malignancy. Surgery 138: 1087-1094, 2005. 330. Vidal V, Schedl A. Requirement of WT1 for gonad and adrenal development: Insights from transgenic animals. Endocr Res 26: 1075-1082, 2000. 331. Vilain E, Le Merrer M, Lecointre C, Desangles F, Kay MA, Maroteaux P, McCabe ER. IMAGe, a new clinical association of intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies. J Clin Endocrinol Metab 84: 4335-4340, 1999. 332. Vlangos CN, O’Connor BC, Morley MJ, Krause AS, Osawa GA, Keegan CE. Caudal regression in adrenocortical dysplasia (acd) mice is caused by telomere dysfunction with subsequent p53-dependent apoptosis. Dev Biol 334: 418-428, 2009. 333. Volante M, Buttigliero C, Greco E, Berruti A, Papotti M. Pathological and molecular features of adrenocortical carcinoma: An update. J Clin Pathol 61: 787-793, 2008.

325


334. Voutilainen R, Miller WL. Coordinate tropic hormone regulation of mRNAs for insulin-like growth factor II and the cholesterol side-chaincleavage enzyme, P450scc [corrected], in human steroidogenic tissues. Proc Natl Acad Sci U S A 84: 1590-1594, 1987. 335. Wagner J, Portwine C, Rabin K, Leclerc JM, Narod SA, Malkin D. High frequency of germline p53 mutations in childhood adrenocortical cancer. J Natl Cancer Inst 86: 1707-1710, 1994. 336. Wakatsuki S, Sasano H, Matsui T, Nagashima K, Toyota T, Horii A. Adrenocortical tumor in a patient with familial adenomatous polyposis: A case associated with a complete inactivating mutation of the APC gene and unusual histological features. Hum Pathol 29: 302-306, 1998. 337. Wang B, Fallon JF, Beachy PA. Hedgehog-regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb. Cell 100: 423-434, 2000. 338. Warman DM, Costanzo M, Marino R, Berensztein E, Galeano J, Ramirez PC, Saraco N, Baquedano MS, Ciaccio M, Guercio G, Chaler E, Maceiras M, Lazzatti JM, Bailez M, Rivarola MA, Belgorosky A. Three new SF-1 (NR5A1) gene mutations in two unrelated families with multiple affected members: Within-family variability in 46,XY subjects and low ovarian reserve in fertile 46,XX subjects. Horm Res Paediatr 75: 70-77, 2011. 339. Warthin AS. Classics in oncology. Heredity with reference to carcinoma as shown by the study of the cases examined in the pathological laboratory of the University of Michigan, 1895-1913. By Aldred Scott Warthin. 1913. CA Cancer J Clin 35: 348-359, 1913. 340. West AN, Neale GA, Pounds S, Figueredo BC, Rodriguez Galindo C, Pianovski MA, Oliveira Filho AG, Malkin D, Lalli E, Ribeiro R, Zambetti GP. Gene expression profiling of childhood adrenocortical tumors. Cancer Res 67: 600-608, 2007. 341. Wood MA, Acharya A, Finco I, Swonger JM, Elston MJ, Tallquist MD, Hammer GD. Fetal adrenal capsular cells serve as progenitor cells for steroidogenic and stromal adrenocortical cell lineages in M. musculus. Development 140: 4522-4532, 2013. 342. Wood MA, Hammer GD. Adrenocortical stem and progenitor cells: Unifying model of two proposed origins. Mol Cell Endocrinol 336: 206-212, 2011. 343. Wrobel KH, Suss F. On the origin and prenatal development of the bovine adrenal gland. Anat Embryol (Berl) 199: 301-318, 1999. 344. WuQiang F, Yanase T, Wei L, Oba K, Nomura M, Okabe T, Goto K, Nawata H. Functional characterization of a new human Ad4BP/SF1 variation, G146A. Biochem Biophys Res Commun 311: 987-994, 2003. 345. Xin H, Liu D, Wan M, Safari A, Kim H, Sun W, O’Connor MS, Songyang Z. TPP1 is a homologue of ciliate TEBP-beta and interacts with POT1 to recruit telomerase. Nature 445: 559-562, 2007. 346. Xu M, Wu X, Li Y, Yang X, Hu J, Zheng M, Tian J. CITED2 Mutation and methylation in children with congenital heart disease. J Biomed Sci 21: 7, 2014.

326


347. Yamakita N, Murai T, Ito Y, Miura K, Ikeda T, Miyamoto K, Onami S, Yoshida T. Adrenocorticotropin-independent macronodular adrenocortical hyperplasia associated with multiple colon adenomas/carcinomas which showed a point mutation in the APC gene. Intern Med 36: 536542, 1997. 348. Yano T, Linehan M, Anglard P, Lerman MI, Daniel LN, Stein CA, Robertson CN, LaRocca R, Zbar B. Genetic changes in human adrenocortical carcinomas. J Natl Cancer Inst 81: 518-523, 1989. 349. Yates LA, Norbury CJ, Gilbert RJ. The long and short of microRNA. Cell 153: 516-519, 2013. 350. Ye JZ, Hockemeyer D, Krutchinsky AN, Loayza D, Hooper SM, Chait BT, de Lange T. POT1-interacting protein PIP1: A telomere length regulator that recruits POT1 to the TIN2/TRF1 complex. Genes Dev 18: 1649-1654, 2004. 351. Yu RN, Ito M, Jameson JL. The murine Dax-1 promoter is stimulated by SF-1 (steroidogenic factor-1) and inhibited by COUP-TF (chicken ovalbumin upstream promoter-transcription factor) via a composite nuclear receptor-regulatory element. Mol Endocrinol 12: 1010-1022, 1998. 352. Yu RN, Ito M, Saunders TL, Camper SA, Jameson JL. Role of Ahch in gonadal development and gametogenesis. Nat Genet 20: 353-357, 1998. 353. Zazopoulos E, Lalli E, Stocco DM, Sassone-Corsi P. DNA binding and transcriptional repression by DAX-1 blocks steroidogenesis. Nature 390: 311-315, 1997. 354. Zhang P, Liegeois NJ, Wong C, Finegold M, Hou H, Thompson JC, Silverman A, Harper JW, DePinho RA, Elledge SJ. Altered cell differentiation and proliferation in mice lacking p57KIP2 indicates a role in Beckwith-Wiedemann syndrome. Nature 387: 151-158, 1997. 355. Zhao J, Roth J, Bode-Lesniewska B, Pfaltz M, Heitz PU, Komminoth P. Combined comparative genomic hybridization and genomic microarray for detection of gene amplifications in pulmonary artery intimal sarcomas and adrenocortical tumors. Genes Chromosomes Cancer 34: 48-57, 2002. 356. Zhao J, Speel EJ, Muletta-Feurer S, Rutimann K, Saremaslani P, Roth J, Heitz PU, Komminoth P. Analysis of genomic alterations in sporadic adrenocortical lesions. Gain of chromosome 17 is an early event in adrenocortical tumorigenesis. Am J Pathol 155: 1039-1045, 1999. 357. Zubair M, Ishihara S, Oka S, Okumura K, Morohashi K. Two-step regulation of Ad4BP/SF-1 gene transcription during fetal adrenal development: Initiation by a Hox-Pbx1-Prep1 complex and maintenance via autoregulation by Ad4BP/SF-1. Mol Cell Biol 26: 4111-4121, 2006. 358. Zubair M, Parker KL, Morohashi K. Developmental links between the fetal and adult zones of the adrenal cortex revealed by lineage tracing. Mol Cell Biol 28: 7030-7040, 2008. 359. Zwermann O, Beuschlein F, Mora P, Weber G, Allolio B, Reincke M. Multiple endocrine neoplasia type 1 gene expression is normal in sporadic adrenocortical tumors. Eur J Endocrinol 142: 689-695, 2000.


Adrenocortical cancer update.

Growth in children with adrenocortical tumors.

Growth patterns after for virilising adrenocortical adenoma.

Angiotensin stimulation of bovine adrenocortical cell growth.

Diagnosis, treatment and outcome of adrenocortical cancer.

Growth patterns of placental and paraovarian adrenocortical heterotopias are different.

cMET Pathway Activation Enhances Cancer Hallmarks in Adrenocortical Carcinoma.

IGF2 promotes growth of adrenocortical carcinoma cells, but its overexpression does not modify phenotypic and molecular features of adrenocortical carcinoma.

The effects of suramin on human adrenocortical cells in vitro: suramin inhibits cortisol secretion and adrenocortical cell growth.

Growth patterns after surgery for virilising adrenocortical adenoma.

microRNAs as Potential Biomarkers in Adrenocortical Cancer: Progress and Challenges.

Hypothermia and adrenocortical function.

Kidney and adrenocortical hormones.

Hair cortisol measurement in mitotane-treated adrenocortical cancer patients.

Ketoacidosis and adrenocortical insufficiency.

Improving Outcomes in Adrenocortical Cancer: An Australian Perspective.

Metformin as a new anti-cancer drug in adrenocortical carcinoma.

Adrenocortical carcinoma.

Adrenocortical blastoma.

The effect of cyproheptadine and human growth hormone on adrenocortical function in children with hypopituitarism.

Virilizing adrenocortical tumor superimposed on congenital adrenocortical hyperplasia.

Adrenocortical carcinoma: review and update.

Adrenocortical function tests in dogs with hyperfunctioning adrenocortical tumours.

Oxidative stress and adrenocortical insufficiency.