Familial Cancer DOI 10.1007/s10689-014-9703-x
ORIGINAL ARTICLE
Potential genetic anticipation in hereditary leiomyomatosis-renal cell cancer (HLRCC) Mei Hua Wong • Chuen Seng Tan • Soo Chin Lee • Yvonne Yong • Aik Seng Ooi Joanne Ngeow • Min Han Tan
•
Ó Springer Science+Business Media Dordrecht 2014
Abstract Hereditary leiomyomatosis-renal cell cancer (HLRCC) is an autosomal dominant disorder characterised by cutaneous leiomyomas, symptomatic uterine leiomyomas and aggressive type II papillary renal cell carcinoma. It is caused by heterozygous mutations in the fumarate hydratase (FH) gene on chromosome 1q43. We present evidence of genetic anticipation in HLRCC syndrome. A comprehensive literature review was performed to determine the potential for genetic anticipation in HLRCC syndrome. The normal random effects model was used to evaluate for genetic anticipation to ensure reduction in bias. A total of 11 FH kindreds with available multi-generational data were identified for analysis. The mean difference in age at diagnosis of RCC between the first and second generation was -18.6 years (95 % CI -26.6 to -10.6, p \ 0.001). The mean difference in age at diagnosis of RCC between the first and third generation was
M. H. Wong J. Ngeow M. H. Tan (&) Department of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore e-mail: [email protected] C. S. Tan Department of Epidemiology and Public Health, National University of Singapore, Singapore, Singapore S. C. Lee Y. Yong Cancer Science Institute, National University of Singapore, Singapore, Singapore A. S. Ooi Laboratory of Interdisciplinary Urological Oncology, Van Andel Research Institute, Grand Rapids, MI, USA M. H. Tan Institute of Bioengineering and Nanotechnology, Singapore, Singapore
-36.2 years (95 % CI -47.0 to -25.4, p \ 0.001). No evidence of anticipation for uterine leiomyomas was observed (p = 0.349). We report preliminary evidence of genetic anticipation of RCC in HLRCC syndrome. Additional clinical validation is important to confirm this observation, which may have practical implications on counseling and timing of surveillance initiation. Exploration of the underlying mechanisms of anticipation in HLRCC would be of considerable biological interest. Keywords Fumarate hydratase Genetic anticipation Krebs cycle Hereditary leiomyomatosis-renal cell carcinoma syndrome Papillary renal cell carcinoma
Introduction Hereditary leiomyomatosis and renal cell cancer (HLRCC), also known as Reed syndrome, is characterised by variable development of multiple cutaneous leiomyomas, symptomatic uterine leiomyomas (uterine fibroids) and aggressive type II papillary renal cell carcinoma [1]. HLRCC is transmitted in an autosomal dominant fashion with incomplete penetrance. The lifetime risk of renal cancer in HLRCC has not been clarified. In cohorts of families, the prevalence of renal cancer varies widely. The prevalence been reported to be 2–6 % in the UK [2], and 62 % in US for families seen at the National Cancer Institute [3]. The differences in reported prevalence may be in part due to differences in the recruitment approaches [3]. A reasonable summary of the prevalence from the literature has been suggested to be between 20 and 25 % [4]. Of note, the youngest age at diagnosis of RCC is 11 years old, in an asymptomatic child with a confirmed mutation in the FH gene who underwent screening imaging [5]. Further,
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metastatic RCC has been diagnosed in several patients in their late teens, between 16 and 18 years, and all were deceased before 20 years old [2, 6, 7]. Hereditary leiomyomatosis-renal cell cancer is due to mutations of the fumarate hydratase (FH) gene which is located on chromosome 1q43. The gene consists of 10 exons, encoding fumarase, which is an enzyme that catalyses the reversible hydration and dehydration reactions between fumarate and malate. Fumarase exists in both mitochondrial and cytosolic forms; the mitochondrial isoenzyme participates in the Krebs cycle, and the cytosolic form participates in amino acid and fumarate metabolism. The oncogenic mechanisms of FH inactivation are being actively investigated, with two main competing theories [8]. The best studied theory is that FH inactivation results in activation of the hypoxia-inducible factor through increased expression of its alpha-subunit. An alternative theory suggests that inactivated FH leads to activation of nuclear factor (erythroid-derived 2)-like 2 (NRF2) as the primary oncogenic mechanism. Genetic anticipation refers to the earlier onset of disease, increased burden or both in succeeding generations of a family afflicted with a hereditary disorder. This phenomenon has been reported in certain degenerative disorders, as well as a number of cancers such as hereditary breast cancer [9], ovarian cancer [10], chronic lymphocytic leukaemia [11], myeloproliferative neoplasms (MPN) [12], pancreatic cancer [13], non-medullary thyroid carcinoma [14] and cavernous angioma [15]. Genetic anticipation has also been observed in Lynch syndrome [16, 17] and Li Fraumeni syndrome (LFS) [18]. To date, this has not been reported in any hereditary kidney cancer syndrome, including HLRCC syndrome. The genetic basis for anticipation in several neuromuscular diseases has been shown to be attributable to generational expansion of a repeated trinucleotide segment of DNA. Telomere attrition has been suggested to be the biological basis of anticipation in LFS [18], familial MPN [12] and hereditary breast cancer [19]. In familial MPN, it has been shown that affected individuals have shorter telomeres than the reference population and the secondgeneration have significant shortening relative to the firstgeneration patients [12]. In LFS, the proposed mechanism is that a threshold for telomere length exists, below which the risk of cancer initiation is high. Affected individuals with shorter telomeres reach this threshold faster within their lifetime [18]. In patients with Lynch syndrome, the average frequencies of mutant microsatellite fragments in non-tumour cells heterozygous for germline MMR mutations has been demonstrated to be significantly higher than age-matched normal controls. It has been postulated that such instability may also occur in germ cells such that mutant alleles are passed on to offspring at a higher
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frequency [20]. These proposed molecular mechanisms commonly suggest that the basis is an unstable mutation which is magnified in subsequent generations. Demonstrating genetic anticipation in familial cancers has been difficult as there are multiple sources of bias that can influence findings of genetic anticipation. Tsai et al. investigated genetic anticipation in 308 pedigrees with Lynch Syndrome, and found no evidence to support anticipation, concluding that apparent anticipation appears to reflect a birth cohort bias of ascertainment [21]. Certainly, ascertainment bias is an important consideration as families with early-onset cases tend to be preferentially selected and constitutes a sampling error. Another bias that can be introduced is the change in screening practices over time. For example, in Lynch syndrome, the interval between colonoscopies may be shortened or the mean age of first colonoscopy may be reduced. Similarly in HLRCC, radiological screening may be performed earlier or more frequently. From earlier studies that investigate genetic anticipation in other familial cancers, most prominently Lynch Syndrome, the importance of selecting appropriate statistical techniques to account for these biases has become evident [22]. The motivation for this study was our observation of possible genetic anticipation in the HLRCC families under our care. We therefore undertook a comprehensive examination of the worldwide literature to evaluate if this observation might be supported by other reports of HLRCC families with multi-generational information on age of diagnosis of RCC.
Patients and methods Local patient selection Subjects were identified through comprehensive review of patients seen at the clinical cancer genetics services in the National Cancer Centre Singapore and National University Hospital, Singapore, since 2002. Genetic counseling was performed by specialized clinical cancer geneticists before informed consent was taken to obtain blood samples for genetic testing. Patients and their families with confirmed FH mutations who presented to the National Cancer Centre and National University Hospital’s cancer genetics services were selected for the study. Institutional Review Board approval was obtained for this study. Ascertainment of patients Diagnosis of RCC was confirmed with a histopathological specimen for all of our patients, although the detailed histological report was not available for two individuals.
Potential genetic anticipation
Bidirectional exon sequencing for the ten exons of FH was conducted for all probands, and mutations confirmed using accredited clinical laboratory services. Mutations were cross-checked with the TCA Cycle Gene Mutation database [23] to determine if they had been previously reported. The diagnosis of uterine leiomyomas for probands 2 and 4 was based on radiological imaging. The mother of proband 4 was deceased at age 45 and her medical records were not accessible; her history of uterine leiomyoma was based on the account of proband 4. All probands were evaluated by a clinical cancer geneticist, and received abdominal and pelvic imaging for evaluation of renal cancer and uterine leiomyomas where appropriate. Dermatology consultation was not obtained. Literature search strategy Fig. 1 CONSORT flow diagram. RCC indicates renal cell carcinoma
A systematic search was performed using PubMed. The search strategy, ‘‘(HLRCC OR hereditary leiomyomatosis and renal cell carcinoma OR ‘‘Reed’s syndrome’’ OR ‘‘Reed syndrome’’ OR Leiomyomatosis and renal cell cancer, hereditary OR FH OR multiple cutaneous and uterine leiomyomata OR leiomyomata, multiple cutaneous)’’, retrieved 276 articles on 22 Dec 2012. Two independent reviewers evaluated all abstracts for reported HLRCC kindreds. The full text was obtained if the following criteria were fulfilled, (1) contains clinical description of family history, (2) not a review, (3) article in English. 61 publications were reviewed to identify kindreds in which RCC were manifest in at least two generations. Families were included for analysis only if the age at diagnosis of RCC was available for all affected individuals (Fig. 1). For family members reported to be mutation positive but not diagnosed with RCC, we collected information on the last age at which they were unaffected by RCC. Information on age of onset for cutaneous and uterine leiomyomas was also collected from the publications reviewed. Statistical analysis We chose to analyse age of onset of RCC because this is uniform and easy to diagnose requiring fewer assumptions. For mutation-positive individuals not diagnosed with RCC, we recorded the age for which they were last reported to be well. Methods The normal random effects model that accounts for right censoring is used to model the age at which the disease was
diagnosis. The following is the proposed model where the subscripts j and i correspond to the j-th individual in the i-th family: Tij ¼ bi0 þ b1 Xij1 þ b2 Xij2 þ eij ;
ð1Þ
Note that bi0 is a family-specific random effect, b’s are the fixed effect parameters. Using the third generation as the reference group, Xij1 and Xij2 indicate the j-th individual is from the first and second generation in the i-th family respectively, and eij is the residual with mean zero and a given variance component. The random family effect accounts for the within family correlation and is assumed to be independent and identically distribution with a normal distribution. Tij represents the age at diagnosis, or ascertainment which depends on whether the individual had the event of interest. In the analysis, we remove all individuals with unknown age information and set the oldest generation as the first generation. We also performed a sensitivity analysis by removing age corresponding to age at death for RCC and removing those reported with leiomyosarcoma for uterine leiomyoma. The analyses are performed with the statistical program STATA, Release 13. We also analyzed age of onset for uterine leiomyomas (Table 1). The true prevalence of uterine leiomyomas is likely to be under-estimated [24], as there is a tendency for uterine leiomyomas to be asymptomatic [25]. We also did not analyse the age of onset of cutaneous leiomyomas (Table 2) as this was dependent on the patient’s recollection of when they first noticed it, and some patients did not notice the cutaneous leiomyoma(s) which was discovered by their doctor on clinical examination.
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M. H. Wong et al. Table 1 Families in which uterine leiomyomas were diagnosed in at least two generations and age of diagnosis was available Family with uterine leiomyoma
Age of affected individual from older generation
1
36
Age of affected individual from younger generation
Relationship
27
Mother–daughter
27 23 35 28
49
65 27
9
Aunt–niece
Tolvanen et al. [32]
13 1
23
Mother–daughter
5
27
Aunt–niece
1
27
1
35
-7
27
Reported
9
Aunt–niece
22
27
22
23
26
35 2
Difference in age
14
31
Mother–daughter
34
30
Aunt–niece
35
31
Aunt–niece
-4
30
Smit et al. [33]
-3
3
38
24
Aunt–niece
4 5
39 35
37 27
Mother–daughter Mother–daughter
14 2 8
Frey et al. [27]
6
33
23
Mother–daughter
10
7
20-30
20–30
Mother–daughter
–
Varol et al. [35]
8
27a
23
Aunt–niece
4
Kiuru et al. [36]
9
40
34 40
-7 Mother–daughter
6
37
3
39
a
-4 -8
35a
5
39
1
40a
39
Launonen et al. [37]
1 Aunt–niece
48
35a
0
34
44
Lehtonen et al. [34]
0
29
Grandaunt–grandniece
11
25 29
Mother–daughter
15 6
25
Aunt–niece
10
25
Mother–daughter
14
29
Aunt–niece
10
Leiomyosarcoma
Results Clinical findings Clinico-pathological and tumour characteristics of the 10 affected individuals from 4 HLRCC families identified in Singapore are summarised in Tables 3 and 4
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respectively. With the exception of one kindred, all the patients are Singaporeans of Chinese ethnicity. The mean age at diagnosis of RCC was 39.1 years (range 17–69 years). 6/9 (66.7 %) of patients presented with metastatic RCC at diagnosis, of which 2/9 (22.2 %) had bilateral RCC. All the tumours were evaluated as histological grade 4.
Potential genetic anticipation Table 2 Families in which cutaneous leiomyomas were diagnosed in at least two generations and age of diagnosis was available
Family with cutaneous leiomyoma
Age of affected individual from older generation
1
40–50
Age of affected individual from younger generation
Relationship
Reported
40–50
Mother–son
Heinritz et al. [38]
17
First cousin once removed
2
30–40
30–40
Mother–son
Chan et al. 2005 [39]
3
31
35
Aunt–nephew
Kiuru et al. [36]
28
Grandaunt–grandniece
4
10
Grandaunt–grandnephew
35
10 28
Father–son Uncle–niece
18
10–20
Mother–daughter
Konig et al. [40]
Table 3 Summary of clinico-pathological and genetic characteristics of affected families and their members Family
Patient/ gender
Ethnicity
Mutation
RCC/age of onset
Leiomyoma
Current status
1
Proband 1/M
Chinese
c.1123delA/
Y/17
None
Died of RCC at age 19
p. T375Lfs*6
Y/45
None
Died of RCC at age 50
Uncle 2/M
Y/34
None
Died of RCC at age 37
Grandmother/F
Y/69
None
Died of RCC at age 72
c.698G[A/
Y/27
Uterine only
Alive with disease
p.R233H
Y/47
None
Died of RCC at age 48
Y/56 Y/34
None None
Died of RCC at age 58 Died of RCC at age 34
Y/35
None
Died of RCC at age 35
Uncle 1/M
2
Proband 2/F
Chinese
Father/M Uncle 1/M Uncle 2/M 3
Proband 3/M
Chinese
c.569G[A/
4
Proband 4/F
Arab
c.425A[G/
Y/27
Uterine only
Died of RCC at age 27
Mother/F
Arab
p.Q142R
Unknown/unknown
Uterine
Died of intra-abdominal cancer at age 45
p.R190H
Table 4 RCC characteristics Patient
Metastatic RCC
Sites of metastasis
AJCC7 stage
Radiological findings
Histology and Fuhrman grade
Bone
Lung
LN
Liver
T
N
M
Size* (cm)/extent
Proband 1
At dx
?
?
?
-
1b
1
0
5.3/right
Son 1
5 year after dx
?
?
?
-
3b
1
0
4.9/bilateral
sRCC, 4
Son 2
At dx
?
-
?
-
1a
1
1
1.0/left
sRCC, 4
Grand-mother
At dx
-
-
?
-
4
1
1
9.0/right
No data
Proband 2
Non applicable
3a
0
0
6.0/left
4
Father
At dx
?
-
Unk
-
2
9
1
Unk/bilateral
sRCC, 4
Uncle 1 Uncle 2
At dx No data
?
?
-
-
3b 0 No data
1
8.3/left
sRCC, 4
Proband 3
At dx
?
?
?
?
4
1
1
20.0/right
Papillary, 4
Proband 4
At dx
?
-
?
-
1b
1
1
6.0/left
sRCC, 4
sRCC, 4
LN lymph node, Size* greatest diameter, Dx diagnosis, sRCC sarcomatoid renal cell carcinoma, Unk unknown
We first observed decreasing age of onset of RCC in successive generations in a 3-generation, non-consanguineous family affected with HLRCC syndrome (Fig. 2). The proband
of Family 1 presented with metastatic RCC at age 17. He had two uncles who were diagnosed with RCC at ages 45 and 34. His grandmother was diagnosed with RCC at 69 years old.
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Fig. 2 Pedigrees of HLRCC kindreds identified in Singapore
Genetic anticipation in onset of RCC was similarly, albeit less strongly, suggested by Family 2. The proband from this family had a history of symptomatic uterine leiomyomas and was diagnosed with left-sided RCC at 27 years old. Her father was diagnosed at age 45 with bilateral RCC. She had six paternal uncles, of whom two were diagnosed with RCC at 56 and 34 years old. The proband of Family 3 was an ethnic Chinese male of age 35. He presented with sporadic RCC, but HLRCC syndrome was suspected because of his relatively young age, alongside the papillary RCC histology. Additionally, both his mother and sister had a history of benign uterine tumours. His maternal uncle had a tumour on the hand, but no histological information for this was available. The proband of Family 4 was a 27 year old ethnic Arab lady from Oman. Similar to the proband of Family 2, she had a history of symptomatic uterine leiomyomas, and was diagnosed with metastatic RCC at age 27. Her mother previously had excision of uterine fibroids and was deceased at age 45 from an intra-abdominal tumour. Her parents were first cousins.
individuals not all available) was reported by Grubb et al. [26]. In families with three affected generations, the difference in age between the first and third generation at which RCC was diagnosed ranged from 41 to 54 years (Table 5). Statistical analysis Comparing the age at which RCC was diagnosed between the first and second generations, the mean difference is -18.6 years (95 % CI -26.6 to -10.6, p \ 0.001), suggesting reduced age of diagnosis in the younger generation (Table 6). Comparing the age at diagnosis between the first and third generation within a family, the mean difference is -36.2 years (95 % CI -47.0 to -25.4, p \ 0.001). Similar conclusions were obtained in the sensitivity analysis. The same analysis was applied to the data on families with two generations affected with uterine leiomyoma. No evidence of anticipation was observed (Table 7).
Literature review Discussion Nine families with available information were identified using the described search strategy (Table 5). The mean difference in age at which RCC was diagnosed between 11 parent–child pairs was 22.4 years (range 6–35 years). Eight of the parent–child pairs were from reported literature, and three were from our series of patients. To our knowledge, only three families in which RCC was diagnosed in three consecutive generations have been reported. One family was reported in this series (Fig. 2), family #9 (Table 5) and the third family (age at diagnosis for affected
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Alongside our observations of four HLRCC families with two novel mutations, we observed reduced age onset in each successive generation in two pedigrees, particularly reminiscent of anticipation and reviewed the literature to evaluate this possibility. Although only a small number of families with clear age information of disease onset could be identified, our findings support a potential consideration of genetic anticipation that could be answered by a large multi-center study.
Potential genetic anticipation Table 5 Families in which RCC was diagnosed in at least two generations and age at which RCC was diagnosed was available
Family
Age of affected individual from older generation
Age of affected individual from younger generation
Relationship
Difference in age
Reported
1
47
31
Father–son
16
Raymond et al. [4]
2
37
11*
Aunt–nephew
26
Alrashdi et al. [5]
40
11*
29
65
40
Uncle– nephew Mother– daughter
69
Mother–son
-4
3
4
50
40
Father–son
10
Soni et al. [28]
65a
21
Grandfather– grandson
44
Ahvenainen et al. [29]
6
40
17
Father–son
23
Refae et al. [6]
7
68
38
Father–son
30
Wei et al. [3]
8
48
42**
Mother– daughter
6
Vahteristo et al. [30]
33***
Aunt–niece
26
42**
First-cousin once removed
-3
33*** 42** 33***
First-cousin once removed
10 19
52
9
10
71****
Aunt–nephew
19
71****
49
Father– daughter
22
36
Father– daughter
35
69
45
Mother–son
24
34
Mother–son
35
17
Grandmother– grandson
52
47
27*****
Father– daughter
20
34
27*****
Uncle–niece
13
56
27*****
Uncle–niece
29
Age of death from RCC, not age of diagnosis FH mutation positive but atypical HLRCC histology (clear cell), lack second FH hit in the tumour, and late age at disease onset
11
6
90b
a
b
Frey et al. [27]
5
39
*; **; ***; ****; ***** indicate same individual
25
Vahteristo et al. [30], Lehtonen et al. [30, 31]
This series
This series
Table 6 Parameter estimates of the fixed effect of generations on the age of diagnosis of RCC from all family members
Table 7 Parameter estimates of the fixed effect of generations on the age of diagnosis of uterine leiomyoma from all family members
Parameter
Parameter estimate
95 % CI
Variable
Parameter estimate
Standard error
p value
Overall p value
Second generation
-18.6
-26.6 to -10.6 \0.001 \0.001
First generation
6.4
-4.8 to 17.5
0.263
0.349
Third generation
-36.2
-47.0 to -25.4 \0.001
Third generation
2.1
-7.7 to 11.9
0.675
p value
Overall p value
It is challenging to develop surveillance recommendations for HLRCC, but the potential effect from anticipation demonstrated here supports the need to initiate surveillance programs at a young age. For example, an 18 year old woman from a previously described Dutch HLRCC kindred, presented unexpectedly early with metastatic renal cancer and died 8 months after diagnosis. About 7 % of HLRCC
patients are diagnosed with RCC before age 20 [7], with the youngest diagnosed at 11 years old [5]. Early intervention to minimise morbidity and mortality is a primary goal in cancer predisposition syndromes. Many of these issues have been carefully discussed by van Spaendonck-Zwarts et al. [7], particularly in relation to initiating of surveillance during childhood. The purpose of surveillance is the reduction of
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morbidity and mortality through pre-symptomatic detection and effective treatment which alters the natural history of the disease. Given that the primary life-limiting feature of this syndrome is renal cell carcinoma, and considering the potential effect of anticipation, we agree with van Spaendonck-Zwarts et al. that renal surveillance using noninvasive techniques that minimize distress such as ultrasound would be most suitable from the age of 10. One limitation in this study was that there is limited multigenerational age information reported in the literature. Several two-generation families had incomplete information for ages at diagnosis of RCC and had to be excluded. This data may potentially have revealed findings that contradict our hypothesis but all available cases were recruited. Additionally, we could not exclude birth cohort effects or a common environmental exposure that may possibly account for anticipation. There are also potential ascertainment biases arising from referral, incomplete information on the most recent generation, as well as potentially reduced fertility intrinsic with rare disorders that may account for this. Nonetheless, our data represents a reasonable summary and analysis of best available information, and an approach using an international registry may be useful to evaluate this interesting observation. In conclusion, we report preliminary evidence of genetic anticipation in HLRCC syndrome based on observation of affected patients, as well as a comprehensive literature evaluation surveying all reported HLRCC kindreds. External validation of this observation would have implications for surveillance of patients. Acknowledgments We would like to thank all our patients, and referring clinicians, particularly Dr. John Yuen and Dr. Sim Hong Gee of the Department of Urology, Singapore General Hospital.
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7. van Spaendonck-Zwarts KY, Badeloe S, Oosting SF et al (2012) Hereditary leiomyomatosis and renal cell cancer presenting as metastatic kidney cancer at 18 years of age: implications for surveillance. Fam Cancer 11:123–129 8. Ooi A, Furge KA (2012) Fumarate hydratase inactivation in renal tumors: HIF1alpha, NRF2 and ‘‘cryptic targets’’ of transcription factors. Chin J Cancer 9. Dagan E, Gershoni-Baruch R (2002) Anticipation in hereditary breast cancer. Clin Genet 62:147–150 10. Martinez-Borges AR, Petty JK, Hurt G et al (2009) Familial small cell carcinoma of the ovary. Pediatr Blood Cancer 53:1334–1336 11. Wiernik PH, Ashwin M, Hu XP et al (2001) Anticipation in familial chronic lymphocytic leukaemia. Br J Haematol 113:407–414 12. Rumi E, Passamonti F, Della Porta MG et al (2007) Familial chronic myeloproliferative disorders: clinical phenotype and evidence of disease anticipation. J Clin Oncol 25:5630–5635 13. Schneider R, Slater EP, Sina M et al (2011) German national case collection for familial pancreatic cancer (FaPaCa): ten years experience. Fam Cancer 10:323–330 14. Bonora E, Tallini G, Romeo G (2010) Genetic predisposition to familial nonmedullary thyroid cancer: an update of molecular findings and state-of-the-art studies. J Oncol 2010:385206 15. Siegel AM, Andermann F, Badhwar A et al (1998) Anticipation in familial cavernous angioma: ascertainment bias or genetic cause. Acta Neurol Scand 98:372–376 16. Westphalen AA, Russell AM, Buser M et al (2005) Evidence for genetic anticipation in hereditary non-polyposis colorectal cancer. Hum Genet 116:461–465 17. Bozzao C, Lastella P, Stella A (2011) Anticipation in lynch syndrome: where we are where we go. Curr Genomics 12:451–465 18. Tabori U, Nanda S, Druker H et al (2007) Younger age of cancer initiation is associated with shorter telomere length in Li-Fraumeni syndrome. Cancer Res 67:1415–1418 19. Martinez-Delgado B, Yanowsky K, Inglada-Perez L et al (2011) Genetic anticipation is associated with telomere shortening in hereditary breast cancer. PLoS Genet 7:28 20. Coolbaugh-Murphy MI, Xu JP, Ramagli LS et al (2010) Microsatellite instability in the peripheral blood leukocytes of HNPCC patients. Hum Mutat 31:317–324 21. Tsai YY, Petersen GM, Booker SV et al (1997) Evidence against genetic anticipation in familial colorectal cancer. Genet Epidemiol 14:435–446 22. Boonstra PS, Gruber SB, Raymond VM et al (2010) A review of statistical methods for testing genetic anticipation: looking for an answer in Lynch syndrome. Genet Epidemiol 34:756–768 23. Bayley JP, Launonen V, Tomlinson IP (2008) The FH mutation database: an online database of fumarate hydratase mutations involved in the MCUL (HLRCC) tumor syndrome and congenital fumarase deficiency. BMC Med Genet 9:20 24. Newbold RR, DiAugustine RP, Risinger JI et al (2000) Advances in uterine leiomyoma research: conference overview, summary, and future research recommendations. Environ Health Perspect 108(Suppl 5):769–773 25. Baird DD, Dunson DB, Hill MC et al (2003) High cumulative incidence of uterine leiomyoma in black and white women: ultrasound evidence. Am J Obstet Gynecol 188:100–107 26. Grubb RL 3rd, Franks ME, Toro J et al (2007) Hereditary leiomyomatosis and renal cell cancer: a syndrome associated with an aggressive form of inherited renal cancer. J Urol 177:2074–2079 27. Frey MK, Worley MJ Jr, Heyman KP et al (2010) A case report of hereditary leiomyomatosis and renal cell cancer. Am J Obstet Gynecol 202:e8–e9 28. Soni SS, Gowrishankar S, Adikey GK et al (2008) Hereditary leiomyomatosis with renal cell carcinoma. Indian J Dermatol Venereol Leprol 74:63–64
Potential genetic anticipation 29. Ahvenainen T, Lehtonen HJ, Lehtonen R et al (2008) Mutation screening of fumarate hydratase by multiplex ligation-dependent probe amplification: detection of exonic deletion in a patient with leiomyomatosis and renal cell cancer. Cancer Genet Cytogenet 183:83–88 30. Vahteristo P, Koski TA, Naatsaari L et al (2010) No evidence for a genetic modifier for renal cell cancer risk in HLRCC syndrome. Fam Cancer 9:245–251 31. Lehtonen HJ, Kiuru M, Ylisaukko-Oja SK et al (2006) Increased risk of cancer in patients with fumarate hydratase germline mutation. J Med Genet 43:523–526 32. Tolvanen J, Uimari O, Ryynanen M et al (2012) Strong family history of uterine leiomyomatosis warrants fumarate hydratase mutation screening. Hum Reprod 27:1865–1869 33. Smit DL, Mensenkamp AR, Badeloe S et al (2011) Hereditary leiomyomatosis and renal cell cancer in families referred for fumarate hydratase germline mutation analysis. Clin Genet 79:49–59 34. Lehtonen HJ, Blanco I, Piulats JM et al (2007) Conventional renal cancer in a patient with fumarate hydratase mutation. Hum Pathol 38:793–796
35. Varol A, Stapleton K, Roscioli T (2006) The syndrome of hereditary leiomyomatosis and renal cell cancer (HLRCC): the clinical features of an individual with a fumarate hydratase gene mutation. Australas J Dermatol 47:274–276 36. Kiuru M, Launonen V, Hietala M et al (2001) Familial cutaneous leiomyomatosis is a two-hit condition associated with renal cell cancer of characteristic histopathology. Am J Pathol 159:825–829 37. Launonen V, Vierimaa O, Kiuru M et al (2001) Inherited susceptibility to uterine leiomyomas and renal cell cancer. Proc Natl Acad Sci USA 98:3387–3392 38. Heinritz W, Paasch U, Sticherling M et al (2008) Evidence for a founder effect of the germline fumarate hydratase gene mutation R58P causing hereditary leiomyomatosis and renal cell cancer (HLRCC). Ann Hum Genet 72:35–40 39. Chan I, Wong T, Martinez-Mir A et al (2005) Familial multiple cutaneous and uterine leiomyomas associated with papillary renal cell cancer. Clin Exp Dermatol 30:75–78 40. Konig A, Happle R (2000) Two cases of type 2 segmental manifestation in a family with cutaneous leiomyomatosis. Eur J Dermatol 10:590–592
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ORIGINAL ARTICLE
Potential genetic anticipation in hereditary leiomyomatosis-renal cell cancer (HLRCC) Mei Hua Wong • Chuen Seng Tan • Soo Chin Lee • Yvonne Yong • Aik Seng Ooi Joanne Ngeow • Min Han Tan
•
Ó Springer Science+Business Media Dordrecht 2014
Abstract Hereditary leiomyomatosis-renal cell cancer (HLRCC) is an autosomal dominant disorder characterised by cutaneous leiomyomas, symptomatic uterine leiomyomas and aggressive type II papillary renal cell carcinoma. It is caused by heterozygous mutations in the fumarate hydratase (FH) gene on chromosome 1q43. We present evidence of genetic anticipation in HLRCC syndrome. A comprehensive literature review was performed to determine the potential for genetic anticipation in HLRCC syndrome. The normal random effects model was used to evaluate for genetic anticipation to ensure reduction in bias. A total of 11 FH kindreds with available multi-generational data were identified for analysis. The mean difference in age at diagnosis of RCC between the first and second generation was -18.6 years (95 % CI -26.6 to -10.6, p \ 0.001). The mean difference in age at diagnosis of RCC between the first and third generation was
M. H. Wong J. Ngeow M. H. Tan (&) Department of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore e-mail: [email protected] C. S. Tan Department of Epidemiology and Public Health, National University of Singapore, Singapore, Singapore S. C. Lee Y. Yong Cancer Science Institute, National University of Singapore, Singapore, Singapore A. S. Ooi Laboratory of Interdisciplinary Urological Oncology, Van Andel Research Institute, Grand Rapids, MI, USA M. H. Tan Institute of Bioengineering and Nanotechnology, Singapore, Singapore
-36.2 years (95 % CI -47.0 to -25.4, p \ 0.001). No evidence of anticipation for uterine leiomyomas was observed (p = 0.349). We report preliminary evidence of genetic anticipation of RCC in HLRCC syndrome. Additional clinical validation is important to confirm this observation, which may have practical implications on counseling and timing of surveillance initiation. Exploration of the underlying mechanisms of anticipation in HLRCC would be of considerable biological interest. Keywords Fumarate hydratase Genetic anticipation Krebs cycle Hereditary leiomyomatosis-renal cell carcinoma syndrome Papillary renal cell carcinoma
Introduction Hereditary leiomyomatosis and renal cell cancer (HLRCC), also known as Reed syndrome, is characterised by variable development of multiple cutaneous leiomyomas, symptomatic uterine leiomyomas (uterine fibroids) and aggressive type II papillary renal cell carcinoma [1]. HLRCC is transmitted in an autosomal dominant fashion with incomplete penetrance. The lifetime risk of renal cancer in HLRCC has not been clarified. In cohorts of families, the prevalence of renal cancer varies widely. The prevalence been reported to be 2–6 % in the UK [2], and 62 % in US for families seen at the National Cancer Institute [3]. The differences in reported prevalence may be in part due to differences in the recruitment approaches [3]. A reasonable summary of the prevalence from the literature has been suggested to be between 20 and 25 % [4]. Of note, the youngest age at diagnosis of RCC is 11 years old, in an asymptomatic child with a confirmed mutation in the FH gene who underwent screening imaging [5]. Further,
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metastatic RCC has been diagnosed in several patients in their late teens, between 16 and 18 years, and all were deceased before 20 years old [2, 6, 7]. Hereditary leiomyomatosis-renal cell cancer is due to mutations of the fumarate hydratase (FH) gene which is located on chromosome 1q43. The gene consists of 10 exons, encoding fumarase, which is an enzyme that catalyses the reversible hydration and dehydration reactions between fumarate and malate. Fumarase exists in both mitochondrial and cytosolic forms; the mitochondrial isoenzyme participates in the Krebs cycle, and the cytosolic form participates in amino acid and fumarate metabolism. The oncogenic mechanisms of FH inactivation are being actively investigated, with two main competing theories [8]. The best studied theory is that FH inactivation results in activation of the hypoxia-inducible factor through increased expression of its alpha-subunit. An alternative theory suggests that inactivated FH leads to activation of nuclear factor (erythroid-derived 2)-like 2 (NRF2) as the primary oncogenic mechanism. Genetic anticipation refers to the earlier onset of disease, increased burden or both in succeeding generations of a family afflicted with a hereditary disorder. This phenomenon has been reported in certain degenerative disorders, as well as a number of cancers such as hereditary breast cancer [9], ovarian cancer [10], chronic lymphocytic leukaemia [11], myeloproliferative neoplasms (MPN) [12], pancreatic cancer [13], non-medullary thyroid carcinoma [14] and cavernous angioma [15]. Genetic anticipation has also been observed in Lynch syndrome [16, 17] and Li Fraumeni syndrome (LFS) [18]. To date, this has not been reported in any hereditary kidney cancer syndrome, including HLRCC syndrome. The genetic basis for anticipation in several neuromuscular diseases has been shown to be attributable to generational expansion of a repeated trinucleotide segment of DNA. Telomere attrition has been suggested to be the biological basis of anticipation in LFS [18], familial MPN [12] and hereditary breast cancer [19]. In familial MPN, it has been shown that affected individuals have shorter telomeres than the reference population and the secondgeneration have significant shortening relative to the firstgeneration patients [12]. In LFS, the proposed mechanism is that a threshold for telomere length exists, below which the risk of cancer initiation is high. Affected individuals with shorter telomeres reach this threshold faster within their lifetime [18]. In patients with Lynch syndrome, the average frequencies of mutant microsatellite fragments in non-tumour cells heterozygous for germline MMR mutations has been demonstrated to be significantly higher than age-matched normal controls. It has been postulated that such instability may also occur in germ cells such that mutant alleles are passed on to offspring at a higher
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frequency [20]. These proposed molecular mechanisms commonly suggest that the basis is an unstable mutation which is magnified in subsequent generations. Demonstrating genetic anticipation in familial cancers has been difficult as there are multiple sources of bias that can influence findings of genetic anticipation. Tsai et al. investigated genetic anticipation in 308 pedigrees with Lynch Syndrome, and found no evidence to support anticipation, concluding that apparent anticipation appears to reflect a birth cohort bias of ascertainment [21]. Certainly, ascertainment bias is an important consideration as families with early-onset cases tend to be preferentially selected and constitutes a sampling error. Another bias that can be introduced is the change in screening practices over time. For example, in Lynch syndrome, the interval between colonoscopies may be shortened or the mean age of first colonoscopy may be reduced. Similarly in HLRCC, radiological screening may be performed earlier or more frequently. From earlier studies that investigate genetic anticipation in other familial cancers, most prominently Lynch Syndrome, the importance of selecting appropriate statistical techniques to account for these biases has become evident [22]. The motivation for this study was our observation of possible genetic anticipation in the HLRCC families under our care. We therefore undertook a comprehensive examination of the worldwide literature to evaluate if this observation might be supported by other reports of HLRCC families with multi-generational information on age of diagnosis of RCC.
Patients and methods Local patient selection Subjects were identified through comprehensive review of patients seen at the clinical cancer genetics services in the National Cancer Centre Singapore and National University Hospital, Singapore, since 2002. Genetic counseling was performed by specialized clinical cancer geneticists before informed consent was taken to obtain blood samples for genetic testing. Patients and their families with confirmed FH mutations who presented to the National Cancer Centre and National University Hospital’s cancer genetics services were selected for the study. Institutional Review Board approval was obtained for this study. Ascertainment of patients Diagnosis of RCC was confirmed with a histopathological specimen for all of our patients, although the detailed histological report was not available for two individuals.
Potential genetic anticipation
Bidirectional exon sequencing for the ten exons of FH was conducted for all probands, and mutations confirmed using accredited clinical laboratory services. Mutations were cross-checked with the TCA Cycle Gene Mutation database [23] to determine if they had been previously reported. The diagnosis of uterine leiomyomas for probands 2 and 4 was based on radiological imaging. The mother of proband 4 was deceased at age 45 and her medical records were not accessible; her history of uterine leiomyoma was based on the account of proband 4. All probands were evaluated by a clinical cancer geneticist, and received abdominal and pelvic imaging for evaluation of renal cancer and uterine leiomyomas where appropriate. Dermatology consultation was not obtained. Literature search strategy Fig. 1 CONSORT flow diagram. RCC indicates renal cell carcinoma
A systematic search was performed using PubMed. The search strategy, ‘‘(HLRCC OR hereditary leiomyomatosis and renal cell carcinoma OR ‘‘Reed’s syndrome’’ OR ‘‘Reed syndrome’’ OR Leiomyomatosis and renal cell cancer, hereditary OR FH OR multiple cutaneous and uterine leiomyomata OR leiomyomata, multiple cutaneous)’’, retrieved 276 articles on 22 Dec 2012. Two independent reviewers evaluated all abstracts for reported HLRCC kindreds. The full text was obtained if the following criteria were fulfilled, (1) contains clinical description of family history, (2) not a review, (3) article in English. 61 publications were reviewed to identify kindreds in which RCC were manifest in at least two generations. Families were included for analysis only if the age at diagnosis of RCC was available for all affected individuals (Fig. 1). For family members reported to be mutation positive but not diagnosed with RCC, we collected information on the last age at which they were unaffected by RCC. Information on age of onset for cutaneous and uterine leiomyomas was also collected from the publications reviewed. Statistical analysis We chose to analyse age of onset of RCC because this is uniform and easy to diagnose requiring fewer assumptions. For mutation-positive individuals not diagnosed with RCC, we recorded the age for which they were last reported to be well. Methods The normal random effects model that accounts for right censoring is used to model the age at which the disease was
diagnosis. The following is the proposed model where the subscripts j and i correspond to the j-th individual in the i-th family: Tij ¼ bi0 þ b1 Xij1 þ b2 Xij2 þ eij ;
ð1Þ
Note that bi0 is a family-specific random effect, b’s are the fixed effect parameters. Using the third generation as the reference group, Xij1 and Xij2 indicate the j-th individual is from the first and second generation in the i-th family respectively, and eij is the residual with mean zero and a given variance component. The random family effect accounts for the within family correlation and is assumed to be independent and identically distribution with a normal distribution. Tij represents the age at diagnosis, or ascertainment which depends on whether the individual had the event of interest. In the analysis, we remove all individuals with unknown age information and set the oldest generation as the first generation. We also performed a sensitivity analysis by removing age corresponding to age at death for RCC and removing those reported with leiomyosarcoma for uterine leiomyoma. The analyses are performed with the statistical program STATA, Release 13. We also analyzed age of onset for uterine leiomyomas (Table 1). The true prevalence of uterine leiomyomas is likely to be under-estimated [24], as there is a tendency for uterine leiomyomas to be asymptomatic [25]. We also did not analyse the age of onset of cutaneous leiomyomas (Table 2) as this was dependent on the patient’s recollection of when they first noticed it, and some patients did not notice the cutaneous leiomyoma(s) which was discovered by their doctor on clinical examination.
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M. H. Wong et al. Table 1 Families in which uterine leiomyomas were diagnosed in at least two generations and age of diagnosis was available Family with uterine leiomyoma
Age of affected individual from older generation
1
36
Age of affected individual from younger generation
Relationship
27
Mother–daughter
27 23 35 28
49
65 27
9
Aunt–niece
Tolvanen et al. [32]
13 1
23
Mother–daughter
5
27
Aunt–niece
1
27
1
35
-7
27
Reported
9
Aunt–niece
22
27
22
23
26
35 2
Difference in age
14
31
Mother–daughter
34
30
Aunt–niece
35
31
Aunt–niece
-4
30
Smit et al. [33]
-3
3
38
24
Aunt–niece
4 5
39 35
37 27
Mother–daughter Mother–daughter
14 2 8
Frey et al. [27]
6
33
23
Mother–daughter
10
7
20-30
20–30
Mother–daughter
–
Varol et al. [35]
8
27a
23
Aunt–niece
4
Kiuru et al. [36]
9
40
34 40
-7 Mother–daughter
6
37
3
39
a
-4 -8
35a
5
39
1
40a
39
Launonen et al. [37]
1 Aunt–niece
48
35a
0
34
44
Lehtonen et al. [34]
0
29
Grandaunt–grandniece
11
25 29
Mother–daughter
15 6
25
Aunt–niece
10
25
Mother–daughter
14
29
Aunt–niece
10
Leiomyosarcoma
Results Clinical findings Clinico-pathological and tumour characteristics of the 10 affected individuals from 4 HLRCC families identified in Singapore are summarised in Tables 3 and 4
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respectively. With the exception of one kindred, all the patients are Singaporeans of Chinese ethnicity. The mean age at diagnosis of RCC was 39.1 years (range 17–69 years). 6/9 (66.7 %) of patients presented with metastatic RCC at diagnosis, of which 2/9 (22.2 %) had bilateral RCC. All the tumours were evaluated as histological grade 4.
Potential genetic anticipation Table 2 Families in which cutaneous leiomyomas were diagnosed in at least two generations and age of diagnosis was available
Family with cutaneous leiomyoma
Age of affected individual from older generation
1
40–50
Age of affected individual from younger generation
Relationship
Reported
40–50
Mother–son
Heinritz et al. [38]
17
First cousin once removed
2
30–40
30–40
Mother–son
Chan et al. 2005 [39]
3
31
35
Aunt–nephew
Kiuru et al. [36]
28
Grandaunt–grandniece
4
10
Grandaunt–grandnephew
35
10 28
Father–son Uncle–niece
18
10–20
Mother–daughter
Konig et al. [40]
Table 3 Summary of clinico-pathological and genetic characteristics of affected families and their members Family
Patient/ gender
Ethnicity
Mutation
RCC/age of onset
Leiomyoma
Current status
1
Proband 1/M
Chinese
c.1123delA/
Y/17
None
Died of RCC at age 19
p. T375Lfs*6
Y/45
None
Died of RCC at age 50
Uncle 2/M
Y/34
None
Died of RCC at age 37
Grandmother/F
Y/69
None
Died of RCC at age 72
c.698G[A/
Y/27
Uterine only
Alive with disease
p.R233H
Y/47
None
Died of RCC at age 48
Y/56 Y/34
None None
Died of RCC at age 58 Died of RCC at age 34
Y/35
None
Died of RCC at age 35
Uncle 1/M
2
Proband 2/F
Chinese
Father/M Uncle 1/M Uncle 2/M 3
Proband 3/M
Chinese
c.569G[A/
4
Proband 4/F
Arab
c.425A[G/
Y/27
Uterine only
Died of RCC at age 27
Mother/F
Arab
p.Q142R
Unknown/unknown
Uterine
Died of intra-abdominal cancer at age 45
p.R190H
Table 4 RCC characteristics Patient
Metastatic RCC
Sites of metastasis
AJCC7 stage
Radiological findings
Histology and Fuhrman grade
Bone
Lung
LN
Liver
T
N
M
Size* (cm)/extent
Proband 1
At dx
?
?
?
-
1b
1
0
5.3/right
Son 1
5 year after dx
?
?
?
-
3b
1
0
4.9/bilateral
sRCC, 4
Son 2
At dx
?
-
?
-
1a
1
1
1.0/left
sRCC, 4
Grand-mother
At dx
-
-
?
-
4
1
1
9.0/right
No data
Proband 2
Non applicable
3a
0
0
6.0/left
4
Father
At dx
?
-
Unk
-
2
9
1
Unk/bilateral
sRCC, 4
Uncle 1 Uncle 2
At dx No data
?
?
-
-
3b 0 No data
1
8.3/left
sRCC, 4
Proband 3
At dx
?
?
?
?
4
1
1
20.0/right
Papillary, 4
Proband 4
At dx
?
-
?
-
1b
1
1
6.0/left
sRCC, 4
sRCC, 4
LN lymph node, Size* greatest diameter, Dx diagnosis, sRCC sarcomatoid renal cell carcinoma, Unk unknown
We first observed decreasing age of onset of RCC in successive generations in a 3-generation, non-consanguineous family affected with HLRCC syndrome (Fig. 2). The proband
of Family 1 presented with metastatic RCC at age 17. He had two uncles who were diagnosed with RCC at ages 45 and 34. His grandmother was diagnosed with RCC at 69 years old.
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Fig. 2 Pedigrees of HLRCC kindreds identified in Singapore
Genetic anticipation in onset of RCC was similarly, albeit less strongly, suggested by Family 2. The proband from this family had a history of symptomatic uterine leiomyomas and was diagnosed with left-sided RCC at 27 years old. Her father was diagnosed at age 45 with bilateral RCC. She had six paternal uncles, of whom two were diagnosed with RCC at 56 and 34 years old. The proband of Family 3 was an ethnic Chinese male of age 35. He presented with sporadic RCC, but HLRCC syndrome was suspected because of his relatively young age, alongside the papillary RCC histology. Additionally, both his mother and sister had a history of benign uterine tumours. His maternal uncle had a tumour on the hand, but no histological information for this was available. The proband of Family 4 was a 27 year old ethnic Arab lady from Oman. Similar to the proband of Family 2, she had a history of symptomatic uterine leiomyomas, and was diagnosed with metastatic RCC at age 27. Her mother previously had excision of uterine fibroids and was deceased at age 45 from an intra-abdominal tumour. Her parents were first cousins.
individuals not all available) was reported by Grubb et al. [26]. In families with three affected generations, the difference in age between the first and third generation at which RCC was diagnosed ranged from 41 to 54 years (Table 5). Statistical analysis Comparing the age at which RCC was diagnosed between the first and second generations, the mean difference is -18.6 years (95 % CI -26.6 to -10.6, p \ 0.001), suggesting reduced age of diagnosis in the younger generation (Table 6). Comparing the age at diagnosis between the first and third generation within a family, the mean difference is -36.2 years (95 % CI -47.0 to -25.4, p \ 0.001). Similar conclusions were obtained in the sensitivity analysis. The same analysis was applied to the data on families with two generations affected with uterine leiomyoma. No evidence of anticipation was observed (Table 7).
Literature review Discussion Nine families with available information were identified using the described search strategy (Table 5). The mean difference in age at which RCC was diagnosed between 11 parent–child pairs was 22.4 years (range 6–35 years). Eight of the parent–child pairs were from reported literature, and three were from our series of patients. To our knowledge, only three families in which RCC was diagnosed in three consecutive generations have been reported. One family was reported in this series (Fig. 2), family #9 (Table 5) and the third family (age at diagnosis for affected
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Alongside our observations of four HLRCC families with two novel mutations, we observed reduced age onset in each successive generation in two pedigrees, particularly reminiscent of anticipation and reviewed the literature to evaluate this possibility. Although only a small number of families with clear age information of disease onset could be identified, our findings support a potential consideration of genetic anticipation that could be answered by a large multi-center study.
Potential genetic anticipation Table 5 Families in which RCC was diagnosed in at least two generations and age at which RCC was diagnosed was available
Family
Age of affected individual from older generation
Age of affected individual from younger generation
Relationship
Difference in age
Reported
1
47
31
Father–son
16
Raymond et al. [4]
2
37
11*
Aunt–nephew
26
Alrashdi et al. [5]
40
11*
29
65
40
Uncle– nephew Mother– daughter
69
Mother–son
-4
3
4
50
40
Father–son
10
Soni et al. [28]
65a
21
Grandfather– grandson
44
Ahvenainen et al. [29]
6
40
17
Father–son
23
Refae et al. [6]
7
68
38
Father–son
30
Wei et al. [3]
8
48
42**
Mother– daughter
6
Vahteristo et al. [30]
33***
Aunt–niece
26
42**
First-cousin once removed
-3
33*** 42** 33***
First-cousin once removed
10 19
52
9
10
71****
Aunt–nephew
19
71****
49
Father– daughter
22
36
Father– daughter
35
69
45
Mother–son
24
34
Mother–son
35
17
Grandmother– grandson
52
47
27*****
Father– daughter
20
34
27*****
Uncle–niece
13
56
27*****
Uncle–niece
29
Age of death from RCC, not age of diagnosis FH mutation positive but atypical HLRCC histology (clear cell), lack second FH hit in the tumour, and late age at disease onset
11
6
90b
a
b
Frey et al. [27]
5
39
*; **; ***; ****; ***** indicate same individual
25
Vahteristo et al. [30], Lehtonen et al. [30, 31]
This series
This series
Table 6 Parameter estimates of the fixed effect of generations on the age of diagnosis of RCC from all family members
Table 7 Parameter estimates of the fixed effect of generations on the age of diagnosis of uterine leiomyoma from all family members
Parameter
Parameter estimate
95 % CI
Variable
Parameter estimate
Standard error
p value
Overall p value
Second generation
-18.6
-26.6 to -10.6 \0.001 \0.001
First generation
6.4
-4.8 to 17.5
0.263
0.349
Third generation
-36.2
-47.0 to -25.4 \0.001
Third generation
2.1
-7.7 to 11.9
0.675
p value
Overall p value
It is challenging to develop surveillance recommendations for HLRCC, but the potential effect from anticipation demonstrated here supports the need to initiate surveillance programs at a young age. For example, an 18 year old woman from a previously described Dutch HLRCC kindred, presented unexpectedly early with metastatic renal cancer and died 8 months after diagnosis. About 7 % of HLRCC
patients are diagnosed with RCC before age 20 [7], with the youngest diagnosed at 11 years old [5]. Early intervention to minimise morbidity and mortality is a primary goal in cancer predisposition syndromes. Many of these issues have been carefully discussed by van Spaendonck-Zwarts et al. [7], particularly in relation to initiating of surveillance during childhood. The purpose of surveillance is the reduction of
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morbidity and mortality through pre-symptomatic detection and effective treatment which alters the natural history of the disease. Given that the primary life-limiting feature of this syndrome is renal cell carcinoma, and considering the potential effect of anticipation, we agree with van Spaendonck-Zwarts et al. that renal surveillance using noninvasive techniques that minimize distress such as ultrasound would be most suitable from the age of 10. One limitation in this study was that there is limited multigenerational age information reported in the literature. Several two-generation families had incomplete information for ages at diagnosis of RCC and had to be excluded. This data may potentially have revealed findings that contradict our hypothesis but all available cases were recruited. Additionally, we could not exclude birth cohort effects or a common environmental exposure that may possibly account for anticipation. There are also potential ascertainment biases arising from referral, incomplete information on the most recent generation, as well as potentially reduced fertility intrinsic with rare disorders that may account for this. Nonetheless, our data represents a reasonable summary and analysis of best available information, and an approach using an international registry may be useful to evaluate this interesting observation. In conclusion, we report preliminary evidence of genetic anticipation in HLRCC syndrome based on observation of affected patients, as well as a comprehensive literature evaluation surveying all reported HLRCC kindreds. External validation of this observation would have implications for surveillance of patients. Acknowledgments We would like to thank all our patients, and referring clinicians, particularly Dr. John Yuen and Dr. Sim Hong Gee of the Department of Urology, Singapore General Hospital.
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