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Oncology 1990;47:75-79

SBLA Syndrome Revisited1 Henry T. Lynch, Barbera Radford, Jane F. Lynch Department of Preventive Medicine/Public Health, Creighton University School of Medicine. Omaha. Ncbr., USA

Key Words. Sarcoma ■Breast cancer • Brain tumors • Leukemia • Lymphoma • Adrenal cortical carcinoma • Genetics

Introduction Broca [1], in 1866, described a significant excess of carcinoma of the breast and gastrointestinal tract in his wife’s family. A century later, Bottomley et al. [2,4] and Bottomley and Condit [3] described a family (No. 2152) showing remarkably early onset breast cancer in association with a broad spectrum of cancer of variable anatomic sites. Li and Fraumeni [5, 6] pro­ vided insight into this disorder when they described 4 nuclear kindreds with sarcoma and breast cancer. They subsequently published a prospective observa­ tion of these families that covered a 12-year time frame (1969-1981) [7], Of interest was the fact that in 31 surviving family members, 16 additional cancers developed (the expected number was 0.5). Five of these were carcinomas of the breast, 4 were soft tissue sarcomas, and 7 were cancers of other anatomic sites. Eight of the patients had multiple primary cancers. Four cancers occurred at sites of prior radiotherapy (3 1 Support for this effort was provided by the Council for Tobacco Research, grant No. I297C and National Cancer Institute grant No. IROI CA 48802-01.

soft tissue sarcomas and 1 mesothelioma). This disor­ der has been appropriately referred to as the LiFraumeni syndrome [8]. These findings are in accord with what are now more clearly recognized concepts of tumor heterogeneity in breast-cancer-prone fami­ lies [9], We [10] subsequently described an informative seg­ ment of the kindred described by Bottomley et al. [2,4] and Bottomley and Condit [3] in concert with other families showing differing tumor combinations in as­ sociation with cancer of the breast. In a later study of a similar extended kindred, the tumor findings were found to show a pattern of sarcoma, breast cancer and brain tumors, lung and laryngeal cancer, leukemia, lymphoma, and adrenal cortical carcinoma. The ac­ ronym SBLA was ascribed to this syndrome [11, 12]. Our purpose is to describe detailed cancer findings, covering more than two decades of follow-up, in a highly informative SBLA kindred referred to above (family No. 2152, fig. 1). These observations clearly depict the consistency of cancer segregation of specific anatomic sites involving all three germinal layers. The transmission in this family is consonant with an auto­ somal dominantly inherited factor.

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Abstract. We have provided an in-depth, longitudinal, clinical/genetic/pathologic investigation of a family consonant with the sarcoma, breast cancer and brain tumors, lung and laryngeal cancer, leukemia, lymphoma, and adrenalcortical carcinoma syndrome. The pattern of cancer expression involves all three germinal layers with transmission through multiple generations. Segregation of these cancers occur in a manner consonant with an autosomal dominant mode of genetic transmission. It is hoped that recognition of the significance of this tumor pattern within families will provide an impetus for cancer surveillance, control, and laboratory research in the quest for clues to biomarkers which correlate with its cancer-prone genotype.

Lynch Radford/Lynch

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Fig. 1. Pedigree of SBLA kin­ dred with segment noted by dotted line, recently reassessed, and shown to perpetuate the expected tumor pattern.

F.xtcnsive family history, medical, and pathology records from prior investigations of kindred No. 2152 [2-5] facilitated the present study. Key relatives were recontacted through telephone queries and questionnaires requesting detailed medical, cancer, and family history information. Permission forms, when signed by living affecteds or legal next of kin, enabled us to secure primary medical and pathology records for cross-checking of these multiple sources so that maximum accuracy of genealogy and cancer occurrence/distribution within the family could be attained. A field visit was then conducted for evaluation of a segment of the kindred (fig. 1 en­ closed in box) which showed a recent excess of syndrome-related cancer.

Results The pedigree was first published by Bottomley and Condit [3]. Figure 1 shows the current, extended SBLA kindred. Table 1 depicts the distribution of the specific forms of cancers and their sources of docu­ mentation. The highlighted branch of the family shows a lineage in which new syndrome cancers have been diagnosed and in which an excess of childhood syndrome cancers have appeared and have been trans­ mitted to a sixth generation. In 1859, the patriarch and matriarch of this extend­ ed kinship emigrated to the United State from Ger­ many while young adults. They settled in a predomi­ nantly German county of Minnesota and had 10 chil-

Table 1. Distribution of specific cancer forms and their sources of documentation Pedigree ID No.

Diagnosis/cancer site

Sex

Age at diag­ nosis

Source of infor­ mation

H 1 II—2 II 3 Il^ t 11-8 III-l 111-3 III 5 111-9 III 10

CSU prostate liver CSU breast breast breast brain tumor breast leiomyosarcoma of kidney lung lymphoblastic lymphoma leiomyosarcoma of prostate breast breast osteogenic sarcoma liposarcoma uterine cervix CSU lung uterine cervix infiltrating ductal breast breast

F M M F F F F M F

d.29 d.62 d.60 d.51 d.34 d.24 d.29 d.37 42

FH FH DC FH FH FH FH FH DC

M

47 61 59

PR FH PR

59 40 d.42 22 38 d.42 d.32 d.76 49 73 42

PR DC FH PR MR FH FH FH FH PR FH

III 11

III—12 111—13 III 14 111-15 III 16 III 18 III—21 111-23 III 27

M

F F M F F F F F F

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Materials and Methods

77

SBLA Syndrome

No 2152

0

B

$

bb

Cancer verified by pathology report

(D

DD Cancer reported by family history

o



©

Q ] Unaffected progeny

Cancer reported by death c e rtifica te or medical record Multiple primary cancers verified by pathology report

0 0 Oead A

SBLA syndrome cancer diagnosed since 1972

Pedigree ID No.

Diagnosis/cancer site

111-28

small cylindrical cell sarcoma breast scirrhous carcinoma. left breast intraductal carcinoma. right breast acute myeloblastic leukemia retroperitoneal leiomyosarcoma jaw osteogenic sarcoma osteogenic sarcoma uterine cervix carcinoma in situ CSU lymphocytic lymphosarcoma leiomyosarcoma adenocarcinoma breast glioblastoma multiforme lymphoma prostate renal cell, kidney prostate

IV-4 IV -10

IV-11 IV -15 IV 16 IV -17 IV 20 IV—23 IV-24 IV-32 IV—33 IV—35 IV-36 IV-37 IV-38

Sex

Age at diag­ nosis

Source of infor­ mation

M F

36 d.30

DC FH

F

37

PR

37

PR

47

PR

F M M F

59 d.23 15 18

PR FH MR FH

V-10 V 13 V-14

F F

46 UNK

PR FH

V—15 VI 1

M F F M F M M

52 33 34 30 59 73 67 68

PR PR PR PR FH PR PR PR

Pedigree ID No.

Diagnosis/cancer site

IV 40

adenocarcinoma of rectum leukemia leukemia adrenal cortical carcinoma sarcoma of humerus fibrosarcoma malignant fibrous histiocytoma osteogenic sarcoma Hodgkin’s disease fibrosarcoma, L breast comedocarcinoma. R breast sarcoma, right orbit embryonal rhabdomyosarcoma

V-2 V-3 V-4 V-7 V-8 V-9

Sex

Age at diag­ nosis

Source of infor­ mation

M F M

58 15 10

PR DC DC

F F F

48 h 10 16

PR DC PR

M M M F

33 22 29 20

PR PR PR PR

F

25 3

PR PR

F

2

PR

CSU = Cancer site unknown; d = age at death when age at diagnosis unknown; DC = deaih certificate; FH = family history; MR = medical record; PR = pathology report; UNK = unknown.

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Table 1 cont.

dren, 8 of whom survived infancy. The matriarch (1-1) died at age 39, 9 months after giving birth to her last child. There is family rumor that she may have died of cancer, but there is no objective verification at this time since historical records from the year of her death have been lost. Of the 8 siblings in generation 11who survived infancy,5 (II-l, 11-2.11-3, ll-4,and 11-8)died ofcancer. The patriarch (1-2) remarried, and by his second wife had 11 children. This sibship and their offspring do not have the family reputation of multiple cancers. The pa­ triarch died at age 67,2 weeks after a ‘stroke’. Findings in figure 1 and table 1 show SBLA syn­ drome cancers to have occurred in the descendants of patients II-l, 11-2,11-3, 11-5, and 11-8. Patient 11-4 and several of her descendants manifested cancer. How­ ever, to date, cervical cancer, as noted in her daughter (111-15) and granddaughter (IV-20) has not been found to be an integral lesion in this syndrome. We have not been able to establish the cancer site of other reported cancers in this lineage; therefore, we cannot determine whether or not they are consonant with the tumor spectrum of the SBLA. Individual II-6 had a daughter (II1-23) who was diagnosed with breast can­ cer at age 75. Because of the late onset of the breast cancer and the lack of other SBLA syndrome cancer occurrences in this lineage, it is likely that this branch of the family is not part of the syndrome. As far as we know, patient II-7 and her descendents have remained cancer-free. The descendants of 11-2 constitute the major con­ cern of this paper. One of his sons (111-10) had died at age 61 in 1955 of a leiomyosarcoma, and one of III10's daughters and 5 grandchildren were affected with syndrome cancers. When this family was reassessed by us in 1988, it was found that new syndrome cancers had occurred; namely, a daughter (IV-11) of III-10 had developed a retroperitoneal leiomyosarcoma. Her son (V-10) manifested an osteogenic sarcoma of the right mandible with infiltration into the frontal sinus at age 22. His brother (V-9) was diagnosed with malig­ nant fibrous histiocytoma of the thigh at age 32, the same week that his 2-year-old daughter (VI-1) was found to have an embryonal rhabdomyosarcoma of the right cheek.

Discussion Family studies provide powerful methods for un­ derstanding cancer genetic transmission. Undoubted­

ly, myriad environmental events may perturb the can­ cer-prone genotype. Secular changes in such expo­ sures, while difficult to document, may nevertheless provide partial explanations for differences in cancer expression. The pattern of the SBLA’s cancer phenotype, particularly as expressed from one genera­ tion to the next in family No. 2152, provides con­ fidence in the cancer genetic syndrome diagnosis. This is particularly germane when one encounters rarely occurring cancer types, like sarcomas, in multiple firstdegree relatives, as occurred in patient 111-10 and his descendants. The clinical/pathology findings relevant to cancer expression in this extended family continue to evolve in accord with the original predictions of the SBLA heritage [10-12], While we lack surveillance programs for the majority of these tumors, their highly predict­ able occurrence in families such as this one and others [5, 8, 13], should provide an impetus for cancer control research. The frequency of the SBLA syndrome remains elu­ sive, partly due to the lack of a biomarker of its cancer-prone genotype; therefore, the need for de­ tailed family studies. However, the syndrome may be relatively common. For example, Birch et al. [14] evaluated families of young children with soft tissue sarcoma, predominantly rhabdomyosarcomas. They observed the breast cancer incidence in the mothers of these cancer-affected children to be significantly in­ creased. Findings in several of these patients were suggestive of the SBLA syndrome. Clues to SBLA’s etiology and pathogenesis may evolve through laboratory investigations. For exam­ ple, Chang et al. [15] studied noncancerous skin fibro­ blasts from family members of a highly informative Li-Fraumeni (SBLA) syndrome kindred. Karyotypic abnormalities were not identified in this family. How­ ever, the skin fibroblasts were found to be uniquely resistant to the killing effect of ionizing radiation. In addition, they observed these fibroblasts to show a 3to 18-fold elevation in expression of c-myc and an apparent activation of c-raJ'-\ gene. These inves­ tigators postulated that their observations may pro­ vide additional evidence for the underlying genetic predisposition to the spectrum of cancer in this dis­ order. Molecular genetic studies of cancer-prone families which show a diverse tumor spectrum consonant with the SBLA syndrome may one day explain etiology and pathogenesis relevant to the manner in which herita­

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SBLA Syndrome

References 1 Broca PP: Traité des tumeurs. Paris, Asselin. 1866-1869, vols 1,2. 2 Bottomley RH, Condit PT, Chanes RE: Cytogenetic studies in familial malignancy. Clin Res 1967; 15:334. 3 Bottomley RH . Condit PT: Cancer families. Cancer Bull 1968;20:22-24. 4 Bottomley RH. Trainer AL, Condit PT: Chromosome studies in a ‘cancer family’. Cancer 1971;28:519-528. 5 Li FP. Fraumeni JF: Soft-tissue sarcomas, breast cancer, and other neoplasms, a familial syndrome? Ann Intern Med 1969;71:747-752. 6 Li FP, Fraumeni JF: Familial breast cancer, soft-tissue sarco­ mas, and other neoplasms. Ann Intern Med 1975:83:833.

7 Li FP, Fraumeni JF: Prospective study of a family cancer syndrome. JAMA 1982:247:2692-2694. 8 Pearson AD J. Craft AW, Ratclifie J M. et al: Two families with the Li-Fraumeni cancer family syndrome. J Med Genet 1982;19:362-365. 9 Lynch HT: Genetics and Breast Cancer. New York. Rcinhold, 1981. 10 Lynch HT. Krush AJ, Lemon HM, et al: Tumor variation in families with breast cancer. JAMA 1972;222:1631-1635. 11 Lynch HT. Mulcahy G M . Harris RE, et al: Genetic and patho­ logic findings in a kindred with hereditary sarcoma, breast cancer, brain tumors, leukemia, lung, laryngeal, and adrenal cortical carcinoma. Cancer 1978:41:2055-2064. 12 Lynch HT, Katz DA. Bogard PJ. et al: The sarcoma, breast cancer, lung cancer, and adrenocortical carcinoma syndrome revisited: childhood cancer. AJDC 1985;139:134-136. 13 Blattncr WA. McGuire DB. Mulvihill JJ, et al: Genealogy of cancer in a family. JAMA 1979;241:259-261. 14 Birch JM , Hartley AL. Marsden HB, et al: Excess of breast cancer in mothers of children with soft tissue sarcomas. Br J Cancer 1988:49:325. 15 Chang EH. Pirollo K F, Quiang Zou Z. et al: Oncogenes in radioresistant noncancerous skin fibroblasts from a cancerprone family. Science 1987:237:1036-1039. 16 Birrer MJ. Minna JD: Molecular genetics of lung cancer. Semin Oncol 1988:15:226-235. 17 Bishop JM: The molecular genetics of cancer. Science 1986;235:305-311. 18 Knudson AG: Retinoblastoma, a prototypic hereditary neo­ plasm. Semin Oncol 1978;5:57-60. Addendum Patient V-10 has now developed a second primary cancer, namely an embryonal rhabdomyosarcoma of the chest wall. Henry T. Lynch. MD Department of Preventive Medicine Creighton University School of Medicine California at 24th Street Omaha. NE 68178 (USA)

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ble genetic defects predispose patients to somatic events leading to cancer excess of specific targeted sites when compared to their nongenetic cancer counter­ partis) [16-18). Priority should be given to such biomolecular/genetic studies in this and other heredit­ ary precancer disorders since anti-oncogenes provide the potential for development of an antithesis to can­ cer expression. Thus, members of SBLA families whe­ rein there is a relentless expression of a bizarre tumor spectrum, may become prime candidates for poten­ tially important biomolecular/pharmacologic cancer control measures. In conclusion, this family provides a clear example of the highly predictable consequences of the SBLA genotype over a relatively short time interval. In this particular situation, sarcomas predominated. Our findings clearly denote the need for highly targeted surveillance, intense education of the high risk in­ dividuals, genetic counselling, and intervention at the biomolecular level.

SBLA syndrome revisited.

We have provided an in-depth, longitudinal, clinical/genetic/pathologic investigation of a family consonant with the sarcoma, breast cancer and brain ...
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