Greene H.M.
Chief, Clinical Genetics Branch, U.S. National Cancer Institute, Bethesda, MD, USA
Background: A familial predisposition has also been well documented: sons of men with TGCT consistently display a 4- to 6-fold increased risk ofTC compared with the general population, while brothers of affected siblings have an 8- to lO-fold increased risk. However, specific susceptibility genes that predispose to testicular cancer have not yet been identified. Although an autosomal recessive model provided the best data fit in the two segregation analyses performed to date, patterns of affection in multiplecase families are compatible with autosomal dominant, autosomal recessive and X-linked modes of inheritance, suggesting considerable genetic heterogeneity. Linkage analyses have revealed several potential genomic regions of interest, including 2p23, 3p12, 3q26, 12p13-q21, 18q21q23 and Xq27, and a specific deletion in the Y chromosome has also been identified as conferring an increased risk of both sporadic and familial testicular cancer in a small percentage of men. Overall, the preponderance of data suggest that no single major locus can account for the majority of the familial aggregation of TGCT, but rather that multiple susceptibility loci each with weak effects appear to be involved.
Aims: The U.s. National Cancer Institute's Clinical Genetics Branch (CGB) is conducting a multidisciplinary etiologic study of familial testicular cancer (FTC) aimed at ascertaining and studying TGCT families. Study objectives include: (1) characterize the clinical phenotype of familial TGCT; (2) determine the underlying genetic susceptibility mechanism(s); (3) evaluate psychosocial and behavioral issues arising in FTGCT family members; and (4) create a repository of annotated biospecimens for translational research investigations.
Methods: An FTC family was defined as having ~2 objectively-confirmed testicular or extra-gonadal GCTs. To date, we have enrolled 557 members of 113 eligible families; 510 have provided blood samples, and 136 have been examined in detail at the NIH Clinical Center. Additional data collected include detailed family history, medical history, risk factor and psychosocial/behavioral questionnaires, plus physical and dysmorphology examinations, genitourinary imaging and semen samples from subjects seen in person.
Results: Initial results from this unique cohort will be presented and discussed.
Conclusion: The multidisciplinary, etiologically-focused, epidemiologically-based approach to the evaluation of familial cancer aggregates remains a powerful.