Testicular cancer is a disease of very young men. Until recently, it was the leading cancer among men aged 15-29, and it is now second only to the AIDS-related neoplasm, Kaposi's sarcoma. Although survival has improved, young men still die from this neoplasm, and many survivors live most of their adult years with very undesirable consequences of their disease. The steady rise in incidence of this group of tumors needs to be explained, and is made all the more alarming by the possibility that the set of factors responsible for increasing incidence rates of testicular cancer may also be causing a poorly measured increase in the prevalence of various urogenital malformations in male infants. The two established risk factors are family history of testis cancer (relative risk of 10 for brothers) and a personal history of cryptorchidism or congenitally undescended testicles (relative risk 2.5-18). Familial risk, segregation analysis and preliminary linkage analyses suggest that major susceptibility genes predispose to testis cancer and possibly to the antecedent condition cryptorchidism. Linkage analysis of 180 families conducted by the International Testis Cancer Linkage Consortium (ITCLC) identified a region of Xq27 with significant evidence for linkage, with a pattern of occurrence suggesting that a gene in the region, TGCT1, confers risk of both testis cancer and cryptorchidism. We have identified and partially enrolled a population- based sample of 301 multiple case families informative for genetic linkage analysis of testis cancer and cryptorchidism. To search for major susceptibility genes, we propose to complete enrollment of a full set of 497 such families; contribute to the ongoing effort to clone TGCT; and conduct a two-stage genome scan among this series of 497 families in which we will collaborate with the ITCLC both to identify regions to be studied in the second, fine mapping stage, and to implement fine mapping efforts. The 497 enrolled families will be the largest set of informative families assembled, and this research should substantially accelerate discovery of genes predisposing to these conditions. Because this is a population-based study, the resource assembled in the proposed research will be appropriate for immediate gene characterization upon identification and cloning of major susceptibility genes for these conditions.
