A Genetic Linkage Study of Testicular Cancer

描述（由申请人提供）：睾丸癌是一种非常年轻的男性疾病。直到最近，它还是15-29岁男性的头号癌症，现在仅次于与艾滋病相关的肿瘤卡波西氏肉瘤。尽管生存率有所提高，但年轻人仍然死于这种肿瘤，许多幸存者在成年后的大部分时间里都伴随着疾病的不良后果。这类肿瘤发病率的稳步上升需要解释，而且更令人担忧的是，导致睾丸癌发病率上升的一系列因素可能也导致了男性婴儿中各种泌尿生殖系统畸形患病率的增加。两个确定的危险因素是睾丸癌家族史（兄弟的相对危险度为10）和隐睾或先天性睾丸不全的个人病史（相对危险度为2.5-18）。家族风险、分离分析和初步连锁分析表明，主要易感基因易患睾丸癌，并可能与隐睾症相关。国际睾丸癌连锁联盟（International Testis Cancer Linkage Consortium， ITCLC）对180个家族进行的连锁分析发现，Xq27的一个区域存在显著的连锁证据，其发生模式表明，该区域的一个基因TGCT1会增加睾丸癌和隐睾的风险。我们已经确定并部分登记了301个多病例家庭的基于人群的样本，为睾丸癌和隐睾的遗传连锁分析提供了信息。为了寻找主要的易感基因，我们建议完成497个这样的家族的全套入组；为正在进行的TGCT克隆工作做出贡献；并对这一系列的497个家族进行两阶段的基因组扫描，我们将与ITCLC合作，在第二阶段，即精细制图阶段确定要研究的区域，并实施精细制图工作。入选的497个家庭将是信息量最大的家庭集合，这项研究将大大加速发现易患这些疾病的基因。因为这是一项基于人群的研究，在拟议的研究中收集的资源将适合在鉴定和克隆这些疾病的主要易感基因后立即进行基因表征。

DESCRIPTION (provided by applicant): 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.