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岁男性的主要癌症，现在仅次于艾滋病相关肿瘤卡波西肉瘤。虽然存活率有所提高，但年轻人仍死于这种肿瘤，许多幸存者在成年后的大部分时间里都生活在疾病的不良后果中。这组肿瘤的发病率稳步上升需要解释，并且由于导致睾丸癌发病率增加的一系列因素也可能导致男婴各种泌尿生殖系统畸形的患病率增加，这一点更加令人担忧。两个确定的风险因素是睾丸癌家族史（兄弟的相对风险为10）和隐睾或先天性隐睾的个人史（相对风险为2.5-18）。家族危险性、分离分析和初步连锁分析表明，主要易感基因易患睾丸癌，并可能与隐睾症有关。国际睾丸癌连锁联盟（ITCLC）对180个家庭进行的连锁分析发现了Xq 27的一个区域，该区域具有显著的连锁证据，其发生模式表明该区域的基因TGCT 1赋予睾丸癌和隐睾症的风险。我们已经确定并部分纳入了一个基于人群的样本，包括301个多病例家族，为睾丸癌和隐睾症的遗传连锁分析提供了信息。为了寻找主要的易感基因，我们建议完成一整套497个这样的家庭的登记;有助于正在进行的努力克隆TGCT;并进行两个阶段的基因组扫描这一系列的497个家庭中，我们将与ITCLC合作，以确定在第二，精细定位阶段的研究区域，并实施精细定位工作。这497个入选的家庭将是最大的一组信息丰富的家庭，这项研究将大大加快发现易患这些疾病的基因。由于这是一项基于人群的研究，因此在拟议的研究中收集的资源将适用于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.