Molecular Epidemiology of Testicular Carcinoma

描述(申请人提供)：睾丸生殖细胞癌(TGCC)是年轻人中最常见的恶性肿瘤，自20世纪50年代以来发病率增加了几倍。TGCC的病因尚不清楚，我们对危险因素的了解主要限于人口学特征、家族史和隐睾史。TGCC的临床、非人类实验和流行病学研究表明，无论是在子宫、围产期和/或生命早期，暴露于异常水平的雌激素和/或雄激素可能是TGCC的关键病因。在过去的4.5年里，我们进行了一项基于人群的病例对照和病例-父母三联体研究，以开始使用分子遗传学方法检验以下假设：TGCC风险与以下假设有关：1)男性控制睾酮合成、代谢和信号的基因变异；2)孕妇在怀孕早期的荷尔蒙环境中的基因变异(作为宫内暴露的替代)，此时胎儿组织最容易受到损害。正在从西雅图-普吉特湾的大都市居民中确定和招募病例(预计285例)、对照(预计747例)和病例的父母(预计187例-父母组)。关于病史和生活方式史，病例和对照已经进行了面谈，并通过电话采访了父母。从几乎每个参与者身上获取DNA样本并分析候选多态(仅在病例对照研究中有4个基因座，在病例-父母三联体研究中只有8个基因座，在两个设计中都有7个基因座)。 我们建议继续病例对照和病例亲本成分，通过增加一倍的样本量，并在每个基因中包括一组更全面的候选基因和多态，以更严格地测试我们最初的特定目标。此外，我们提出了两个新的特定目标，以扩大“类固醇激素”假说的检验范围：TGCC风险与男性基因编码的变异有关：1)影响睾丸类固醇合成的细胞因子(及其受体)，以及2)碱基切除修复蛋白，保护DNA免受由反应性雌激素代谢产物引起的氧化DNA损伤。继续我们的研究将使我们能够解决我们的具体目标，总共570起事件。TGCC病例，1,514个人口学相似的对照，714个父母(产生约375个病例-父母组)。我们将确定每个个体大约420000个基因座的基因类型，并使用多基因座分析方法来评估总体相关性和基因-基因相互作用。这项研究的发现将增加关于TGCC流行病学和病因学的新信息，并将作为未来研究遗传和非遗传因素在这些恶性肿瘤中相互作用的资源。

DESCRIPTION (provided by applicant): The incidence of testicular germ cell carcinoma (TGCC), the most common malignancy developing in young men, has increased several-fold since the 1950s. The etiology of TGCC is obscure and our knowledge of risk factors is limited largely to demographic characteristics, family history, and a history of undescended testes. Clinical, non-human experimental and epidemiologic studies of TGCC provide evidence that exposure to abnormal levels of estrogens and/or androgens, either in utero, perinatally, and/or early in life, may be a key etiologic factor for TGCC. During the past 4.5 years, we have conducted a combined population-based case-control and case-parent triad study to begin to test, using molecular genetic methods, the hypotheses that TGCC risk is associated with 1) variation in a man's genes controlling testosterone synthesis, metabolism, and signaling; and 2) maternal variation in genes her hormonal milieu in early pregnancy (as a surrogate for in utero exposure), when fetal tissue is most susceptible to damage. Cases (n=285 expected), controls (n=747 expected), and parents of cases (n=187 case-parent sets expected) are being ascertained and recruited from among metropolitan Seattle-Puget Sound residents. Cases and controls have been interviewed in-person, and parents via telephone, regarding medical and lifestyle histories. DNA samples have been obtained from nearly every participant and assayed for candidate polymorphisms (4 loci in the case-control study only, 8 loci in case-parent triad study only, and 7 loci in both designs). We propose to continue both the case-control and case-parent components to test our initial specific aims with increased rigor by doubling our sample size, and by including a more comprehensive set of candidate genes and polymorphisms within each gene. In addition, we propose two new specific aims that extend the test of the "steroid hormone" hypothesis: that TGCC risk is related to variation in a man's genes coding for: 1) cytokines (and their receptors) that influence testicular steroidogenesis, and 2) base-excision repair proteins that protect against oxidative DNA damage resulting from reactive estrogen metabolites. Continuing our study will allow us to address our specific aims with a total of 570 incident. TGCC cases, 1,514 demographically similar controls, and 714 parents (yielding about 375 case-parent sets). We will determine genotypes for approximately 420 hundred loci per individual and use multilocus analysis methods to assess overall associations and gene-gene interactions. The findings from this study will add new information regarding the epidemiology and etiology of TGCC, and will serve as a resource for future investigations of the interplay of genetic and non-genetic factors in these malignancies.