Molecular Epidemiology of Testicular Carcinoma

描述（由申请人提供）：睾丸生殖细胞癌（TGCC）是年轻男性中最常见的恶性肿瘤，自20世纪50年代以来，其发病率增加了数倍。TGCC的病因是模糊的，我们对危险因素的了解主要限于人口统计学特征、家族史和隐睾史。TGCC的临床、非人类实验和流行病学研究提供的证据表明，在子宫内、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的关键病因因素。在过去的4.5年中，我们进行了一项基于人群的病例对照和病例父母三联研究，开始使用分子遗传学方法来检验TGCC风险与以下假设有关：1）控制睾酮合成、代谢和信号传导的男性基因变异;和2）母亲在怀孕早期的激素环境中的基因变异（作为子宫内暴露的替代物），此时胎儿组织最容易受到损害。病例（n=285预期），对照（n=747预期），和父母的情况下（n=187例父母集预期）正在确定和招募从大都市西雅图普吉特湾居民。病例组和对照组接受了面对面的访谈，父母通过电话进行了有关病史和生活方式的访谈。从几乎每个参与者获得DNA样本，并测定候选多态性（仅病例对照研究中的4个位点，仅病例父母三联体研究中的8个位点，两种设计中的7个位点）。 我们建议继续病例对照和病例父母的组成部分，以测试我们最初的具体目标，增加严格性，增加一倍，我们的样本量，并包括一个更全面的候选基因和每个基因内的多态性。此外，我们提出了两个新的具体目标，扩展了“类固醇激素”假设的测试：TGCC风险与男性基因编码的变化有关：1）影响睾丸类固醇生成的细胞因子（及其受体），以及2）保护免受活性雌激素代谢产物引起的氧化DNA损伤的碱基切除修复蛋白。继续我们的研究将使我们能够解决我们的具体目标，共有570起事件。TGCC病例，1，514例人口统计学相似的对照，714例父母（产生约375个病例-父母集）。我们将确定每个个体大约42000个位点的基因型，并使用多位点分析方法来评估总体关联和基因-基因相互作用。这项研究的结果将增加有关TGCC的流行病学和病因学的新信息，并将作为未来调查这些恶性肿瘤中遗传和非遗传因素相互作用的资源。

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.