MOLECULAR EPIDEMIOLOGY OF TESTICULAR CARCINOMA

描述(改编自申请人的摘要)： 睾丸生殖细胞癌(TGCC)是发生于 自20世纪50年代以来，年轻男性的数量增加了几倍。尽管三十年来 在人群中的研究，TGCC的病因仍然不清楚，我们的 对风险因素的了解在很大程度上限于人口特征和 隐睾症的病史。临床，非人类实验，和 TGCC的流行病学研究提供了接触异常环境的证据 子宫、围产期和/或生命早期的类固醇激素水平， 可能是TGCC的重要病因之一。这一现象的流行病学支持 然而，假设是不一致的，这一现象至少可以归因于 部分原因是面谈和病历数据捕获的能力有限 相关的曝光。基因多态检测的最新进展 促进内源性类固醇激素代谢提供了一个机会 超越先前流行病学研究的范围，通过解决 在分子遗传学水平上推测TGCC的激素病因。 具体地说，我们建议检验这样一种假设，即 参与刺激睾丸类固醇生成、合成和分泌的基因 代谢睾酮和雄激素信号与患高血压的风险有关 发展TGCC。 将进行以人群为基础的病例对照研究。案件将会是 1998年10月至2005年间确诊的约280例TGCC病例 2003年9月，谁是三县都会区的居民 华盛顿州西部。人口统计学上相似的对照(n=840)将是 使用随机数字电话拨号从普通人群中确定。 病例和控制措施将就医疗和医疗问题亲自面谈 生活方式的历史。将从所有同意的人那里获取静脉血液样本 受试者和外周血白细胞分离保存。基因组DNA 从白细胞中提取的物质将被检测出下列基因的变异 参与1)刺激睾丸类固醇合成(黄体化 激素和胰岛素样生长因子-1)，2)合成和代谢 睾酮(细胞色素P450 11a[CyP11a]，CyP17，3β-羟基类固醇 脱氢酶II、细胞色素P3A4和UDP-葡萄糖醛酸基转移酶2B15)，以及3) 睾酮信号(雄激素受体)。病例和对照将进行比较 关于假定的“高危”基因型和等位基因的流行情况 对于每一个基因。样本量也将提供足够的统计能力 以确定高危基因类型之间的相互作用。由此得出的结论是 因此，这项研究将增加有关流行病学和 TGCC的病因学，并将作为未来研究的资源 基因关联。

DESCRIPTION (Adapted from the Applicant's Abstract): The incidence of testicular germ cell carcinoma (TGCC), the most common malignancy developing in young men, has increased several-fold since the 1950s. Despite three decades of research in human populations, the etiology of TGCC remains obscure and our knowledge of risk factors is limited largely to demographic characteristics and a history of undescended testes. Clinical, non-human experimental, and epidemiologic studies of TGCC have provided evidence that exposure to abnormal levels of steroid hormones, either in utero, perinatally, and/or early in life, may be a key etiologic factor for TGCC. Epidemiologic support of this hypothesis, however, has been inconsistent, a phenomena attributable at least in part to the limited ability of interview and medical record data to capture the relevant exposures. Recent progress in identifying polymorphisms in genes contributing to endogenous steroid hormone metabolism presents an opportunity to expand beyond the scope of prior epidemiologic studies by addressing the hypothesized hormonal etiology of TGCC at the molecular genetic level. Specifically, we propose to test the hypothesis that inherited variation in genes involved in stimulating testicular steroidogenesis, synthesizing and metabolizing testosterone, and androgen signaling, is related to the risk of developing TGCC. A population-based case-control study will be conducted. Cases will be approximately 280 incident cases of TGCC diagnosed between October 1998 and September 2003 and who are residents of a three county metropolitan region in western Washington State. Demographically similar controls (n=840) will be ascertained from the general population using random digit telephone dialing. Cases and controls will be interviewed in-person regarding medical and lifestyle histories. A venous blood sample will be obtained from all consenting participants and peripheral leukocytes isolated and stored. Genomic DNA extracted from leukocytes will be tested for variants in the following genes involved in 1) the stimulation of testicular steroidogenesis (Luteinizing Hormone and Insulin-Like Growth Factor-1), 2) the synthesis and metabolism of testosterone (Cytochrome p450 11a [CYP11a], CYP17, 3Beta-Hydroxysteroid Dehydrogenase Type II, CYP3A4, and UDP-Glucuronosyltransferase 2B15), and 3) testosterone signaling (Androgen Receptor). Cases and controls will be compared with respect to the prevalence of putative "high risk" genotypes and alleles for each gene. The sample size also will provide sufficient statistical power to identify interaction between high-risk genotypes. The findings from this study therefore will add new information regarding the epidemiology and etiology of TGCC, and will serve as a resource for future investigations of genetic associations.