Inherited genetic variation and predisposition to testicular germ cell tumor

描述（申请人提供）：睾丸生殖细胞肿瘤（TGCT）是20-40岁男性最常见的癌症。TGCT的发病率在过去的40年里增加了一倍多，没有明确的病因。遗传效应和环境暴露，特别是在产前，可能在确定TGCT易感性方面发挥重要作用。已知TGCT由原始生殖细胞（PGCs）发育而来。我们假设影响PGCs分化和成熟的基因变异将是TGCT易感性的重要决定因素，并基于这一假设选择了三个重要途径进行研究，i)男性生殖细胞发育，ii)雄激素和雌激素的生物合成和代谢，iii) IGF信号传导。参与早期男性生殖细胞发育的蛋白，通常只在PGCs中表达，是TGCT的标记物，并且在TGCT中过表达。在多项研究中，子宫内雌激素暴露增加（或相对减少雄激素暴露）和外源性雌激素暴露的标志物，如内分泌干扰物，与TGCT病例状态有关。IGF信号是小鼠睾丸分化和成熟所必需的，并与雌激素信号通路协同作用。我们将在费城市区进行一项基于人群的病例对照研究，分析这些途径中的遗传变异对TGCT风险的贡献。我们的目标是收集550例TGCT病例和1100例年龄、种族和手机使用匹配的无TGCT病史的对照，这将分别产生500例和1000例白色病例和对照，用于最终分析。所有病例将通过新泽西州和宾夕法尼亚州的癌症登记处进行枚举。我们将采用两层方法进行病例招募：以医院诊所为基础，然后以登记为基础。控制将通过随机数字拨号来识别。病例和对照组均需填写一份问卷，列出已知的、假定的和假设的TGCT危险因素，并提供血液样本或口腔拭子。通过对病例的病理切片检查来确定TGCT的诊断亚型。单倍型和功能单核苷酸多态性将在感兴趣的基因中分型。在对潜在混杂因素进行适当调整后，将对特定变异、常见单倍型单独或相互结合进行分析，并对暴露数据进行分析。这项研究的结果将极大地有助于我们了解TGCT易感性的决定因素。

DESCRIPTION (provided by applicant): Testicular germ cell tumors (TGCT) are the most common cancer in men ages 20-40. The incidence of TGCT has more than doubled over the past forty years, without clear etiology. Both genetic effects and environmental exposures, specifically during the pre-natal period, are likely to play an important role in determining TGCT susceptibility. TGCT is known to develop from primordial germ cells (PGCs). We hypothesize that variation in genes that impact upon the differentiation and maturation of PGCs will be important determinants of TGCT susceptibility and based on this hypothesis have selected three important pathways for study, i) male germ cell development, ii) androgen and estrogen biosynthesis and metabolism, and iii) IGF signaling. The proteins involved in early male germ cell development, normally only expressed in PGCs, are markers of and are overexpressed in TGCT. Markers of increased exposure to estrogen (or relatively decreased exposure to androgen) in utero and exogenous estrogen exposures, such as endocrine disrupters, have been associated with TGCT case status in multiple studies. IGF signaling is necessary for testis differentiation and maturation in mice and interacts synergistically with the estrogen signaling pathway. We will analyze the contribution of genetic variants in these pathways to TGCT risk using a population-based case-control study in the Philadelphia metropolitan area. Our goal is the collection of 550 TGCT cases and 1100 age, race and cell phone use matched controls without a history of TGCT, which will yield 500 and 1000 white cases and controls, respectively, available for final analyses. All cases will be enumerated through the New Jersey and Pennsylvania state cancer registries. We will use a two-tiered approach for case recruitment: hospital clinic-based followed by registry-based. Controls will be identified through random digit dialing. Both cases and controls will complete a questionnaire addressing known, presumed, and hypothesized risk factors for TGCT and provide a blood sample or buccal swab. Pathological slides will be reviewed to cases to confirm diagnostic sub-type of TGCT. Haplotypes and functional SNPs will be typed in the genes of interest. Analyses will be conducted for specific variants, common haplotypes, alone and in conjunction with each other and exposure data after appropriate adjustment for potential confounders. The findings from this study will greatly contribute to our understanding of determinants of TGCT susceptibility.