Inherited genetic variation and predisposition to testicular germ cell tumor

遗传性遗传变异和睾丸生殖细胞肿瘤的易感性

• 批准号: 7930069
• 负责人: Katherine L. Nathanson
• 金额: $ 29.49万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7930069
• 关键词: Accounting; Address; Age; Age of Onset; Anabolism; Androgens; Area; Blood specimen; Case-Control Studies; Cell Maturation; Cellular Phone; Cessation of life; Clinic; Clinics and Hospitals; Collection; County; Data; Defect; Development; Diagnosis; Diagnostic; Digit structure; Emotional; Endocrine Disruptors; Enrollment; Environmental Exposure; Estrogen Metabolism; Estrogens; Etiology; Exposure to; Fox Chase Cancer Center; Genes; Genetic; Genetic Variation; Germ Cells; Goals; Haplotypes; IGF1 gene; Incidence; Inherited; Life; Malignant Neoplasms; Metabolism; Mus; New Jersey; Pathway interactions; Pennsylvania; Perinatal; Perinatal Exposure; Philadelphia; Play; Population; Predisposition; Proteins; Questionnaires; Race; Recording of previous events; Recruitment Activity; Registries; Relative (related person); Relative Risks; Research Personnel; Risk; Risk Factors; Role; Signal Pathway; Signal Transduction; Signaling Pathway Gene; Slide; Somatomedins; Stem cells; Structure of primordial sex cell; Surrogate Markers; Swab; Syndrome; Testicular Germ Cell Tumor; Testis; United States; Universities; University Hospitals; Variant; base; case control; gene environment interaction; gene interaction; genetic variant; in utero; interest; male; men; metropolitan; neoplasm registry; overexpression; population based; programs

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.

描述（由申请人提供）：睾丸生殖细胞肿瘤（TGCT）是 20-40 岁男性中最常见的癌症。过去四十年来，TGCT 的发病率增加了一倍多，但病因尚不清楚。遗传效应和环境暴露（特别是在产前时期）可能在确定 TGCT 易感性方面发挥重要作用。已知 TGCT 是由原始生殖细胞 (PGC) 发展而来。我们假设影响 PGC 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的研究途径：i) 雄性生殖细胞发育，ii) 雄激素和雌激素生物合成和代谢，和iii) IGF信号传导。参与早期雄性生殖细胞发育的蛋白质通常仅在 PGC 中表达，但它们是 TGCT 的标记，并且在 TGCT 中过度表达。在多项研究中，子宫内雌激素暴露增加（或雄激素暴露相对减少）和外源性雌激素暴露（例如内分泌干扰物）的标志物与 TGCT 病例状态相关。 IGF 信号对于小鼠睾丸分化和成熟是必需的，并与雌激素信号通路协同相互作用。我们将使用费城都会区基于人群的病例对照研究来分析这些途径中遗传变异对 TGCT 风险的贡献。我们的目标是收集 550 个 TGCT 病例和 1100 个年龄、种族和手机使用情况匹配且没有 TGCT 病史的对照，这将分别产生 500 个和 1000 个白色病例和对照，可用于最终分析。所有病例都将通过新泽西州和宾夕法尼亚州癌症登记处进行统计。我们将使用两层方法进行病例招募：基于医院诊所，然后是基于登记。控制将通过随机数字拨号来识别。病例和对照都将完成一份调查问卷，涉及 TGCT 的已知、假定和假设风险因素，并提供血样或口腔拭子。将审查病例的病理切片以确认 TGCT 的诊断亚型。单倍型和功能性 SNP 将在感兴趣的基因中进行分型。在对潜在的混杂因素进行适当调整后，将对特定变异、常见单倍型、单独和相互结合以及暴露数据进行分析。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。