Gene-environment Cancer Risks in Melanoma

描述(由申请人提供) 这一职业发展计划的目标是在分子流行病学方面启动一项独立的研究计划，特别强调评估基因与环境的相互作用。为此，它包括分子生物学/遗传学和分子流行病学领域的教学课程和实践培训。黑色素瘤是研究基因-环境相互作用的独特模型，因为有越来越多的证据表明，低外显性遗传多态可能会降低黑色素瘤暴露在太阳紫外线下的风险。碱基切除修复(BER)途径的基因修复UVA暴露后的DNA损伤。候选人将使用国际基因、环境和黑色素瘤(GEM)3366主题病例对照研究作为平台，测试紫外线辐射和BER变体交互影响黑色素瘤风险的假设。每个受试者都有终生日晒史和DNA样本。候选人的研究将：(A)确定BER变种在GEM黑色素瘤病例和对照中的流行率；(B)评估候选BER变种和长期阳光暴露对黑色素瘤风险的交互影响；以及(C)调查BER变种和GEM研究中目前正在检查的其他基因(MC1R和核苷酸切除修复基因)中根据阳光照射进行调整的其他基因(MC1R和核苷酸切除修复基因)之间的基因-基因相互作用是否影响黑色素瘤风险。这项研究提案将使应聘者对开展环境相关疾病的分子流行病学研究所需的实验室和流行病学分析技术有所了解。通过与GEM财团和其他多学科研究人员的深入互动，分子生物学和流行病学的正式课程以及研究，这项职业发展奖将确立候选人在遗传学、流行病学和环境健康领域的多学科研究技能，并使她能够建立关于黑色素瘤复杂遗传-环境相互作用机制的新理论。

DESCRIPTION (provided by applicant) The goal of this career development plan is to launch an independent research program in molecular epidemiology with specific emphasis on the evaluation of gene-environment interactions. To this end, it includes both didactic coursework and hands-on training in the areas of molecular biology/ genetics and molecular epidemiology. Melanoma is a unique model for studying gene-environment interactions as there is mounting evidence that low-penetrance genetic polymorphisms may moderate the melanoma risk of solar UV exposure. Genes of the base excision repair (BER) pathway repair DNA damage secondary to UVA exposure. The candidate will use the international Genes, Environment and Melanoma (GEM) 3366-subject case-control study as a platform to test the hypothesis that UV radiation and BER variants interactively affect melanoma risk. Lifetime sun exposure history and DNA specimens are available for each subject. The candidate's research will (a) determine the prevalence of BER variants in GEM melanoma cases and controls; (b) evaluate the interactive influence of candidate BER variants and chronic sun exposure on melanoma risk; and (c) investigate whether melanoma risk is influenced by gene-gene interactions between BER variants and variants in other genes currently being examined in the GEM study (MC1R and nucleotide excision repair genes) adjusting for sun exposure. This research proposal will provide the candidate with an appreciation for and understanding of the laboratory and epidemiologic analyses techniques needed to conduct molecular epidemiologic research on environmentally related diseases. Through intensive interactions with the GEM consortium and other multidisciplinary investigators, formal coursework in molecular biology and epidemiology, and research, this career development award will establish the candidate's multidisciplinary research skills at the interface of genetics, epidemiology and environmental health, and position her to establish novel theories regarding the mechanisms underlying complex genetic-environmental interactions in melanoma.