Genome-Wide molecular epidemiology of treatment outcome and cancer risk

描述（由申请人提供）：本指导职业发展奖申请的目标是将我在实验室和临床药理学，人类遗传学和临床研究方面的多样化培训经验整合到“治疗结果和癌症风险的全基因组分子流行病学”的重点研究项目中。这个项目的目的是发现和测试新的生殖系遗传变异的生物学功能，这些变异可能作为1)化疗癌症患者的严重毒性和生存的标志，以及2)癌症易感性的标志。这些标记将通过全基因组关联研究（GWAS）进行鉴定，而我之前的培训和研究经验与全基因组关联研究无关。为了进行将GW数据与分子、遗传、流行病学和生物信息学技术相结合的研究，我将被要求将这些技术应用于基因组种群数据。该计划将通过一系列临床、流行病学和实验室研究来构建。我建议使用无偏见的基因组方法来发现新的候选基因作为化疗结果的标记。同样的方法也将应用于通过从没有癌症的对照个体中获得的公开的GW信息资源来确定新的癌症易感性候选者。从GW数据中产生的丰富信息将来自于对GWAS中显示出显著关联的基因组区域的额外基因分型和/或重测序。GWAS中重要的单核苷酸多态性（SNPs）很可能没有确定的分子功能，并且将使用几种策略来支持观察到的临床关联。

DESCRIPTION (provided by applicant): The goal of this mentored career development award application is to consolidate my diverse training experiences in laboratory and clinical pharmacology, human genetics, and clinical investigation into a focused research program in "Genome-wide molecular epidemiology of treatment outcome and cancer risk". The purpose of this program will be to discover and test the biological function of novel germline genetic variation that might serve as markers of 1) severe toxicity and survival in cancer patients treated with chemotherapy, and 2) cancer susceptibility. These markers will be identified through genome-wide (GW) association studies (GWAS), and my previous training and research experience do not pertain to GW investigations. To undertake research that combines GW data with molecular, genetic, epidemiology and bioinformatics techniques, I will be required to apply these technologies to genomic population data. This program will be constructed through a series of clinical, epidemiology, and laboratory studies. I propose to use unbiased genomic approaches for the discovery of novel candidate genes as markers of outcome of chemotherapy. The same approaches will be also applied to identify novel candidates of cancer susceptibility by benefiting from publicly available resources of GW information from control individuals without cancer. Enrichment of the information generated from the GW data will be derived from additional genotyping and/or resequencing of genomic regions that showed significant associations in the GWAS. It is very likely that the significant single nucleotide polymorphisms (SNPs) in the GWAS will not have an established molecular function, and several strategies will be used to support the observed clinical associations. The proposed research plan and subsequent investigations will substantially increase the understanding of the pleiotropic effects of heritable genetic information in humans. This work will provide a knowledge framework for designing controlled replication studies of treatment outcome and cancer risk using highly selected informative markers. These applications could inform interventions designed to establish the risk-benefit ratio of cancer chemotherapy and to reduce the prevalence of cancer in the population.