Genetic Etiology of Cancer Drug Response

描述（由申请人提供）：在大多数常见癌症的治疗方面继续取得重要进展，但治疗效果仍然难以预测，严重或致命的不良事件经常发生。人类基因组计划推动了这样一种观念，即遗传信息可以为个体患者提供有效且成本效益高的治疗选择，但预测大多数化疗方案反应的有效遗传特征仍有待确定。许多基因可能影响药物反应，但目前的候选基因方法受到有关基因的先验知识要求的限制，而且大多数临床试验的中等规模往往限制了体外基因组广泛关联研究（GWAS）用于癌症药物基因组学发现的能力。为了应对这些限制，我们对大多数FDA批准的抗癌化合物的细胞毒性作用进行了彻底的药物基因组学评估，使用离体模型系统来确定药物诱导细胞杀伤的遗传性，以优先考虑药物基因组学制图。这些结果是重要的第一步，虽然一个性状的高遗传力并不能保证成功的关联作图结果，但它代表了重要的第一步，结果将用于优先考虑具有高遗传力的药物进行全基因组关联作图。在目前的建议中，将在欧美人群中进行细胞毒性药物的GWAS图谱绘制，然后在东亚人群中进行复制GWAS图谱绘制。除了发现和验证预测药物反应的遗传变异外，收集的大量数据将用于剖析药物反应特征的潜在病因，包括评估变异的遗传、环境和相互作用成分的相对贡献。这些结果将为宝贵的临床人群资源的随访提供重要的遗传变异优先级，并可能揭示药物反应的总体病因学的新见解。

DESCRIPTION (provided by applicant): Important progress continues to be made in the treatment of most common cancers, but therapeutic benefit remains difficult to predict and severe or fatal adverse events occur frequently. The Human Genome Project has fueled the notion that genetic information can produce effective and cost-efficient selection of therapies for individual patients, but validated genetic signatures that predict response to most chemotherapy regimens remain to be identified. Numerous genes potentially influence drug response, but current candidate-gene approaches are limited by the requirement of a priori knowledge about the genes involved and the moderate size of most clinical trials often limits the power of in vitro genome wide association studies (GWAS) for cancer pharmacogenomics discovery. In response to these limitations, we have undertaken a thorough, pharmacogenomic assessment of cytotoxic effect of the majority of FDA approved anti-cancer compounds using an ex vivo model system to determine the heritability of drug-induced cell killing to prioritize drugs for pharmacogenomic mapping. These results are an important first step, and while high heritability of a trait does not guarantee successful association mapping results, it represents an important first step and the results will be used to prioritize drugs with high heritabilities for genome-wide association mapping. In the current proposal, GWAS mapping of cytotoxic agents will be performed in a European American population, and then replication GWAS mapping will be performed in an East Asian population. In addition to discovering and validating genetic variants that predict drug response, the wealth of data collected will be used to dissect the underlying etiology of drug response traits, including assessing the relative contribution of genetic, environmental, and interaction components of variation. These results will provide crucial insight to prioritize genetic variants for follow-up in precious clinical population resources, and potentially reveal new insight into the overall etiology of drug responses.