Genetic Etiology of Cancer Drug Response

癌症药物反应的遗传病因学

• 批准号: 8246212
• 负责人: RONALD M KRAUSS
• 金额: $ 50.01万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8246212
• 关键词: Adverse event; American; Antineoplastic Agents; Asians; Biological Models; Candidate Disease Gene; Chemotherapy-Oncologic Procedure; Clinical; Clinical Trials; Cytotoxic agent; Data; Etiology; European; FDA approved; Future; Genes; Genetic; Genetic Predisposition to Disease; Genome; Genotype; Goals; Heritability; Human Genome Project; In Vitro; Individual; Knowledge; Malignant Neoplasms; Maps; Outcome; Patients; Pharmaceutical Preparations; Pharmacogenomics; Phenotype; Population; Relative (related person); Resources; Therapeutic; Variant; Work; cell killing; cohort; cost effective; cytotoxic; follow-up; gene environment interaction; genetic association; genetic variant; genome wide association study; genome-wide; insight; interest; response; trait

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. PUBLIC HEALTH RELEVANCE: We will build on our previous work to conduct ex vivo GWAS studies in two large, independent population cohorts on drug response phenotypes, and use cutting-edge statistical approaches to dissect the genetic etiology of these traits. Our overall goal is to identify high interest genes and characterize the trait etiology of these drug response outcomes so that they may be further investigated in future studies. This application leverages previously completed genome-wide genotyping for efficient association mapping, and will evaluate genetic associations in two independent cohorts.

描述(申请人提供)：大多数常见癌症的治疗继续取得重要进展，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。人类基因组计划助长了这样一种观念，即遗传信息可以为个别患者带来有效和成本效益高的治疗选择，但预测大多数化疗方案疗效的有效基因签名仍有待确定。许多基因可能会影响药物的反应，但目前的候选基因方法受到对所涉及基因的先验知识的限制，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)发现癌症药物基因组学的能力。为了应对这些局限性，我们对FDA批准的大多数抗癌化合物的细胞毒作用进行了彻底的药物基因组学评估，使用体外模型系统来确定药物诱导细胞杀伤的遗传性，以确定药物的优先药物基因组图谱。这些结果是重要的第一步，虽然一个性状的高遗传力不能保证成功的关联作图结果，但它代表着重要的第一步，结果将被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。在目前的提议中，将在欧洲美洲人群中进行细胞毒剂的GWA谱绘制，然后在东亚人口中进行复制GWAS图绘制。除了发现和验证预测药物反应的遗传变异外，收集的丰富数据还将用于剖析药物反应特征的潜在病因学，包括评估变异的遗传、环境和交互作用成分的相对贡献。这些结果将为在宝贵的临床人群资源中优先处理遗传变异提供重要的见解，并可能揭示药物反应的总体病因学的新见解。 公共卫生相关性：我们将在之前工作的基础上，在两个大型、独立的人群队列中进行关于药物反应表型的体外GWAS研究，并使用尖端统计方法来剖析这些特征的遗传病因。我们的总体目标是识别高兴趣基因并表征这些药物反应结果的特征病因，以便在未来的研究中进一步研究它们。这项应用利用之前完成的全基因组基因分型来进行有效的关联映射，并将评估两个独立队列中的遗传关联。