Genome-wide Pleiotropy Scan across Multiple Cancers

项目摘要 癌症是一种常见但复杂的疾病，围绕其潜在的问题有许多尚未解决的问题。 遗传基础最近的研究表明，一些表型不同的癌症可能是由于类似的 遗传因素我们建议使用现有的遗传措施来评估这种潜在的多效性， Kaiser Permanente基因、环境和健康研究项目。这 队列包括超过110，266个具有全基因组阵列数据的个体，其中22，575个个体将 在这个项目开始之前被诊断出患有癌症。我们将利用这些信息进行 全面评估癌症的共同遗传基础。特别是，我们的初步目标将 评估不同癌症部位的遗传性和总体共享遗传基础。然后我们会调查 特定的遗传变异是否会影响不同癌症的风险，将我们的分析信息纳入其中， 关于癌症器官系统和可能改变遗传关联的暴露（例如，吸烟）。我们的第三 aim将破译发生在同一个体中的多种癌症的遗传基础，包括外显子组。 对队列中约1，800名被诊断患有多种癌症的个体及其基因进行测序 家庭成员可用。基于我们从这些目标中获得的发现，我们将评估潜在的生物学 和显示致癌多效性的遗传变异的功能相关性。总体而言，该项目 提供了一个独特的，创新的，有效的机会，以检测多效性协会在一系列的 在一个单一的大的队列中的癌症位点。来自基本上以人群为基础的研究的个人水平数据 这使我们能够评估关于多种癌症共有遗传基础的新假设， 补充了最常见癌症部位的不同GWAS的现有荟萃分析工作。 了解这种潜在的致癌多效性可能有助于澄清这种疾病的生物学基础， 解释和预测多种癌症的发生，并深入了解可能的治疗策略， 患有不同癌症的病人

Project Summary Cancer is a common but complex disease with a number of unresolved issues surrounding its underlying genetic basis. Recent work suggests that some phenotypically distinct cancers may arise due to similar genetic factors. We propose to evaluate this potential pleiotropy using existing genetic measures in the large, well-characterized Kaiser Permanente Research Program in Genes, Environment and Health cohort. This cohort includes over 110,266 individuals with a genome-wide array data, and 22,575 of these individuals will have been diagnosed with cancer by the start of this project. We will leverage this information to undertake a comprehensive evaluation of the shared genetic basis underlying cancers. In particular, our initial aim will evaluate the heritability and overall shared genetic basis of different cancers sites. Then we will investigate whether specific genetic variants impact risk of different cancers, incorporating into our analyses information about cancer organ systems and exposures that may modify the genetic associations (e.g., smoking). Our third aim will decipher the genetic basis of multiple cancers occurring in the same individual, including exome sequencing of the approximately 1,800 individuals diagnosed with multiple cancers in the cohort and their family members as available. Based on our findings from these aims, we will evaluate the potential biological and functional relevance of genetic variants exhibiting carcinogenic pleiotropy. Taken together, this project provides a unique, innovative, and efficient opportunity to detect pleotropic associations across a range of cancer sites in a single, large cohort. he individual-level data from an essentially population-based study allows us to evaluate novel hypotheses about the shared genetic basis of multiple cancers, and nicely complements existing meta-analyses efforts across different GWAS of the most common cancer sites. Understanding such potential carcinogenic pleiotropy may help clarify the biological basis of this disease, explain and predict the occurrence of multiple cancers, and insights into possible treatment strategies among patients with seemingly distinct cancers.