Genome-wide Pleiotropy Scan across Multiple Cancers

项目摘要 癌症是一种常见但复杂的疾病，围绕其潜在的许多问题尚未解决 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方法来评估这种潜在的多效性， 凯撒永久基因、环境和健康队列研究计划。这 队列包括超过110,266个拥有全基因组阵列数据的个体，其中22,575个个体将 在这个项目开始时都被诊断出患有癌症。我们将利用这些信息进行 对共同的癌症基因基础进行综合评估。特别是，我们最初的目标将是 评估不同癌症部位的遗传力和总体共有的遗传基础。然后我们会调查 特定的基因变异是否会影响不同癌症的风险，将信息纳入我们的分析 关于癌症器官系统和可能改变遗传联系的暴露(例如，吸烟)。我们的第三个 AIM将破译发生在同一个人身上的多种癌症的遗传基础，包括外显子组 队列中约1,800名被诊断患有多种癌症的人及其 有空的家庭成员。基于我们从这些目标中发现的，我们将评估潜在的生物学 以及表现出致癌多效性的基因变体的功能相关性。总而言之，这个项目 提供了一种独特、创新和高效的机会来检测一系列 在单一的，大的队列中的癌症地点。个人层面的数据来自一项基本上以人群为基础的研究 使我们能够评估关于多种癌症共同遗传基础的新假设，并很好地 补充现有的荟萃分析工作，跨越最常见的癌症部位的不同GWA。 了解这种潜在的致癌多效性可能有助于阐明这种疾病的生物学基础。 解释和预测多种癌症的发生，以及对可能的治疗策略的洞察 看似截然不同的癌症患者。

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.