Validation and Fine-Scale Mapping of Pancreatic Cancer Susceptibility Loci (Study)

 描述(申请人提供)：遗传遗传因素在胰腺癌风险中起重要作用，高达10%的胰腺癌患者报告有家族病史。尽管我们过去在使用全基因组关联方法识别低风险的常见胰腺癌易感基因或使用基因组测序识别高外显性基因方面取得了成功。胰腺癌的大部分遗传基础仍未得到解释。因此，我们假设，通过将这两个独特的数据集(Gwas和全基因组测序)结合在一起，我们将能够解决我们之前分析的一些局限性，并识别新的胰腺癌易感基因。此外，利用我们的整个基因组测序数据，我们将能够精细绘制最近相关的区域，并为未来的功能研究制定一个优先的变异列表。我们将首先实现这些目标，对593个家族性胰腺癌家族中的638名患者的全基因组测序数据进行关联分析，并与818名对照进行比较。然后，我们使用这些基因组测序数据将这些变异归因于9,220名胰腺癌患者和12,567名对照，然后对推定的数据进行关联分析。我们还将使用这些输入数据来精细绘制先前建立的胰腺癌易感基因座图。然后，将在大约6000名胰腺癌患者和5500名对照中直接对候选变异进行基因分型。我们预计这项工作将识别新的胰腺癌易感性变异，以及识别可能构成最近报道的一些关联信号的功能变异。这将为识别与这些关联信号有关的功能变异以及环境因素如何与变异相互作用铺平道路，这反过来将提高我们对胰腺癌病因的理解。

 DESCRIPTION (provided by applicant): Inherited genetic factors play an important role in pancreatic cancer risk with up to 10% of patients with pancreatic cancer reporting a family history of disease. Despite our past successes in identifying low-risk common pancreatic cancer susceptibility loci using genome-wide association approaches or high-penetrance genes using genomic sequencing. Much of the genetic basis of pancreatic cancer remains unexplained. Therefore, we hypothesize that by bringing together these two unique datasets (GWAS and whole-genome sequencing) we will be able to address some of the limitations of our previous analyses and identify novel pancreatic cancer susceptibility loci. Furthermore, leveraging our whole genome sequencing data we will be able to fine-map recently associated regions and develop a prioritized list of variants for future functional studies. We will accomplish these goal first conducting association analysis of whole genome sequencing data from 638 patients in 593 familial pancreatic cancer kindreds compared to 818 controls. We then use this genomic sequencing data to impute these variants into 9,220 pancreatic cancer patients and 12,567 controls followed by association analysis of the imputed data. We will also use this imputed data to fine-map previously established pancreatic cancer susceptibility loci. Candidate variants will then be directly genotyped in approximately 6,000 pancreatic cancer patients and 5,500 controls. We anticipate this work will identify novel pancreatic cancer susceptibility variants as well as identify putatively functional variants that may underlie some of the recently reported association signals. This will pave the way for identification of functional variants responsible fr these association signals and how environmental factors interact with the variants, which in turn will improve our understanding of the etiology of pancreatic cancer.