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

胰腺癌易感性位点的验证和精细绘图（研究）

• 批准号: 9038044
• 负责人: Alison P Klein
• 金额: $ 73.52万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9038044
• 关键词: 1q32.1; 3q29; 5p15.33; Address; Adenocarcinoma; Affect; Biological Assay; Cancer Etiology; Cancer Patient; Cancer-Predisposing Gene; Case-Control Studies; Cessation of life; Custom; DNA; Data; Data Set; Diagnosis; Disease; Environmental Risk Factor; Etiology; Family; Family history of; First Degree Relative; Funding; Future; Genes; Genetic; Genomic Segment; Genomics; Genotype; Goals; Heritability; Inherited; Malignant neoplasm of pancreas; Maps; Methods; Oncogenes; Pancreas; Pancreatic Adenocarcinoma; Patients; Penetrance; Play; Preparation; Process; Reporting; Research Design; Risk; Role; SNP array; Sample Size; Sampling; Sequence Analysis; Series; Signal Transduction; Survival Rate; Susceptibility Gene; United States; Validation; Variant; Work; advanced disease; base; cancer genome; cancer risk; exome; exome sequencing; genetic variant; genome sequencing; genome wide association study; genome-wide; improved; kindred; novel; public health relevance; success; targeted sequencing; whole genome

 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.

 描述（由申请人提供）：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。尽管我们过去成功地使用全基因组关联方法确定了低风险的常见胰腺癌易感基因位点，或使用基因组测序确定了高风险基因。胰腺癌的大部分遗传基础仍然无法解释。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以前分析的一些局限性，并确定新的胰腺癌易感基因座。此外，利用我们的全基因组测序数据，我们将能够对最近相关的区域进行精细映射，并为未来的功能研究开发优先的变体列表。我们将首先对593例家族性胰腺癌患者的638例全基因组测序数据进行关联分析，并与818例对照组进行比较。然后，我们使用这些基因组测序数据将这些变异输入到9，220名胰腺癌患者和12，567名对照中，然后对输入数据进行关联分析。我们还将使用该插补数据来精细定位先前建立的胰腺癌易感性基因座。然后将在大约6,000名胰腺癌患者和5,500名对照中直接对候选变体进行基因分型。我们预计这项工作将确定新的胰腺癌易感性变异，以及确定可能是最近报道的一些相关信号的基础的puerectin功能变异。这将为识别负责这些关联信号的功能变体以及环境因素如何与变体相互作用铺平道路，这反过来将提高我们对胰腺癌病因学的理解。