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）

基本信息

批准号：
9245636
负责人：
Alison P Klein
金额：
$ 64.64万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
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/9245636
关键词：
13q12 1q32 22q12 3q29 5p15.33 9q34 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 Privatization Reporting 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 risk design exome exome sequencing genetic variant genome sequencing genome wide association study genome-wide improved kindred novel public health relevance success targeted sequencing whole genome

项目摘要

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（适用提供）：遗传因素在胰腺癌风险中起着重要作用，多达10％的胰腺癌患者报告了疾病家族史。尽管我们过去在使用全基因组关联方法或使用基因组测序的高风险胰腺癌易感性局部鉴定出低风险的普通胰腺癌易感性局部取得了成功。胰腺癌的大部分遗传基础仍然出乎意料。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）汇总在一起，我们将能够解决我们先前分析的某些局限性并确定新颖的胰腺癌易感性位置。此外，利用我们的整个基因组测序数据，我们将能够罚款最近关联的区域，并为未来功能研究制定优先级的变体列表。我们将完成这些目标的首次进行联想分析，对593例家庭胰腺癌中638例患者的整个基因组测序数据进行分析，而818例对照组则是。然后，我们使用此基因组测序数据将这些变体归为9,220例胰腺癌患者，并将12,567个对照组合为对估算数据的关联分析。我们还将使用这些估算的数据来填充先前确定的胰腺癌易感性局部。然后，将在约6,000名胰腺癌患者和5500例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颖的胰腺癌易感性变体，并确定可能是一些最近报道的关联信号的推测功能变体。这将为识别负责这些关联信号的功能变体以及环境因素与变体如何相互作用的功能变体铺平道路，这反过来又可以提高我们对胰腺癌病因的理解。