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（由申请人提供）：遗传因素在胰腺癌风险中发挥着重要作用，尽管我们过去成功地利用低风险常见胰腺癌易感位点，但仍有高达 10% 的胰腺癌患者有家族病史。全基因组关联方法或使用基因组测序的高外显率基因仍然无法解释，因此，我们通过将这两个独特的数据集结合在一起来实现这一目标。（GWAS 和全基因组测序）我们将能够解决之前分析的一些局限性，并确定新的胰腺癌易感位点。此外，利用我们的全基因组测序数据，我们将能够精细绘制最近相关的区域和区域。我们将首先对 593 个家族性胰腺癌家族的 638 名患者与 818 名对照者的全基因组测序数据进行关联分析，为未来的功能研究制定优先顺序的变体列表。我们还将利用基因组测序数据将这些数据归入 9,220 名胰腺癌患者和 12,567 名对照者中，然后对归算数据进行关联分析，然后对先前建立的胰腺癌易感位点进行精细定位，然后对候选变异进行大约基因分型。我们预计这项工作将鉴定 6,000 名胰腺癌患者和 5,500 名对照者，并鉴定新的胰腺癌易感性变异。推定的功能变异可能是最近报道的一些关联信号的基础，这将为识别这些关联信号的功能变异以及环境因素如何与变异相互作用铺平道路，这反过来又将提高我们对胰腺病因学的理解。癌症。