Multi-Ancestry Mapping of Pancreatic Cancer Susceptibility Loci

胰腺癌易感性位点的多祖先作图

• 批准号: 10159226
• 负责人: Alison P Klein
• 金额: $ 50.4万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-05 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10159226
• 关键词: Address; African; African American; Age; Alcohol consumption; Asians; BRCA1 gene; BRCA2 gene; Body mass index; CDKN2A gene; Cancer Control; Cancer Etiology; Cancer Patient; Cessation of life; DNA; Data; Diabetes Mellitus; Diagnosis; Disease; Ethnic group; Etiology; European; Family history of; Frequencies; Funding; Genes; Genetic; Genetic Variation; Genetic study; Genomic Segment; Genotype; Geographic Locations; Goals; Hereditary Disease; Heritability; Incidence; Individual; Inherited; Knowledge; Laboratory Research; Lead; Malignant Neoplasms; Malignant neoplasm of pancreas; Maps; Meta-Analysis; Methods; Mismatch Repair; Mutation; National Cancer Institute; Newly Diagnosed; Oncogenes; PALB2 gene; Pancreatic Ductal Adenocarcinoma; Pathogenicity; Patients; Population; Population Genetics; Population Group; Prevention; Research; Risk; Risk Factors; Role; Sample Size; Signal Transduction; Smoking; Susceptibility Gene; Testing; Twin Multiple Birth; United States; Variant; Work; admixture mapping; base; cancer diagnosis; cancer genomics; cancer risk; case control; cohort; design; epidemiology study; exome sequencing; gene environment interaction; gene repair; genetic analysis; genetic testing; genome sequencing; genome wide association study; genome-wide analysis; genomic locus; improved; multi-ethnic; novel; pancreatic cancer patients; recruit; risk variant; study population; whole genome

The goal of this application is to improve our understanding of the genetic basis of pancreatic cancer. Pancreatic cancer is currently the 3rd leading cause of cancer death in the United States and it is projected there will be 56,770 new pancreatic cancer diagnosed in the United States in 2019. Over the past decade the incidence of pancreatic cancer has been steadily increasing. Despite the fact that pancreatic cancer incidence rates are higher among African Americans compared to the US White population there have been no large- scale genetic studies of pancreatic cancer in African Americans conducted to date. Furthermore, the relative rarity of pancreatic ductal adenocarcinoma cancer (PDAC) and the rapidly fatal disease course has resulted in limited samples sizes for all prior genome-wide association studies regardless of ancestral population. As such many common PDAC loci have yet to be identified due to limited statistical power. Large-scale, diverse collaborative studies of PDAC, are needed to dramatically increase our understanding of the inherited basis of this deadly disease. Our proposal is designed to specifically address this need. First, we will conduct the first genetic study of pancreatic cancer risk specifically focused on African Americans through whole genome sequencing. As part of this study we are bringing together African American pancreatic cancer patients and controls from our two, large established, successful pancreatic cancer consortiums, the Pancreatic Cancer Cohort Consortium and the Pancreatic Cancer Case Control Consortium (PanC4). Secondly, we also expand our power to detect pancreatic cancer association across all ethnic groups by doubling the size of prior GWAS studies and conducting the first multi-ethnic genetic study of pancreatic cancer risk. We will conduct both ancestry stratified and ancestry-informed analysis including both single variant and gene-based tests of association of pancreatic cancer patients and controls. In addition, we will conduct gene x environment interaction analysis with known risk factors of smoking, BMI, diabetes, and alcohol intake. The specific aims of the project are to: Aim 1: To identify pancreatic cancer susceptibility loci in the African American population, Aim 2: To identify novel pancreatic cancer loci through multi-ethnic GWAS analyses; Aim 3: To fine-map regions associated with pancreatic cancer risk. In summary, this application seeks to identify novel pancreatic cancer loci, conduct the first genetic analysis of pancreatic cancer in individuals of African Ancestry, and leverage cross population genetic diversity to fine-map known pancreatic cancer susceptibility loci. !

该应用的目的是提高我们对胰腺癌遗传基础的理解。 胰腺癌目前是美国癌症死亡的第三主要原因，预计 2019年，美国将有56,770个新的胰腺癌。在过去的十年中 胰腺癌的发病率一直在稳步增加。尽管事实是胰腺癌发病率 与美国白人相比，非洲裔美国人的比率更高。 迄今为止，非洲裔美国人的胰腺癌的规模遗传研究。此外，亲戚 胰腺导管腺癌癌（PDAC）的稀有性和快速致命的疾病病程已导致 所有先前全基因组关联研究的样品量有限，无论祖先人群如何。作为 由于统计能力有限，因此尚未确定如此常见的PDAC基因座。大规模，多样 需要对PDAC进行协作研究，以极大地增加我们对继承的理解 这种致命的疾病。我们的建议旨在特别满足这一需求。首先，我们将进行第一个 胰腺癌风险的遗传研究专门针对非裔美国人，通过整个基因组 测序。作为这项研究的一部分，我们将非裔美国胰腺癌患者和 来自我们两个大型，成功的胰腺癌财团，胰腺癌的控制 队列联盟和胰腺癌病例对照联盟（PANC4）。其次，我们也扩展 我们通过将先前GWA的规模加倍来检测所有种族群体胰腺癌协会的能力 研究并进行了胰腺癌风险的首次多民族遗传研究。我们将进行两者 祖先分层和祖先信息分析，包括单个变体和基于基因的测试 胰腺癌患者和对照组的关联。此外，我们将进行基因X环境 与吸烟，BMI，糖尿病和酒精摄入量的已知危险因素的相互作用分析。具体目的 该项目是：目标1：确定非裔美国人人口中的胰腺癌易感位点， 目标2：通过多种族的GWAS分析来鉴定新的胰腺癌基因座；目标3：进行绘制图 与胰腺癌风险相关的区域。总而言之，该应用程序旨在识别新颖的胰腺 癌症基因座，对非洲血统个体的胰腺癌进行了首次遗传分析， 利用跨种群的遗传多样性来为已知的胰腺癌易感位点。 呢