Multi-Ancestry Mapping of Pancreatic Cancer Susceptibility Loci

胰腺癌易感性位点的多祖先作图

基本信息

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
项目类别：
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

项目摘要

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. !

该应用的目标是提高我们对胰腺癌遗传基础的了解。胰腺癌目前是美国癌症死亡的第三大原因，预计 2019 年，美国将新诊断出 56,770 例胰腺癌。在过去十年中，胰腺癌的发病率一直在稳步上升。尽管胰腺癌的发病率与美国白人相比，非裔美国人的发病率更高，但没有出现大规模的迄今为止对非裔美国人胰腺癌进行的大规模遗传学研究。此外，相对胰腺导管腺癌 (PDAC) 的罕见性和快速致命的病程导致无论祖先群体如何，所有先前的全基因组关联研究的样本量都有限。作为由于统计能力有限，许多常见的 PDAC 位点尚未确定。规模宏大、形式多样需要对 PDAC 进行合作研究，以极大地增进我们对 PDAC 遗传基础的理解这种致命的疾病。我们的提案旨在专门解决这一需求。首先，我们将进行第一个通过全基因组专门针对非裔美国人进行胰腺癌风险的遗传研究测序。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、成功的胰腺癌联盟——胰腺癌联盟的控制队列联盟和胰腺癌病例控制联盟 (PanC4)。其次，我们还拓展了我们有能力通过将先前 GWAS 的规模加倍来检测所有种族的胰腺癌关联研究并进行了第一个关于胰腺癌风险的多种族遗传研究。我们将同时进行祖先分层和祖先知情分析，包括单变异和基于基因的测试胰腺癌患者和对照组的关联。另外，我们还会进行基因x环境与吸烟、体重指数、糖尿病和酒精摄入等已知危险因素的相互作用分析。具体目标该项目的目标是：目标 1：确定非裔美国人人群中的胰腺癌易感位点，目标 2：通过多种族 GWAS 分析确定新的胰腺癌位点；目标 3：精细绘制地图与胰腺癌风险相关的区域。总之，本申请旨在识别新型胰腺癌症位点，对非洲血统个体进行首次胰腺癌基因分析，以及利用跨群体遗传多样性来精细绘制已知的胰腺癌易感性位点。！