Multi-Ancestry Mapping of Pancreatic Cancer Susceptibility Loci

本申请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大原因， 2019年美国将有56,770例新的胰腺癌诊断。近十年来 胰腺癌的发病率一直在稳步上升。尽管胰腺癌的发病率 与美国白色人口相比，非洲裔美国人的发病率更高， 迄今为止，在非裔美国人中进行的大规模胰腺癌遗传研究。此外，相对 胰腺导管腺癌（PDAC）的罕见性和快速致命的疾病过程导致 所有先前的全基因组关联研究的样本量有限，无论祖先群体如何。作为 由于有限的统计能力，这些常见的PDAC基因座还有待鉴定。规模大、形式多样 PDAC的合作研究，需要大大增加我们对遗传基础的理解， 这种致命的疾病。我们的建议是专门针对这一需要而设计的。首先，我们将进行第一次 胰腺癌风险的遗传学研究通过全基因组特别关注非洲裔美国人 测序作为这项研究的一部分，我们将非洲裔美国胰腺癌患者聚集在一起， 我们的两个大型成功的胰腺癌联盟，胰腺癌 队列联盟和胰腺癌病例对照联盟（PanC4）。其次，我们还扩大 我们通过将既往GWAS的规模增加一倍来检测所有种族中胰腺癌相关性的能力 研究并进行了第一次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的分析，包括单一变异和基于基因的测试， 胰腺癌患者和对照组的相关性。此外，我们将进行基因x环境 与吸烟、BMI、糖尿病和饮酒等已知危险因素的相互作用分析。的具体目标 该项目是：目的1：鉴定非裔美国人群体中的胰腺癌易感性基因座， 目的2：通过多种族GWAS分析确定新的胰腺癌位点;目的3：精细定位 与胰腺癌风险相关的区域。总之，本申请寻求鉴定新的胰腺癌细胞。 癌症基因座，在非洲癌症个体中进行首次胰腺癌遗传分析， 利用交叉群体遗传多样性来精细绘制已知的胰腺癌易感基因座。 !

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. !