Leveraging GxE interaction to understand pancreatic cancer and altered metabolism

利用 GxE 相互作用来了解胰腺癌和代谢改变

• 批准号: 8805140
• 负责人: PETER KRAFT
• 金额: $ 23.04万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-03 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8805140
• 关键词: Accounting; Biological Markers; Biology; Body mass index; Cancer Etiology; Case-Control Studies; Cessation of life; Characteristics; Cohort Studies; Data; Development; Diabetes Mellitus; Diagnosis; Diagnostic; Disease; Disease Progression; Early Diagnosis; Environmental Exposure; Environmental Risk Factor; Family history of; Genetic; Genetic Markers; Genetic Risk; Genetic study; Genomics; Incidence; Individual; Joints; Knowledge; Light; Link; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Metabolic; Metabolism; Modeling; Multivariate Analysis; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Pancreatic Adenocarcinoma; Patients; Publishing; Recording of previous events; Research; Resources; Risk Factors; Risk Marker; Role; Smoking; Statistical Methods; Time; United States; Variant; Work; base; cancer epidemiology; cancer initiation; cancer risk; cancer therapy; clinical risk; cohort; experience; gene environment interaction; genome wide association study; genome-wide; high risk; insight; member; metabolomics; multidisciplinary; novel; prospective; public health relevance; risk variant; screening; tool

DESCRIPTION (provided by applicant): Pancreatic cancer is an aggressive disease: only 5% of patients survive five years after diagnosis. As a consequence, despite being relatively rare, it is the fourth leading cause of cancer death in the United States. Over 80% of patients with pancreatic adenocarcinoma have incurable disease at the time of diagnosis, due in part to a limited understanding of the factors that govern early disease progression. Known risk alleles explain a tiny fraction of the familial aggregation of pancreatic cancer. Research linking clinical risk factors, genetics, and emerging biomarkers including metabolomics can identify new risk factors, shed light on disease mechanism, and identify individuals at high-risk who might benefit from intensive screening. We recently conducted large-scale studies of genetic, metabolomics, and clinical risk factors associated with pancreatic cancer. We propose to use the unique data we developed for these previous studies to identify novel genetic markers associated with pancreatic cancer risk. We propose the following specific aims: (1) Conduct candidate and genome-wide association scans for SNPs associated with pancreatic cancer, leveraging potential interactions with known risk factors individually and in aggregate; (2) conduct genome wide association scans for SNPs associated with 83 circulating metabolites, leveraging potential interactions with known risk factors individually and in aggregate; and (3) conduct analyses to assess whether the effects of genetic and environmental risk factors are mediated through alterations in metabolic profiles. We have assembled a multidisciplinary team with expertise in pancreatic cancer epidemiology and treatment, statistical genetics, and genomics. Alongside our experience with previous GWAS and metabolomic profiling studies of pancreatic cancer, team members have extensive experience in the development and application of statistical methods for the analysis of gene-environment interaction. This project will capitalize on existing resources to expand our knowledge of the genetic basis of pancreatic cancer and the role of altered metabolism in cancer development. Findings from this study will help develop markers of risk and subclinical development, which could provide sorely needed tools for screening and early detection, and they will help identify targets for potential treatments.

描述（由申请人提供）：胰腺癌是一种侵略性疾病：只有5％的患者在诊断后五年生存。结果，尽管相对罕见，但 是美国癌症死亡的第四个主要原因。超过80％的胰腺腺癌患者在诊断时患有无法治愈的疾病，部分原因是对控制早期疾病进展的因素的了解有限。已知的风险等位基因解释了胰腺癌家族性聚集的很小一部分。链接临床的研究 危险因素，遗传学和包括代谢组学在内的新兴生物标志物可以识别新的危险因素，阐明疾病机制，并在高风险中识别可能从密集筛查中受益的个人。我们最近对与胰腺癌相关的遗传，代谢组学和临床风险因素进行了大规模研究。我们建议使用为这些先前研究开发的独特数据来识别与胰腺癌风险相关的新型遗传标记。我们提出以下具体目的：（1）进行候选和全基因组关联扫描与胰腺癌相关的SNP，从而利用与已知风险因素的潜在相互作用，分别和骨料； （2）对与83个循环代谢产物相关的SNP进行基因组范围的扫描，利用与已知风险因素的潜在相互作用分别和骨料中的潜在相互作用； （3）进行分析以评估遗传和环境风险因素的影响是否是通过代谢谱的改变介导的。我们组建了一个具有胰腺癌流行病学和治疗，统计遗传学和基因组学专业知识的多学科团队。除了我们对胰腺癌的GWAS和代谢组分析研究的经验外，团队成员在开发和应用统计方法方面具有丰富的经验，用于分析基因环境相互作用。该项目将利用现有资源，以扩大我们对胰腺癌遗传基础的了解以及代谢改变在癌症发展中的作用。这项研究的发现将有助于开发风险和亚临床发展的标志，这可以为筛查和早期检测提供迫切需要的工具，它们将有助于确定潜在治疗的目标。