Validation and Fine-Scale Mapping of Pancreatic Cancer Susceptibility Loci

胰腺癌易感性位点的验证和精细绘图

• 批准号: 8249831
• 负责人: Alison P Klein
• 金额: $ 59.94万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8249831
• 关键词: 1q32.1; 5p15.33; BRCA2 gene; Cancer Etiology; Cancer Patient; Case-Control Studies; Cessation of life; Chromosomes; Collection; Colon Carcinoma; Custom; DNA; Data; Data Analyses; Development; Diabetes Mellitus; Diagnosis; Disease; Epidemiology; Europe; Family history of; Gene Frequency; Gene Mutation; Genes; Genetic; Genome; Genotype; Goals; Hereditary Disease; Individual; Inherited; Joints; Malignant Neoplasms; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Maps; Pancreatitis; Pathway interactions; Patients; Penetrance; Play; Predisposition; Recording of previous events; Risk; Risk Factors; Role; Signal Transduction; Single Nucleotide Polymorphism Map; Smoking; Survival Rate; Susceptibility Gene; Translating; United States; Validation; Variant; base; cancer genome; cancer risk; case control; cigarette smoking; follow-up; genetic analysis; genome wide association study; genome-wide; high risk; improved; malignant breast neoplasm; member; novel; public health relevance; tool

DESCRIPTION (provided by applicant): Pancreatic cancer is the 4th leading cause of cancer death in the United States. This is in large part due to the rapidly fatal course of this disease, as the vast majority of patients die within months of diagnosis and the five- year survival rate is less than 5%. Like all cancers, pancreatic cancer is a fundamentally genetic disease caused by inherited and acquired genetic mutations. Two genome-wide association studies of pancreatic cancer, PanScan I and PanScan II, have recently been completed. These studies have identified four promising regions involved in pancreatic cancer susceptibility: ABO rs505922 (P=4.3.10-6), two correlated SNPs on chromosome 13q22.1, rs9543325 (P=3.3.10-11) and rs9564966 (P=5.9.10-8), rs3790844 (P=2.4.10-10) on chromosome 1q32.1, and rs401681 (P=3.7.10-7) on 5p15.33. The goal of this project is to conduct fine-mapping and large-scale validation genotyping of the potential pancreatic cancer susceptibility variants identified in the recently completed PanScan I and PanScan II studies, in an independent set of 4,000 cases and 4,000 controls from over 10 studies. This will be the first well-powered large-scale replication of these findings. Joint-analysis of these data with the data from PanScanI and II will also be conducted. We will also determine known risk factors for pancreatic cancer including, cigarette smoking and diabetes modify these associations. PUBLIC HEALTH RELEVANCE: Genome-wide association studies (GWAS) are powerful tools to identify changes in DNA associated with diseases. These studies have identified many genes that play an important role in breast, prostate and colon cancers but the first of these studies have only recently been completed for pancreatic cancer. Before the findings of these studies can be translated into the patient setting, replication of the initial findings needs to be conducted to establish that changes in DNA are "truly" associated with pancreatic cancer, not false findings. Furthermore, follow-up GWA studies also have the potential to identify novel associations. Therefore the goal of this study will be to validate the initial pancreatic cancer GWAS findings and identify novel DNA changes that may be associated with pancreatic cancer.

描述（由申请人提供）：胰腺癌是美国癌症死亡的第四大原因。这在很大程度上是由于这种疾病的快速致命过程，因为绝大多数患者在诊断后几个月内死亡，五年生存率低于5%。与所有癌症一样，胰腺癌是一种由遗传和获得性基因突变引起的基本遗传性疾病。最近完成了两项胰腺癌全基因组关联研究PanScan I和PanScan II。这些研究已经确定了四个与胰腺癌易感性有关的有希望的区域：ABO rs505922（P = 4.3.10 - 6），染色体13q22.1上的两个相关SNP，rs9543325（P = 3.3.10 - 11）和rs9564966（P = 5.9.10 - 8）、rs3790844（P = 2.4.10 - 10）和rs401681（P = 3.7.10 - 7）位于染色体1q32.1和5p15.33。该项目的目标是对最近完成的PanScan I和PanScan II研究中确定的潜在胰腺癌易感性变体进行精细定位和大规模验证基因分型，这些研究包括来自10多项研究的4，000例病例和4，000例对照。这将是这些发现的第一次有力的大规模复制。还将对这些数据与PanScanI和II的数据进行联合分析。我们还将确定胰腺癌的已知风险因素，包括吸烟和糖尿病改变这些关联。 公共卫生相关性：全基因组关联研究（GWAS）是识别与疾病相关的DNA变化的有力工具。这些研究已经确定了许多在乳腺癌，前列腺癌和结肠癌中起重要作用的基因，但这些研究中的第一个最近才完成胰腺癌。在这些研究的结果可以转化为患者设置之前，需要进行初始结果的复制，以确定DNA的变化与胰腺癌“真正”相关，而不是错误的发现。此外，后续GWA研究也有可能发现新的关联。因此，本研究的目标将是验证最初的胰腺癌GWAS结果，并确定可能与胰腺癌相关的新DNA变化。