Mitochondrial DNA Mutations in Pancreatic Cancer

胰腺癌中的线粒体 DNA 突变

基本信息

批准号：
7589327
负责人：
Gregory J. Tranah
金额：
$ 24.85万
依托单位：
CALIFORNIA PACIFIC MED CTR RES INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-01-01 至 2010-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7589327
关键词：
Advanced Development African African American Area Asian Americans Biological Markers Biology Biometry Blood Blood Platelets California Cancer Etiology Case-Control Studies Cessation of life Code Collection DNA DNA Resequencing DNA Sequence Data Data Collection Defect Detection Development Diagnostic Disease Early Diagnosis Environmental Exposure Environmental Risk Factor Exhibits Functional RNA Genes Genetic Genetic Polymorphism Genome Genomics Haplogroup Haplotypes Hispanics Human Human Genetics Incidence Individual Inherited Interview Malignant Neoplasms Malignant neoplasm of pancreas Malignant neoplasm of prostate Mitochondria Mitochondrial DNA Mutation Nuclear Oxidative Stress Population Positioning Attribute Predisposition Reactive Oxygen Species Reference Standards Risk Risk Factors Role Sampling San Francisco Scientist Screening procedure Smoking Somatic Mutation Source Structure Testing Tissues United States Universities Variant cancer cell cancer risk case control cost gene environment interaction genetic association genetic epidemiology men mitochondrial DNA mutation mitochondrial genome mortality neglect population based prevent public health relevance tool tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Pancreatic cancer is the fourth leading cause of cancer-related deaths in the United States, yet strong genetic and environmental risk factors remain elusive. In order to effectively prevent and treat this malignancy it is critical to identify genetic polymorphisms that predispose subsets of the population to pancreatic cancer and determine how these polymorphisms modify the relationship between other risk factors and cancer. Additionally, the discovery of disease-specific genetic aberrations identified from circulating biofluids would advance the development of diagnostic tools for the early detection of pancreatic cancer. While the majority of genetic association studies have focused either exclusively on nuclear gene polymorphisms as susceptibility factors for cancer onset or on somatic alterations as indicators of cancer progression, mitochondrial DNA (mtDNA) variation has not been investigated as a risk factor for pancreatic cancer. This project will assess the association between mtDNA sequence variants and pancreatic cancer in a large population-based case-control study in the San Francisco Bay Area (309 cases and 618 matched controls). By using the recently developed the Affymetrix Mitochondrial Resequencing Array 2.0 (MitoChip) we will be performing a comprehensive analysis of the entire mtDNA genome (~16.5kb) for associations with pancreatic cancer. The MitoChip enables the detection of both germline and acquired mutations and has been shown detect mtDNA mutations in multiple tissues (including blood). This would be the largest population-based assessment of the complete mtDNA genomic sequence and pancreatic cancer to date and has the potential to identify polymorphisms that predispose subsets of the population to this malignancy. In addition, if we determine that unique mtDNA heteroplasmic mutations are detectable in the blood of pancreatic cancer cases; these may potentially serve as powerful biomarkers for the early detection of pancreatic cancer. PUBLIC HEALTH RELEVANCE: This project will assess the association between mitochondrial DNA (mtDNA) sequence variants and pancreatic cancer in a large population-based case-control study in the San Francisco Bay Area. By using the recently developed the Affymetrix Mitochondrial Resequencing Array 2.0 (MitoChip) we will be performing a comprehensive analysis of the entire mtDNA genome (~16.5kb) for associations with pancreatic cancer. This would be the largest population-based assessment of the complete mtDNA genomic sequence and pancreatic cancer to date and has the potential to identify polymorphisms that predispose subsets of the population to this malignancy. In addition, if we determine that unique mtDNA heteroplasmic mutations are detectable in the blood of pancreatic cancer cases; these may potentially serve as powerful biomarkers for the early detection of pancreatic cancer.

描述（由申请人提供）：胰腺癌是美国与癌症相关死亡的第四个主要原因，但强有力的遗传和环境危险因素仍然难以捉摸。为了有效预防和治疗这种恶性肿瘤，至关重要的是，鉴定遗传多态性使人口易于胰腺癌，并确定这些多态性如何改变其他危险因素与癌症之间的关系。此外，从循环生物流体中发现的疾病特异性遗传畸变的发现将推动开发诊断工具以早期检测胰腺癌。尽管大多数遗传关联研究仅集中在核基因多态性上，作为癌症发作的易感因素或作为癌症进展的指标，线粒体DNA（MTDNA）变异尚未作为胰腺癌的危险因素进行研究。该项目将评估旧金山湾地区的大型基于人群的病例对照研究中mtDNA序列变体与胰腺癌之间的关联（309例和618个匹配的对照）。通过使用最近开发的Affymetrix线粒体重新配置阵列2.0（Mitochip），我们将对整个mtDNA基因组（〜16.5KB）进行全面分析，以实现与胰腺癌的关联。线条可以检测生殖线和获得的突变，并已显示出多个组织中的mtDNA突变（包括血液）。迄今为止，这将是对完整mtDNA基因组序列和胰腺癌的最大基于人群的评估，并有可能鉴定出使人口偏爱这种恶性肿瘤的多态性。此外，如果我们确定在胰腺癌病例的血液中可以检测到独特的mtDNA杂质突变；这些可能有可能作为早期检测胰腺癌的强大生物标志物。公共卫生相关性：该项目将评估旧金山湾区的大型基于人群的病例对照研究中线粒体DNA（mtDNA）序列变体与胰腺癌之间的关联。通过使用最近开发的Affymetrix线粒体重新配置阵列2.0（Mitochip），我们将对整个mtDNA基因组（〜16.5KB）进行全面分析，以实现与胰腺癌的关联。迄今为止，这将是对完整mtDNA基因组序列和胰腺癌的最大基于人群的评估，并有可能鉴定出使人口偏爱这种恶性肿瘤的多态性。此外，如果我们确定在胰腺癌病例的血液中可以检测到独特的mtDNA杂质突变；这些可能有可能作为早期检测胰腺癌的强大生物标志物。