Mitochondrial DNA Mutations in Pancreatic Cancer

胰腺癌中的线粒体 DNA 突变

基本信息

批准号：
7752843
负责人：
Gregory J. Tranah
金额：
$ 9.32万
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 2011-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7752843
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）：胰腺癌是美国癌症相关死亡的第四大原因，但强烈的遗传和环境风险因素仍然难以捉摸。为了有效预防和治疗这种恶性肿瘤，识别使部分人群易患胰腺癌的遗传多态性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至关重要。此外，从循环生物液中发现的疾病特异性遗传畸变的发现将促进早期检测胰腺癌的诊断工具的开发。虽然大多数遗传关联研究要么专门关注核基因多态性作为癌症发病的易感因素，要么关注体细胞改变作为癌症进展的指标，但线粒体 DNA (mtDNA) 变异尚未被研究为胰腺癌的危险因素。该项目将在旧金山湾区进行的一项大型人群病例对照研究（309 例病例和 618 例匹配对照）中评估 mtDNA 序列变异与胰腺癌之间的关联。通过使用最近开发的 Affymetrix 线粒体重测序阵列 2.0 (MitoChip)，我们将对整个 mtDNA 基因组 (~16.5kb) 进行全面分析，以了解与胰腺癌的关联。 MitoChip 能够检测种系突变和获得性突变，并且已被证明可以检测多种组织（包括血液）中的 mtDNA 突变。这将是迄今为止对完整 mtDNA 基因组序列和胰腺癌最大规模的基于人群的评估，并有可能识别出使部分人群易患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检测到独特的 mtDNA 异质突变；这些可能成为早期检测胰腺癌的强大生物标志物。公共健康相关性：该项目将在旧金山湾区进行的一项大规模人群病例对照研究中评估线粒体 DNA (mtDNA) 序列变异与胰腺癌之间的关联。通过使用最近开发的 Affymetrix 线粒体重测序阵列 2.0 (MitoChip)，我们将对整个 mtDNA 基因组 (~16.5kb) 进行全面分析，以了解与胰腺癌的关联。这将是迄今为止对完整 mtDNA 基因组序列和胰腺癌最大规模的基于人群的评估，并有可能识别出使部分人群易患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检测到独特的 mtDNA 异质突变；这些可能成为早期检测胰腺癌的强大生物标志物。