Mitochondrial DNA Mutations in Pancreatic Cancer

胰腺癌中的线粒体 DNA 突变

• 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
• 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

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，但强大的遗传和环境风险因素仍然难以捉摸。为了有效地预防和治疗这种恶性肿瘤，关键是要确定易患胰腺癌的人群亚群的遗传多态性，并确定这些多态性如何改变其他危险因素和癌症之间的关系。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促进胰腺癌早期检测诊断工具的开发。虽然大多数遗传关联研究都集中在核基因多态性作为癌症发病的易感因素或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风险因素。该项目将在弗朗西斯科湾区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Affytek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，以确定其与胰腺癌的关联。MitoChip能够检测生殖系和获得性突变，并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进行的最大规模的基于人群的评估，并有可能确定使人群亚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异质性突变，这些突变可能成为胰腺癌早期检测的有力生物标志物。公共卫生相关性：该项目将在旧金山弗朗西斯科湾区的一项大规模基于人群的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Affytek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，以确定其与胰腺癌的关联。这将是迄今为止对完整mtDNA基因组序列和胰腺癌进行的最大规模的基于人群的评估，并有可能确定使人群亚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异质性突变，这些突变可能成为胰腺癌早期检测的有力生物标志物。