Impact of Mitochondrial Genome Variation on extreme Prostate Cancer Disparities

线粒体基因组变异对前列腺癌极端差异的影响

基本信息

批准号：
8370657
负责人：
Vanessa Marie Hayes
金额：
$ 23.35万
依托单位：
J. CRAIG VENTER INSTITUTE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8370657
关键词：
Accounting Address Africa African African American Age Aggressive behavior Aging American Apoptosis Asia Asian Americans Asians Benign Prostatic Hypertrophy Biological Biological Markers Blood Cancer Control Cataloging Catalogs Caucasians Caucasoid Race Cell Cycle Regulation Cell Death Cell Differentiation process Cell Proliferation Cells Characteristics Clinical Computer Simulation DNA DNA Damage Detection Development Diagnosis Disease Disease Marker Disease Progression Early Diagnosis Environment Ethnic group European Event Family history of Frequencies Generations Genetic Genetic Predisposition to Disease Genome Genomics Human Incidence Individual Indolent Infiltration Inherited Introns Link Location Malignant Neoplasms Malignant neoplasm of prostate Metastatic Neoplasm to the Bone Mitochondria Mitochondrial DNA Monitor Morbidity - disease rate Mutation Nature Neoplasm Metastasis Nuclear Outcome Pathogenesis Patients Peripheral Phenotype Play Population Population Study Predisposition Process Production Prostate Public Health Reactive Oxygen Species Reporting Research Design Resistance Resources Role Sampling Severities Signal Transduction Site Somatic Mutation Structure Structure of base of prostate Technology Testing Time Tissues Variant Vertebral column base cancer genome cancer health disparity cancer risk cancer type carcinogenesis cell growth disorder risk early onset genome sequencing health disparity high throughput analysis lifetime risk male men mitochondrial DNA mutation mitochondrial genome molecular marker mortality mutant next generation tool tumor tumor growth tumorigenic

项目摘要

DESCRIPTION (provided by applicant): The genetic etiology of prostate cancer, the most common cancer in western men, is poorly understood. Highest incidences and mortality rates are reported for African-Americans, with 1.6x more likely than European-Americans and 2.6x more likely than Asian-Americans to develop disease. This ethnic disparity and a strong link to a family history of disease, eludes to the importance of genetics in explaining the observed health disparity (including disease risk, aggression and outcomes). We report for the first time a highly significant increase in disease aggression in non-migrant Africa, compared with African-Americans and European-Americans, and hypothesize that a genetic link to Africa plays a fundamental role in unraveling the prostate cancer disparities. The mitochondrial genome is not only a critical target for inherited disparity (due to ethnic-based diversity, which is greatest wihin Africa), but is also an important target for acquired tumor-causing somatic mutations. Mitochondria play a central role not only in generating cellular energy, but also cell death (apoptosis), cell growth and differentiation, signaling and cell cycle control, making the mitochondrial genome an essential target for carcinogenic variation. The high mutation rate and copy number of the mitochondrial compared to the nuclear genome, further impacts on its unique potential for pathogenesis and as a disease marker. This project will provide the first known analysis of the role and extent of acquired mitochondrial genome variation (somatic mutations with functional predictive relevance) on a backbone of inherited variation (polymorphic variants) in defining the increased severity of prostate cancer within Africa. Using a unique study resource of non-admixed Southern African ancestry, combined with whole mitochondrial genome analysis using next generation sequencing technology, will provide an opportunity to identify genetic-based non- invasive biomarkers of aggressive versus indolent prostate cancer disease (a major clinical limitation in the management of prostate cancer), as well as the tools to detect low levels of somatic heteroplasmy (mutant to wild-type mtDNA environment) for early-disease detection and monitoring. This study addresses an important biological explanation for the observed ethnic- based disparities in prostate cancer. PUBLIC HEALTH RELEVANCE: Ones genetics background has been speculated to be a key contributor to the observed disparity in prostate cancer risk and disease status, with increased severity in men of African ancestry compared with European and Asian men. In this study we report for the first time 'extremely' aggressive prostate cancer disease in non-migrant Africans and utilize this unique resource to determine the likely contribution of mitochondrial genome variation (both inherited and somatic) in explaining this disparity. Our study provides a rational biological explanation for this disparity based on the essential role of the mitochondrial genome in carcinogenesis and its ideal application for non-invasive testing, providing the potential for early detection of aggressive versus indolent disease.

描述（由申请人提供）：对西方男性最常见的癌症的遗传病因学很少了解。据报道，非洲裔美国人的发生率和死亡率最高，比欧美人的可能性高1.6倍，比亚裔美国人患疾病的可能性高1.6倍。这种种族差异和与疾病家族史的密切联系，避免了遗传学在解释观察到的健康差异（包括疾病风险，侵略和结果）中的重要性。与非洲裔美国人和欧洲人相比，我们首次报道非洲非移民的疾病侵略性高度显着，并假设与非洲的遗传联系在揭示前列腺癌差异方面起着基本作用。线粒体基因组不仅是遗传差异的关键目标（由于基于种族的多样性，这是非洲的最大的多样性），而且还是获得肿瘤引起肿瘤突变的重要目标。线粒体不仅在产生细胞能量，而且在细胞死亡（细胞凋亡），细胞生长和分化，信号传导和细胞周期控制方面起着核心作用，从而使线粒体基因组成为致癌性变异的基本目标。与核基因组相比，线粒体的高突变率和拷贝数，进一步影响其发病机理的独特潜力和疾病标记。该项目将对获得的线粒体基因组变异（具有功能预测相关性的体细胞突变）的作用和程度进行首次已知分析，以定义非洲遗传性变异（多态性变体）的主链（多态性变体）。使用独特的研究资源，包括使用下一代测序技术的整个线粒体基因组分析，将提供一个机会，以确定基于遗传的非侵入性生物标志物的侵略性和顽固的前列腺癌疾病（主要是在Protostate癌症的管理中），以及工具级别的工具 - 组合级别的临床效果（以及卑鄙的临床局限性） mtDNA环境）用于早期疾病检测和监测。这项研究解决了观察到的前列腺癌基于种族差异的重要生物学解释。公共卫生相关性：据推测，一个遗传学背景是观察到的前列腺癌风险和疾病状况差异的关键因素，与欧洲和亚洲男人相比，非洲血统的男性严重程度增加。在这项研究中，我们首次在非移民非洲人中首次报道了“极具侵略性的前列腺癌疾病”，并利用这种独特的资源来确定线粒体基因组变异（遗传和躯体）可能在解释这种危险时的贡献。我们的研究基于线粒体基因组在致癌作用中的基本作用及其在非侵入性测试中的理想应用，为这种差异提供了理性的生物学解释，从而为早期发现侵略性疾病和顽固疾病提供了潜力。