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：
8519389
负责人：
Mark D ADAMS
金额：
$ 17.79万
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 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8519389
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 analysis genome sequencing health disparity high throughput analysis lifetime risk male men mitochondrial DNA mutation mitochondrial genome molecular marker mortality mutant next generation sequencing 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.

描述（由申请人提供）：前列腺癌是西方男性中最常见的癌症，人们对其遗传病因知之甚少。据报告，非裔美国人的发病率和死亡率最高，其患病可能性是欧洲裔美国人的 1.6 倍，是亚裔美国人的 2.6 倍。这种种族差异以及与家族疾病史的密切联系，回避了遗传学在解释观察到的健康差异（包括疾病风险、攻击性和结果）方面的重要性。我们首次报告，与非洲裔美国人和欧洲裔美国人相比，非移民非洲的疾病侵袭性显着增加，并假设与非洲的遗传联系在揭示前列腺癌差异方面发挥着根本作用。线粒体基因组不仅是遗传差异的关键目标（由于种族多样性，在非洲是最大的），而且也是获得性肿瘤引起体细胞突变的重要目标。线粒体不仅在产生细胞能量方面发挥着核心作用，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发挥着核心作用，使线粒体基因组成为致癌变异的重要靶标。与核基因组相比，线粒体的高突变率和拷贝数进一步影响了其发病机制和作为疾病标志物的独特潜力。该项目将首次对获得性线粒体基因组变异（具有功能预测相关性的体细胞突变）在遗传变异（多态性变异）的基础上的作用和程度进行已知分析，以定义非洲前列腺癌严重程度的增加。使用非混合南部非洲血统的独特研究资源，结合使用下一代测序技术的全线粒体基因组分析，将提供一个机会来识别侵袭性与惰性前列腺癌疾病（主要的临床限制）的基于遗传的非侵入性生物标志物。前列腺癌的治疗），以及检测低水平体细胞异质性（野生型 mtDNA 环境突变）的工具，以进行早期疾病检测和监测。这项研究对所观察到的前列腺癌种族差异提供了重要的生物学解释。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Clinical presentation of prostate cancer in black South Africans.

南非黑人前列腺癌的临床表现。

DOI：
发表时间：
2014-06
期刊：
影响因子：
0
作者：
Tindall, Elizabeth A;Monare, L Richard;Petersen, Desiree C;van Zyl, Smit;Hardie, Rae;Segone, Alpheus M;Venter, Philip A;Bornman, M S Riana;Hayes, Vanessa M
通讯作者：
Hayes, Vanessa M

Spectrum of mitochondrial genomic variation and associated clinical presentation of prostate cancer in South African men.

南非男性线粒体基因组变异谱和前列腺癌的相关临床表现。

DOI：
发表时间：
2016-03
期刊：
影响因子：
0
作者：
McCrow, John P;Petersen, Desiree C;Louw, Melanie;Chan, Eva K F;Harmeyer, Katherine;Vecchiarelli, Stefano;Lyons, Ruth J;Bornman, M S Riana;Hayes, Vanessa M
通讯作者：
Hayes, Vanessa M