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

• 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
• 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

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最常见的癌症，其遗传病因学知之甚少。据报道，非洲裔美国人的发病率和死亡率最高，比欧洲裔美国人高1.6倍，比亚裔美国人高2.6倍。这种种族差异以及与疾病家族史的密切联系，回避了遗传学在解释观察到的健康差异（包括疾病风险，侵略和结果）方面的重要性。我们首次报告了非移民非洲与非裔美国人和欧洲裔美国人相比，疾病侵袭性的显著增加，并假设与非洲的遗传联系在解开前列腺癌差异方面起着重要作用。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，这在非洲是最大的），而且也是获得性肿瘤引起的体细胞突变的重要目标。线粒体不仅在产生细胞能量方面，而且在细胞死亡（凋亡）、细胞生长和分化、信号传导和细胞周期控制方面发挥核心作用，使线粒体基因组成为致癌变异的重要靶点。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独特的发病潜力和作为疾病标志物。该项目将提供第一个已知的线粒体基因组变异（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）的骨干上的作用和程度的分析，以确定非洲前列腺癌的严重程度增加。使用非混合的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，将提供一个机会来鉴定侵袭性与惰性前列腺癌疾病的基于遗传的非侵入性生物标志物。（前列腺癌治疗中的主要临床限制），以及检测低水平体细胞异质性（突变体到野生型mtDNA环境）的工具，用于早期疾病检测和监测。这项研究提出了一个重要的生物学解释，观察到的种族为基础的差异，前列腺癌。

项目成果

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

• DOI: 10.1002/pros.23126
• 发表时间: 2016-03
• 期刊: The Prostate
• 作者: McCrow JP;Petersen DC;Louw M;Chan EK;Harmeyer K;Vecchiarelli S;Lyons RJ;Bornman MS;Hayes VM
• 通讯作者: Hayes VM