Impact of Mitochondrial Genome Variation on extreme Prostate Cancer Disparities

描述（由申请人提供）：前列腺癌是西方男性最常见的癌症，其遗传病因尚不清楚。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所观察到的健康差异（包括疾病风险、攻击性和结果）方面的重要性。我们首次报道了与非裔美国人和欧裔美国人相比，非移民非洲的疾病侵袭性显著增加，并假设与非洲的遗传联系在揭示前列腺癌差异方面起着根本作用。线粒体基因组不仅是遗传差异的关键靶点（由于种族多样性，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靶点。线粒体不仅在产生细胞能量中发挥核心作用，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中发挥核心作用，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了其独特的发病机制和作为疾病标志物的潜力。该项目将提供第一个已知的分析，分析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（多态变异）主干上的作用和程度，以确定非洲前列腺癌日益严重的程度。利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，以确定基于基因的侵袭性与惰性前列腺癌疾病的非侵入性生物标志物（前列腺癌管理的主要临床限制）。以及用于检测早期疾病检测和监测的低水平体细胞异质性（突变型到野生型mtDNA环境）的工具。本研究为观察到的前列腺癌种族差异提供了重要的生物学解释。

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.