Mitochondrial Genetics in Prostate Cancer Health Disparity

描述(由申请者提供)：在美国，前列腺癌存在着巨大的、无法解释的种族/民族差异。非洲裔美国人(AA)被诊断为前列腺癌的可能性是白人的1.6倍，死于前列腺癌的可能性是白人的2.4倍。虽然这种差异可能是多种因素造成的，但遗传易感性可能占了相当大的比例。我们发现线粒体基因组中的遗传突变与前列腺癌风险的增加有关，AA男性在这个基因组中的突变与CA非常不同，AA男性的线粒体DNA(MtDNA)突变率明显高于CA。我们将检验的总体假设是，在患有前列腺癌的AA和CA男性生殖系中发现的种族特异性错义mtDNA突变改变了线粒体生物学，从而提高了前列腺癌的生长和存活率。由于我们正在进行的为期10年的前瞻性标本库计划，我们拥有在埃默里大学医院接受前列腺癌根治术的1000多名男性的生物样本(包括外周血DNA)和临床数据。由于线粒体DNA测序技术的进步，基于芯片的方法可以快速、可靠地对整个线粒体基因组(~16.5kb)进行测序。因此，我们处于独特的地位，可以对患有前列腺癌的AA和CA男性的整个线粒体基因组进行快速测序，并建议对每个种族组的50名男性进行测序，并比较mtDNA突变。将联系所有有错义突变的人进行进一步的静脉抽血和建立淋巴母细胞系，使我们能够“捕获”这些mtDNA突变，并产生与前列腺癌相关的mtDNA突变的前列腺癌细胞系。每个突变将与一个适当的对照细胞系配对，该对照细胞系通过单个mtDNA碱基变化而不同。然后，这些突变/对照对将接受呼吸复合体活性和活性氧物种(ROS)产生的分析，从而使我们能够分配所观察到的突变的功能。我们还将测试抗氧化剂和抗炎药逆转前列腺癌特异性mtDNA突变引起的细胞生物紊乱的能力。如果成功，这些研究将确定前列腺癌mtDNA突变的功能，它们在前列腺癌的种族差异中所起的作用，并开始确定在防止mtDNA突变导致癌症易感性方面可能特别有效的治疗方法，从而选择针对突变的治疗方法。潜在的影响是深远的，因为线粒体变异现在已被确定为癌症、心脏病、神经退行性疾病、阿尔茨海默病、帕金森病、糖尿病和视神经病变的重要特征，所有这些都与线粒体突变有关。 公共卫生相关性：该项目将研究前列腺癌遗传学中的种族差异(健康差异)。具体地说，我们将确定一组患有前列腺癌的非裔美国人和高加索美国人的线粒体DNA的所有突变。一旦发现突变，将在实验室进行研究，以确定它们如何对癌症产生影响，以及可能使用哪些抗癌药物来治疗这些线粒体DNA突变的患者。这项研究的最终用途既是为了了解导致前列腺癌种族差异的基本异常，也是为了确定针对突变的治疗方法。

DESCRIPTION (provided by applicant): There is a dramatic and unexplained racial/ethnic disparity in prostate cancer in the US. African Americans (AA) are 1.6 times more likely to be diagnosed with prostate cancer and 2.4 times more likely to die from prostate cancer than Caucasian Americans (CA). While it is likely that multiple factors account for this disparity, genetic predisposition may account for a substantial proportion. We have discovered that inherited mutations in the mitochondrial genome are associated with an increased risk of prostate cancer and that AA males have very different mutations in this genome than CA and that AA men have significantly greater rates of mitochondrial DNA (mtDNA) mutations than CA. The overall hypothesis we will test is that race-specific missense mtDNA mutations that are found in the germ line of AA and CA men with prostate cancer alter mitochondrial biology so as to enhance prostate cancer growth and survival. Because of our ongoing 10-year prospective specimen banking protocol we have biologic specimens (including peripheral blood DNA) and clinical data on over 1000 men that have undergone radical prostatectomy for prostate cancer at Emory University Hospital. Because of technical advances in mtDNA sequencing, the entire mitochondrial genome (~16.5 kb) can be rapidly and reliably sequenced by chip based methods. We are therefore uniquely positioned to rapidly perform sequencing of the entire mitochondrial genome in AA and CA men with prostate cancer and propose sequencing 50 men from each racial group and comparing the mtDNA mutations. All individuals with missense mutations will be contacted for further phlebotomy and the establishment of lymphoblast cell lines that will allow us to "capture" these mtDNA mutations and generate prostate cancer cell lines with prostate cancer relevant mtDNA mutations. Each mutation will be paired with an appropriate control cell line that differs by a single mtDNA base change. These mutant/control pairs will then undergo analysis of respiratory complex activity and reactive oxygen species (ROS) generation thereby allowing us to assign functionality of the observed mutations. We will also test antioxidant and anti-inflammatory agents for their ability to reverse the cell biologic derangements caused by the prostate cancer specific mtDNA mutations. If successful, these studies will define the functionality of mtDNA mutations in prostate cancer, the role they play in the racial disparity of prostate cancer, and begin to determine treatments that may be particularly effective in preventing mtDNA mutation induced cancer predisposition allowing mutation-specific treatments to be selected. The potential impact is far reaching because mitochondrial variation has now been identified as an important feature of cancer, heart disease, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, diabetes and optic neuropathy, all associated with mitochondrial mutations. PUBLIC HEALTH RELEVANCE: This project will study racial differences (health disparities) in prostate cancer genetics. Specifically, we will determine all mutations in the mitochondrial DNA in a group of African American and Caucasian American men with prostate cancer. Once mutations are identified they will be studied in the laboratory to determine how they exert their effects on cancer and what anti-cancer drugs might be used to treat patients with these mitochondrial DNA mutations. The ultimate use of this research is both to understand the basic abnormalities that account for racial differences in prostate cancer and to identify mutation-specific treatments.