Mitochondrial Genetics in Prostate Cancer Health Disparity

描述（由申请人提供）：在美国，前列腺癌的种族/民族差异显著且无法解释。非裔美国人（AA）被诊断患有前列腺癌的可能性是白种人的1.6倍，死于前列腺癌的可能性是白种人的2.4倍。虽然可能有多种因素造成这种差异，但遗传易感性可能占很大比例。我们已经发现,在线粒体基因组遗传变异与前列腺癌的风险增加相关,AA雄性有非常不同的突变在这个基因组比CA和AA人明显的线粒体DNA (mtDNA)变异率比CA。总体假设我们将测试比赛规格错义突变mtDNA生殖细胞系中AA和CA前列腺癌患者改变线粒体生物学以提高前列腺癌的生长和生存。由于我们正在进行的10年前瞻性标本库协议，我们有超过1000名在埃默里大学医院接受根治性前列腺癌切除术的男性的生物标本（包括外周血DNA）和临床数据。由于线粒体dna测序技术的进步，整个线粒体基因组（~16.5 kb）可以通过基于芯片的方法快速可靠地测序。因此，我们具有独特的优势，可以快速对AA和CA男性前列腺癌患者的整个线粒体基因组进行测序，并建议对每个种族的50名男性进行测序，并比较mtDNA突变。我们将联系所有携带错义突变的个体进行进一步的静脉切断术和淋巴母细胞系的建立，这将使我们能够“捕获”这些mtDNA突变，并产生具有前列腺癌相关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，该对照细胞系因单个mtDNA碱基变化而不同。然后对这些突变/对照对进行呼吸复合物活性和活性氧（ROS）生成的分析，从而使我们能够分配观察到的突变的功能。我们还将测试抗氧化剂和抗炎剂逆转由前列腺癌特异性mtDNA突变引起的细胞生物学紊乱的能力。如果成功，这些研究将确定mtDNA突变在前列腺癌中的功能，它们在前列腺癌的种族差异中所起的作用，并开始确定可能特别有效地预防mtDNA突变诱导的癌症易感性的治疗方法，从而允许选择突变特异性治疗方法。潜在的影响是深远的，因为线粒体变异现在已经被确定为癌症、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。

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.