Mitochondrial Genetics in Prostate Cancer Health Disparity

前列腺癌健康差异中的线粒体遗传学

• 批准号: 8333995
• 负责人: John A. Petros
• 金额: $ 16.86万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-16 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8333995
• 关键词: Accounting; Address; African American; Alzheimer' s Disease; Amino Acids; Anti-Inflammatory Agents; Anti-inflammatory; Antineoplastic Agents; Antioxidants; Biochemical; Biological Assay; Biology; Cell Line; Cells; Clinical Data; Cohort Effect; Complex; DNA; DNA Sequence; Diabetes Mellitus; Diagnosis; Disease; Environmental Risk Factor; Ethnic group; Generations; Genes; Genetic; Genetic Predisposition to Disease; Genome; Germ Lines; Growth; Heart Diseases; Incidence; Individual; Inherited; Laboratories; Malignant Neoplasms; Malignant neoplasm of prostate; Methods; Missense Mutation; Mitochondria; Mitochondrial DNA; Mutation; Neurodegenerative Disorders; Nuclear; PC3 cell line; Parkinson Disease; Patients; Peptides; Pharmaceutical Preparations; Phenotype; Play; Positioning Attribute; Predisposition; Protocols documentation; Race; Radical Prostatectomy; Reactive Oxygen Species; Research; Risk; Role; Specimen; Staging; Testing; Time; University Hospitals; Variant; Venous blood sampling; base; cancer cell; cancer genetics; cancer health disparity; caucasian American; clinically significant; enzyme activity; health disparity; lymphoblast; male; malignant phenotype; member; men; mitochondrial DNA mutation; mitochondrial genome; mortality; mutant; optic nerve disorder; peripheral blood; prevent; prospective; racial and ethnic disparities; racial difference; research study; respiratory; survivorship

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.

描述（由申请人提供）：在美国，前列腺癌存在显著且无法解释的种族/民族差异。非裔美国人（AA）被诊断为前列腺癌的可能性是白人美国人（CA）的1.6倍，死于前列腺癌的可能性是白人美国人（CA）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。我们发现线粒体基因组中的遗传突变与前列腺癌风险增加相关，AA男性在该基因组中的突变与CA非常不同，AA男性的线粒体DNA（mtDNA）突变率显著高于CA。我们将检验的总体假设是，在患有前列腺癌的AA和CA男性的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，从而增强了前列腺癌的生长和存活。由于我们正在进行的10年前瞻性标本库协议，我们有生物标本（包括外周血DNA）和临床数据，超过1000名男性接受了根治性前列腺癌切除术在埃默里大学医院。由于mtDNA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，我们处于独特的位置，可以快速对患有前列腺癌的AA和CA男性进行整个线粒体基因组的测序，并建议对每个种族组的50名男性进行测序，并比较mtDNA突变。所有具有错义突变的个体将被联系以进行进一步的静脉切开术和淋巴母细胞系的建立，这将允许我们“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。每个突变将与适当的对照细胞系配对，该对照细胞系的差异在于单个线粒体DNA碱基变化。这些突变体/对照对然后将经历呼吸复合物活性和活性氧（ROS）产生的分析，从而允许我们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。