Characterizing Mitochondrial DNA Susceptibility to Breast, Colorectal, and Prosta

描述(申请人提供)：线粒体基因组高度专门化，编码能量代谢和自由基产生所必需的蛋白质--这些途径也是致癌的关键途径。直到最近，线粒体基因组在癌症研究中几乎没有受到关注，因为以前的研究主要集中在核基因组上。这项提案的目标是在非洲裔美国人、日裔美国人、夏威夷原住民、拉丁裔和白人男性和女性中识别影响乳腺癌、结直肠癌和前列腺癌风险的胚系线粒体DNA变种。在目标1中，我们建议描述非裔美国人、日裔美国人、夏威夷原住民、拉丁裔和白人之间线粒体基因组的遗传多样性。我们将从公共mtDNA数据库中提取非裔美国人、日裔美国人、拉丁裔和白人的测序数据，同时对夏威夷原住民(225个对照)进行测序，这是一个在公共资源中没有代表性的群体。接下来，我们将在一个由375名个体组成的独立的多种族小组中对从测序工作中识别的mtDNA变体进行分型验证。这项工作将提供常见线粒体DNA变异的多种族目录(MAF&GT；5%)。目的2将测试常见的线粒体DNA基因变异与乳腺癌、前列腺癌和结直肠癌风险之间的关系。根据我们编制的常见mtDNA变异目录，将在我们的大型嵌套病例对照研究中选择(~350个SNPs)并对乳腺癌(2,586例，2,999名对照)、结直肠癌(2,014例，2,708名对照)和前列腺癌(4,326例，4,714名对照)进行基因分型。我们的最终目标3将评估mtDNA效应是否会受到疾病亚组(分期、分级、ER+/-乳腺癌、结肠/直肠肿瘤)、与线粒体活动相关的环境因素(吸烟、体重指数、脂肪、类胡萝卜素、维生素C、维生素E、铁、番茄红素和硒)以及全基因组关联研究确定的乳腺癌、结直肠癌和/或前列腺癌的易感基因的影响。这一建议的优点包括：1)研究的创新性；2)多学科调查小组；3)有效利用现有资源；4)科学和公共卫生意义，特别是对未得到充分研究的少数群体。通过这项研究获得的知识可能会导致对乳腺癌、结直肠癌和前列腺癌生物学的重要洞察，应用这些信息可能会改进这些常见癌症的预防、诊断和治疗。 公共卫生相关性：在这项提案中，我们将全面描述多种族队列研究中非裔美国人、日裔美国人、夏威夷原住民、拉丁裔和白人受试者中线粒体基因组的遗传多样性。利用这些遗传信息，我们将在近9000例癌症病例和10,000多名对照中调查线粒体DNA的遗传差异是否影响乳腺癌、结直肠癌和前列腺癌的风险。此外，我们将根据疾病亚组、环境因素和已知遗传风险因素来评估影响的异质性。

DESCRIPTION (provided by applicant): The mitochondrial genome is highly specialized and encodes for proteins essential for energy metabolism and free radical production-pathways that are also critical for carcinogenesis. Until recently, the mitochondrial genome has received little attention in cancer research as prior studies have largely focused on the nuclear genome. The goal of this proposal is to identify germline mitochondrial DNA variants that influence the risks of breast, colorectal and prostate cancer among a diverse population of African American, Japanese American, Native Hawaiian, Latino and White men and women. We propose in Aim 1 to characterize the genetic diversity of the mitochondrial genome among African Americans, Japanese Americans, Native Hawaiians, Latinos and Whites. We will abstract sequencing data for African Americans, Japanese Americans, Latinos, and Whites from public mtDNA databases, in parallel with sequencing Native Hawaiians (225 controls), a group that is not represented in public resources. Next, we will genotype mtDNA variants identified from sequencing efforts in an independent multiethnic panel of 375 individuals for validation. This work will provide a multiethnic catalog of common mtDNA variation (MAF > 5%). Aim 2 will test the association between common genetic variation in the mtDNA and risks of breast, prostate and colorectal cancer. Based on our compiled catalog of common mtDNA variants, tag SNPs and SNPs representing common haplogroups will be selected (~350 SNPs) and genotyped in our large nested case-control studies of breast (2,586 cases, 2,999 controls), colorectal (2,014 cases, 2,708 controls) and prostate cancer (4,326 cases, 4,714 controls). Our final Aim 3 will evaluate whether mtDNA effects are modified by disease sub-groups (stage, grade, ER+/- breast tumors, colon/rectum tumors), environmental factors related to mitochondrial activity (smoking, BMI, fat, carotenoids, vitamin C, vitamin E, iron, lycopene and selenium) and susceptibility loci for breast, colorectal and/or prostate cancer identified by genome-wide association studies. The strengths of this proposal include: 1) the innovativeness of the research; 2) the multi-disciplinary investigative team, 3) the efficient use of existing resources and 4) the scientific and public health significance, especially in regards to understudied minority populations. The knowledge gained by this study may lead to important insight into the biology of cancers of the breast, colorectal and prostate, and applying this information may improve the prevention, diagnosis and treatment of these common cancers. PUBLIC HEALTH RELEVANCE: For this proposal, we will comprehensively characterize the genetic diversity of the mitochondrial genome among a diverse sample of African American, Japanese American, Native Hawaiian, Latino, and White subjects from the Multiethnic Cohort Study. Using this genetic information, we will investigate whether inherited differences in mitochondrial DNA influence the risk of breast, colorectal, and prostate cancer among nearly 9,000 cancer cases and more than 10,000 controls. In addition, we will evaluate heterogeneity of effects by disease sub-groups, environmental factors and known genetic risk factors.