Characterizing Mitochondrial DNA Susceptibility to Breast, Colorectal, and Prosta

描述（由申请人提供）：线粒体基因组是高度特化的，编码能量代谢和自由基产生所必需的蛋白质，这些蛋白质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很少受到关注，因为之前的研究主要集中在核基因组上。这项提议的目标是确定影响乳腺癌、结直肠癌和前列腺癌风险的种系线粒体DNA变异，这些变异发生在非裔美国人、日裔美国人、夏威夷原住民、拉丁美洲人和白人男性和女性中。在目标1中，我们提议表征非裔美国人、日裔美国人、夏威夷原住民、拉丁美洲人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、拉丁美洲人和白人的测序数据，同时对夏威夷原住民（225个对照）进行测序，这一群体在公共资源中没有代表。接下来，我们将在一个独立的375人的多种族小组中对从测序工作中鉴定出的mtDNA变异进行基因分型以进行验证。这项工作将提供一个多种族的常见mtDNA变异目录（MAF 5%）。目的2将测试mtDNA常见遗传变异与乳腺癌、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，我们将在乳腺癌（2586例，2999例对照）、结直肠癌（2014例，2708例对照）和前列腺癌（4326例，4714例对照）的大型巢式病例对照研究中选择标签snp和代表常见单倍群的snp（约350个snp）并进行基因分型。我们最终的目标3将评估mtDNA效应是否受到疾病亚组（分期、分级、ER+/-乳腺肿瘤、结肠/直肠肿瘤）、与线粒体活性相关的环境因素（吸烟、BMI、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/或前列腺癌的易感位点的影响。本文的优势在于：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，特别是在研究不足的少数民族人口方面。这项研究所获得的知识可能会对乳腺癌、结肠直肠癌和前列腺癌的生物学有重要的认识，应用这些信息可能会改善这些常见癌症的预防、诊断和治疗。

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.