Characterizing Mitochondrial DNA Susceptibility to Breast, Colorectal, and Prosta

表征线粒体 DNA 对乳腺癌、结直肠癌和前列腺癌的敏感性

• 批准号: 7792033
• 负责人: Iona C Cheng
• 金额: $ 47万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-28 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7792033
• 关键词: Address; African; African American; Alleles; Ascorbic Acid; Attention; Breast; Cancer Biology; Carotenoids; Case-Control Studies; Cataloging; Catalogs; Cohort Studies; Colon; Colorectal; Colorectal Cancer; DNA Databases; DNA Sequence; Data; Databases; Defect; Development; Diagnosis; Disease; Energy Metabolism; Environmental Risk Factor; Ethnic group; European; Fatty acid glycerol esters; Free Radicals; Frequencies; Genetic; Genetic Variation; Genome; Genotype; Genus Cola; Goals; Haplogroup; Hawaiian population; Heritability; Heterogeneity; Individual; Inherited; Iron; Japanese American; Japanese Population; Knowledge; Latino; Lead; Malignant Neoplasms; Malignant neoplasm of prostate; Mammary Neoplasms; Minority; Mitochondria; Mitochondrial DNA; Nested Case-Control Study; Nuclear; Pathway interactions; Phenotype; Population; Population Heterogeneity; Predisposition; Prevention; Production; Prostate; Proteins; Public Health; Rectal Cancer; Rectal Neoplasms; Research; Research Personnel; Resources; Risk; Risk Factors; Role; SNP genotyping; Sampling; Selenium; Site; Smoking; Stage Grouping; Staging; Subgroup; Testing; Validation; Variant; Vitamin E; Woman; Work; abstracting; anticancer research; base; burden of illness; cancer cell; cancer genetics; cancer prevention; cancer risk; carcinogenesis; cohort; common treatment; experience; genetic epidemiology; genetic risk factor; genome wide association study; high risk; improved; insight; lycopene; malignant breast neoplasm; men; mitochondrial dysfunction; mitochondrial genome; non-genetic; public health relevance; racial and ethnic; racial/ethnic difference; treatment strategy; tumor

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.

描述（由申请人提供）：线粒体基因组是高度专业化的，并且编码对于能量代谢和自由基生产途径所必需的蛋白质，这对于癌变也至关重要。直到最近，线粒体基因组在癌症研究中几乎没有关注，因为先前的研究主要集中在核基因组上。该提案的目的是确定生殖线线粒体DNA变体，这些变体在非洲裔美国人，日裔美国人，夏威夷人，拉丁裔和白人男性和女性中影响乳房，结直肠癌和前列腺癌的风险。我们建议在AIM 1中表征非裔美国人，日裔美国人，夏威夷人，拉丁美洲人和白人之间线粒体基因组的遗传多样性。我们将与公共MTDNA数据库中的非洲裔美国人，日裔美国人，拉丁美洲人以及白人进行抽象的测序数据，并与对夏威夷原住民的测序（225个控件）并行，这是一个在公共资源中未代表的群体。接下来，我们将基因型mtDNA变体从375个个体的独立多种族小组中的测序工作中鉴定出来，以验证。这项工作将提供普通mtDNA变异的多民族目录（MAF> 5％）。 AIM 2将测试mtDNA中常见的遗传变异与乳腺癌，前列腺和大肠癌的风险之间的关联。根据我们的共同mtDNA变体的编译目录，将选择代表常见单倍群的TAG SNP和SNP（〜350 SNP），并在我们的大型乳房嵌套病例对照研究中进行基因分型（2,586例，2,999例，2,999个对照组），结直肠病例（2,014例，2,014例，2,708例，4,708个控制率），4,4,4,32，4,32癌症（4,32）。我们的最终目标3将评估MTDNA效应是否通过疾病亚组（阶段，等级，ER +/-乳腺肿瘤，结肠/直肠肿瘤），与线粒体活性有关的环境因素（吸烟，BMI，脂肪，类胡萝卜素，类胡萝卜素，维生素C，维生素C，维生素E，维生素，铁，乳液和乳化剂）或乳腺癌，乳腺素和乳腺癌，乳腺素和乳腺癌，乳腺素，脂肪，脂肪，脂肪，脂肪，脂肪，脂肪，脂肪，脂肪，脂肪，脂肪，脂肪，脂肪，乳液，脂肪，乳液和乳头癌全基因组关联研究。该提议的优势包括：1）研究的创新性； 2）多学科调查团队，3）有效利用现有资源和4）科学和公共卫生的意义，尤其是在研究不足的少数民族人群方面。这项研究获得的知识可能会导致对乳腺癌，结直肠和前列腺癌的生物学的重要见解，并且应用此信息可能会改善对这些常见癌症的预防，诊断和治疗。 公共卫生相关性：对于这项提议，我们将全面地描述了多种族裔队列研究中非裔美国人，日裔美国人，夏威夷人，拉丁裔和白人主题的多样化样本中线粒体基因组的遗传多样性。使用这些遗传信息，我们将研究线粒体DNA的遗传差异是否影响近9,000例癌症病例和10,000多个对照的乳腺癌，结直肠癌和前列腺癌的风险。此外，我们将评估疾病亚组，环境因素和已知遗传危险因素的影响的异质性。