Mitochondrial Genetic Susceptibility to Breast and Prostate Cancers

描述（由申请人提供）：线粒体控制许多专门的细胞过程，这些过程对能量产生、脂肪代谢、类固醇合成和程序性细胞死亡途径至关重要，这些途径对致癌作用也至关重要。本申请的目的是鉴定影响非裔美国人、日裔美国人、夏威夷土著人、拉丁美洲人和白色男性和女性的不同人群中乳腺癌和前列腺癌风险的线粒体基因及其途径。我们在目标1中提出，利用创新的基因集富集分析（GSEA）方法，研究线粒体基因与核基因组和线粒体基因组编码的通路之间的关联，以了解它们对乳腺癌和前列腺癌的影响。线粒体基因和线粒体活性的核调节因子将从基于计算基因组学、蛋白质生物化学和成像的线粒体蛋白质的全面目录中确定。我们将测试这些线粒体基因，利用现有的核和线粒体全基因组SNP数据，从我们的乳腺癌（2，241例，2，863对照）和前列腺癌（3，634例，3，713对照）的大型病例对照研究嵌套在多种族队列（MEC）中。目标2将评估基因是否被疾病亚组（阶段，等级，ER+/-乳腺肿瘤），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和前列腺癌的易感基因座修饰。这一应用的优势包括：1）使用创新和复杂的分析方法; 2）强大的调查团队; 3）有效利用现有的遗传和流行病学资源; 4）科学和公共卫生意义，特别是对研究不足的少数民族人口。这项研究获得的知识可能会扩展我们对导致乳腺癌和前列腺癌的潜在遗传因素的理解，并可能导致对癌症发展生物学途径的关键见解。这些发现的最终应用可能会改善乳腺癌和前列腺癌的预防、诊断和治疗。

DESCRIPTION (provided by applicant): Mitochondria control a number of specialized cellular processes that are essential for energy production, fat metabolism, steroid synthesis, and programmed cell death-pathways that are also critical for carcinogenesis. The goal of this application is to identify mitochondrial genes and their pathways that influence the risks of breast 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 examine the association between mitochondrial genes and pathways encoded by both the nuclear and mitochondrial genomes for their impact on breast and prostate cancer, utilizing innovative gene set enrichment analysis (GSEA) approaches. Mitochondrial genes and nuclear regulators of mitochondrial activity will be identified from a comprehensive catalog of mitochondrial proteins based on computational genomics, protein biochemistry, and imaging. We will test these mitochondrial genes, leveraging existing nuclear and mitochondrial genome-wide SNP data, from our large case-control studies of breast (2,241 cases, 2,863 controls) and prostate cancer (3,634 cases, 3,713 controls) nested within the Multiethnic Cohort (MEC). Aim 2 will evaluate whether genes are modified by disease sub-groups (stage, grade, ER+/- breast tumors), environmental factors related to mitochondrial activity (smoking, BMI, fat, carotenoids, vitamin C, vitamin E, iron, lycopene and selenium) and susceptibility loci for breast and prostate cancer identified by genome-wide association studies. The strengths of this application include: 1) the use of innovative and sophisticated analytical methods; 2) the strong investigative team; 3) the efficient use of existing genetic and epidemiologic resources; and 4) the scientific and public health significance, especially in regards to understudied minority populations. The knowledge gained by this study may extend our understanding of the underlying genetic factors that contribute to breast and prostate cancers, and may lead to key insight into the biologic pathways of cancer development. The ultimate application of these findings may improve the prevention, diagnosis and treatment of cancers of the breast and prostate.