Genome-wide sequencing of prostate cancer in men of African ancestry

非洲血统男性前列腺癌的全基因组测序

基本信息

批准号：
8372298
负责人：
Christopher Alan Haiman
金额：
$ 61.38万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-21 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8372298
关键词：
Accounting Adopted Affect African African American Age Alleles American Binding Sites Biological Biological Assay Biological Process Body mass index Calcium Candidate Disease Gene Case-Control Studies Cataloging Catalogs Cells Chromatin Chromosome Mapping Code Cohort Studies Complex DNA Resequencing DNA Sequence Development Disease Disease susceptibility Early Diagnosis Elements Enhancers Environmental Risk Factor Epidemiologic Studies Epigenetic Process Etiology Family Family history of Fatty acid glycerol esters Frequencies Functional RNA Future Gene Frequency Genes Genetic Genetic Markers Genetic Predisposition to Disease Genetic Variation Genome Genotype Goals Heritability Heterogeneity Human In Vitro Incidence Individual Intake Knowledge Link Location Malignant Neoplasms Malignant neoplasm of prostate Maps Measures Minor Modeling Nucleic Acid Regulatory Sequences Nucleosomes Organ PC3 cell line Pathway interactions Phenotype Population Prevention strategy Preventive Process Prostate Proteins Recording of previous events Regulatory Element Relative (related person)Reporter Research Personnel Risk Risk Factors Role Sampling Screening procedure Severity of illness Smoking Staging Testing Therapeutic Time Tissues Transcript United States National Institutes of Health Variant Work base cancer genetics cancer risk cancer site cost design disease phenotype disorder risk epigenomics exome gene environment interaction genetic variant genome wide association study genome-wide high risk men histone modification lifestyle factors lycopene man men nano-string novel prognostic prospective racial and ethnic disparities transcription factor

项目摘要

DESCRIPTION (provided by applicant): African American men have two times or more the incidence rate of prostate cancer than other U.S. populations, and high rates of prostate cancer are also seen in other African and African-derived populations. It is generally accepted that both common and rare genetic variants contribute to risk of complex diseases such as prostate cancer, however their relative contributions to overall heritability is a subject of intense controversy. For rare variants to have a significant influence on the risk of complex disease the spectrum of effect sizes must be considerably larger in magnitude than for common variants; to date however there is only limited evidence for or against this hypothesis since the means of comprehensively testing rare variation in the genome has not been possible until very recently. In this proposal we seek to test the contributions of both common and rare genetic variants to the risk of prostate cancer in men of American ancestry using a targeted genome-wide association study approach. In Aim 1 we plan to sequence (at 30x coverage) the exome and regulatory regions (~160 Mb) of the genome, as defined by epigenetic marks in prostate cancer cell lines, in 1,000 men of African ancestry (500 with aggressive disease) and 1,000 controls. Both single SNP and burden of rare variants analyses will be performed and replication testing of the most statistically significant sequence variations (~24,000) will be examined in additional samples of African ancestry (6,000 cases and 6,000 controls) through the African Ancestry Prostate Cancer (AAPC) consortium. In addition to association testing of single variants, we will conduct "burden of rare variants analyses" of coding and non-coding variants at the gene and pathway level. In Aim 2, we will examine interactions between associated variants, environmental factors (thereby better defining the role of these factors) and disease severity. In Aim 3, we will assess biological function of the novel risk alleles identified in Aim 1 using a staged approach of eQTL analysis followed by in vitro analyses of enhancer activity as well as allele-specific effects. This proposal spans the spectrum of genetic epidemiologic research in prostate cancer, from genetic discovery (for all prostate cancer as well as aggressive disease) to gene environment interaction testing, to biological understanding. We expect this work to significantly advance knowledge of the etiology of prostate cancer and racial/ethnic disparities in prostate cancer risk, and to guide the development of future preventive, early detection, prognostic and even therapeutic measures. PUBLIC HEALTH RELEVANCE: In this proposal, we will conduct targeted genome-wide sequencing in men of African ancestry to reveal genetic markers that may contribute to their greater risk of prostate cancer. We expect findings from this study will make a major contribution to our understanding of genetic susceptibility to prostate cancer and the genetic basis underlying familial aggregation and heritability of this common cancer. Identifying more genetic predictors of risk will have widespread applicability and significance, leading to better risk models to more accurately predict a man's risk of developing prostate cancer, and better intensive screening and preventive strategies that target men at high risk.

描述（由申请人提供）：非洲裔美国男性的前列腺癌发病率比其他美国人群的发病率更高，并且在其他非洲和非洲衍生的人群中也可见前列腺癌的高率。人们普遍认为，常见和罕见的遗传变异都导致了复杂疾病（例如前列腺癌）的风险，但是它们对总体遗传力的相对贡献是引起激烈争议的主题。要使稀有变体对复杂疾病的风险有重大影响，效果大小的范围必须大大要大得多。然而，迄今为止，只有有限的证据或反对该假设的证据，因为直到最近才能全面测试基因组中的罕见变化。在此提案中，我们试图使用针对性的全基因组关联研究方法来检验美国血统男性中普通遗传变异对前列腺癌风险的贡献。在AIM 1中，我们计划在1,000名非洲血统（500名具有侵略性疾病）和1,000个对照组中，在前列腺癌细胞系中的表观遗传标记定义（在前列腺癌细胞系中的表观遗传标记）定义了（在30倍覆盖的基因组和调节区域（约160 MB））。将进行稀有变体分析的单个SNP和负担，并将在非洲血统的其他样本（6,000例和6,000例对照）中检查最统计学上显着的序列变化（约24,000个）的复制测试（〜24,000）。除了对单个变体的关联测试外，我们还将在基因和途径水平上对编码和非编码变体进行“稀有变体分析的负担”。在AIM 2中，我们将研究相关变体，环境因素（从而更好地定义这些因素的作用）和疾病严重程度之间的相互作用。在AIM 3中，我们将使用EQTL分析的分阶段方法评估AIM 1中新型风险等位基因的生物学功能，然后在体外分析增强子活性以及等位基因特异性效应。该建议涵盖了前列腺癌的遗传流行病学研究的范围，从遗传发现（所有前列腺癌和侵略性疾病）到基因环境相互作用测试，再到生物学理解。我们希望这项工作能够大大提高对前列腺癌和种族/种族差异的病因的了解前列腺癌的风险，并指导未来预防，早期检测，预后甚至治疗措施的发展。公共卫生相关性：在此提案中，我们将在非洲血统男性中进行针对性的全基因组测序，以揭示可能有助于其更大的前列腺癌风险的遗传标记。我们期望这项研究的发现将为我们理解前列腺癌的遗传易感性以及这种常见癌症的基础家庭聚集和遗传力做出重大贡献。确定风险的更多遗传预测因素将具有广泛的适用性和意义，从而使更好的风险模型更准确地预测男人患前列腺癌的风险，以及针对男性高风险的更好的强化筛查和预防策略。