Focused Genomic Dissection of the Prostate Cancer Risk Variant on Chromosome 8q24

染色体 8q24 上前列腺癌风险变异的重点基因组解析

基本信息

批准号：
7494146
负责人：
Kari Stefansson
金额：
$ 27.42万
依托单位：
DECODE GENETICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-07 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7494146
关键词：
8q24 Affect African African American American Antibodies Appendix Benign Prostatic Hypertrophy Cancer Control Cell Line Cell physiology Cessation of life Chromosomes Code Cytosine Development Diagnosis Disease Dissection Early Diagnosis Elements Epithelial Cells European Family Frequencies Functional RNA Gene Expression Genes Genetic Genomics Germ Lines Hawaiian population Heritability Incidence Individual Intervention Japanese American Knowledge Label Latino Lead Linkage Disequilibrium Malignant Neoplasms Malignant neoplasm of prostate Methods Methylation Minor Numbers Oligonucleotide Microarrays Oncogenes PC3 cell line Pathway interactions Population Population Attributable Risks Predisposition Preparation Prevention Prostate Proteins RNA RNA Polymerase II Research Personnel Resolution Risk Risk Factors Role Sampling Series Signal Transduction Site Specimen TAF1 gene Technology Time Tissues Transcript Transcription Initiation Transcription Initiation Site Twin Studies Utah Variant base cancer diagnosis cancer risk cancer type case control chromatin immunoprecipitation comparative genomic hybridization follow-up genetic variant male programs promoter

项目摘要

Prostate cancer is the most commonly diagnosed male malignancy in the US with an estimated 33% of all new male cancer diagnoses and 9% of all cancer deaths in 2006. Progress in finding reproducible prostate cancer risk variants has been slow even though family and twin studies show that there is a significant genetic component to the disease. Using a combination of linkage and association analysis, we identified a common genetic variant on chromosome 8q24 that is significantly associated with an increased risk of prostate cancer. Importantly, we have replicated our findings in two populations of European origin and one African American. The variant explains about 8% of prostate cancer risk in populations of European ancestry but up to 16% of the risk in African Americans and may partly explain the higher incidence of prostate cancer in this group. Our findings have now been replicated in Japanese American, Native Hawaiian, Latino American and European American prostate cancer case-control series lending additional support to the presence of risk variants in this region that are important in a wide spectrum of populations. The association signal is located within a linkage disequilibrium block on Chr8q24. This genomic region contains no known genes but is frequently gained or amplified in prostate cancer as well as other cancer types. To delineate the functional consequences of carrying the at risk variant(s) we propose to thoroughly analyze a 2 Mb region on Chr8q24 centered on the genomic region containing the markers that associate significantly to prostate cancer. We will use several complementary high-resolution array based technologies to uncover transcripts, copy number variants and methylated sites in the Chr8q24 region and relate these to the prostate cancer risk variant(s). We thus propose to take the first steps towards identifying the underlying functional prostate cancer risk factor on Chr8q24 and begin to explain why carriers are at an increased risk of developing prostate cancer. A better understanding of the prostate cancer risk factor on Chr8q24 is important for several reasons. First, it will increase our knowledge of how possibly minor differences in normal cellular physiology can over time lead to prostate cancer. Second, this information may unveil new cellular mechanisms that affect predisposition to prostate cancer and possibly other cancer types. Last, but not least, increased knowledge about the functional aspects of predisposition to prostate cancer may lead to the development of new methods for diagnosing and treating the disease.

前列腺癌是美国最常见的男性恶性肿瘤，估计占所有男性恶性肿瘤的 33% 2006 年新增男性癌症诊断，占所有癌症死亡人数的 9%。寻找可复制前列腺的进展尽管家庭和双胞胎研究表明癌症风险变异存在显着差异，但其进展缓慢该疾病的遗传因素。通过结合连锁和关联分析，我们确定了一个常见的遗传变异染色体 8q24 与前列腺癌风险增加显着相关。重要的是，我们在两个欧洲裔人群和一个非洲裔美国人中复制了我们的研究结果。变体解释了欧洲血统人群中约 8% 的前列腺癌风险，但欧洲血统人群中高达 16% 的风险非裔美国人可能部分解释了该群体前列腺癌发病率较高的原因。我们的发现现已在日裔美国人、夏威夷原住民、拉丁美洲人和欧洲人中复制美国前列腺癌病例对照系列为前列腺癌中存在风险变异提供了额外支持该地区对广大人群都很重要。关联信号位于 Chr8q24 上的连锁不平衡块内。该基因组区域不包含已知基因，但在前列腺癌和其他癌症中经常获得或扩增类型。为了描述携带风险变体的功能后果，我们建议彻底分析 Chr8q24 上以包含相关标记的基因组区域为中心的 2 Mb 区域对前列腺癌有显着影响。我们将使用几种互补的基于高分辨率阵列的技术发现 Chr8q24 区域的转录本、拷贝数变异和甲基化位点，并将它们与前列腺癌风险变异。因此，我们建议采取第一步来确定根本原因 Chr8q24 上的功能性前列腺癌风险因素，并开始解释为什么携带者风险增加发展为前列腺癌。出于多种原因，更好地了解 Chr8q24 上的前列腺癌危险因素非常重要。首先，它将增加我们对正常细胞生理学中的微小差异如何可能影响的认识。时间长了会导致前列腺癌。其次，这些信息可能揭示影响的新细胞机制易患前列腺癌和其他癌症类型。最后但并非最不重要的一点是增加知识关于前列腺癌易感性的功能方面可能会导致新的开发诊断和治疗该疾病的方法。