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：
7302234
负责人：
Kari Stefansson
金额：
$ 35.38万
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/7302234
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

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：前列腺癌是美国最常见的男性恶性肿瘤，估计有33％的所有新男性癌症诊断和2006年所有癌症死亡的9％。发现可重复的前列腺癌风险变体的进展也放慢了，即使家人和双胞胎研究表明，这是对疾病的重要遗传组成部分。使用连锁和关联分析的结合，我们确定了8q24染色体上的常见遗传变异，该变异与前列腺癌的风险增加显着相关。重要的是，我们在两个欧洲血统和一名非裔美国人中复制了我们的发现。该变体解释了欧洲血统人群中约8％的前列腺癌风险，但在非洲裔美国人中的风险高达16％，可以部分解释该组中前列腺癌的发病率更高。我们的发现现在已经在日裔美国人，夏威夷原住民，拉丁美洲和欧美前列腺癌病例对照系列中得到了复制，从而为该地区的风险变体提供了额外的支持，这在广泛的人群中很重要。该关联信号位于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类型中经常获得或扩增。为了描述承载AT风险变体的功能后果，我们建议在CHR8Q24上彻底分析以与前列腺癌相关的标记为中心的CHR8Q24上的2 MB区域。我们将使用几种互补的高分辨率阵列技术来发现CHR8Q24区域中的转录本，拷贝数变体和甲基化位点，并将其与前列腺癌风险变体（S）相关联。因此，我们建议在CHR8Q24上识别基本功能性前列腺癌危险因素的第一步，并开始解释为什么携带者会增加患上前列腺癌的风险。在CHR8Q24上，更好地了解前列腺癌危险因素的重要性很重要。首先，这将增加我们对正常细胞生理学可能导致前列腺癌可能会导致正常生理可能较小的差异的了解。其次，这些信息可能会揭示影响前列腺癌和可能其他癌症类型的易感性的新细胞机制。最后但并非最不重要的一点是，关于前列腺癌易感性功能方面的知识增加可能导致开发诊断和治疗该疾病的新方法。