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

• 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
• 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

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，估计有33％ 新的男性癌症诊断和2006年所有癌症死亡的9％。 癌症风险变异型的变化很慢，即使家庭和双胞胎研究表明有重要的 疾病的遗传成分。 使用链接和关联分析的组合，我们确定了一个常见的遗传变异 8Q24染色体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个非洲裔美国人的两个人群中复制了我们的发现。变体 解释了欧洲血统人群中约8％的前列腺癌风险，但多达16％的风险 非洲裔美国人，可以部分解释该组中前列腺癌的发病率更高。我们的发现 现在已在日裔美国人，夏威夷人，拉丁美洲裔和欧洲人中复制 美国前列腺癌​​病例对照系列为在存在风险变异的存在方面提供额外支持 这个地区在各种各样的人群中很重要。 该关联信号位于CHR8Q24上的连锁不平衡块内。这个基因组区域 没有已知的基因，但经常在前列腺癌和其他癌症中得到扩增 类型。为了描述承载AT风险变体的功能后果，我们建议彻底 分析以基因组区域为中心的CHR8Q24上的2 MB区域，该区域包含关联的标记 对前列腺癌的重要意义。我们将使用几种互补的高分辨率阵列技术 要发现成绩单，在CHR8Q24区域中的复制号变体和甲基化位点，并将其与 前列腺癌风险变体。因此，我们建议采取第一步来识别基础 CHR8Q24上的功能性前列腺癌危险因素，并开始解释为什么承运人处于危险中的增加 发展前列腺癌。 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，它将增加我们对正常蜂窝生理可能较小差异的了解 时间导致前列腺癌。其次，这些信息可能会揭示影响影响的新细胞机制 前列腺癌和可能其他癌症类型的倾向。最后但并非最不重要的是增加知识 关于前列腺癌易感性的功能方面可能导致新的发展 诊断和治疗疾病的方法。