Comprehensive functional annotation of 77 prostate cancer risk loci.
Comprehensive functional annotation of 77 prostate cancer risk loci.
复制标题
DOI：
10.1371/journal.pgen.1004102
复制
发表时间：
2014-01
期刊：
影响因子：
4.5
通讯作者：
Coetzee GA
中科院分区：
文献类型：
--
作者：
Hazelett DJ;Rhie SK;Gaddis M;Yan C;Lakeland DL;Coetzee SG;Ellipse/GAME-ON consortium;Practical consortium;Henderson BE;Noushmehr H;Cozen W;Kote-Jarai Z;Eeles RA;Easton DF;Haiman CA;Lu W;Farnham PJ;Coetzee GA
全基因组关联研究（GWAS）已经彻底改变了癌症遗传学领域，但遗传风险增加与疾病过程的发生/进展之间的因果关系仍有待确定。在这里，我们报告的第一步，在这样的奋进，前列腺癌。我们提供了一个全面的注释的77个已知的风险基因座，基于高度相关的变异，在生物学相关的染色质注释-我们确定了727个这样的潜在功能的SNP。我们还提供了可能的蛋白质破坏，microRNA靶序列破坏和所有相关SNP的调控反应元件破坏的详细说明。727个SNP中有88%属于推定的增强子，并且许多改变了已知参与前列腺生物学的转录因子的反应元件中的关键残基。我们将具有前列腺癌相关SNP的前列腺衍生细胞系中具有增强子染色质生物特征的那些区域定义为风险增强子。为了帮助识别这些增强子，我们对H3 K27-乙酰化进行了全基因组ChIP-seq，这是一种活跃参与的增强子的标记，以及转录因子TCF 7 L2。我们深入分析了风险增强子的三种变体，其中两种在LNCaP细胞中显示出显着改变的雄激素敏感性。这包括rs 4907792，它与前列腺组织中NUDT 11（在X染色体上）的eQTL处于连锁不平衡（），以及rs 10486567，7号染色体上JAZF 1基因内含子3中的索引SNP。Rs 4907792位于强共有雄激素反应元件的关键残基内，该元件在保护性等位基因中被中断，导致其雄激素敏感性降低56%，而rs 10486567影响NKX 3 -1和FOXA-AR基序，其中风险等位基因导致基础活性增加39%，雄激素刺激的增强子活性增加28%。鉴定这种增强子变体及其潜在的靶基因代表了将风险与疾病过程联系起来的初步步骤。在下面的工作中，我们提供了一个完整的概括性注释功能假说有关的风险确定的全基因组关联研究的前列腺癌。此外，我们提出了LNCaP细胞中H3 K27-乙酰化和TCF 7 L2结合的新的全基因组概况。我们还介绍了风险增强子的概念，并描述了两种新的雄激素敏感性增强子，其活性特别受前列腺癌风险SNP的影响。我们的研究结果代表了一个初步的方法，系统地识别因果变异潜在的前列腺癌的风险。
Genome-wide association studies (GWAS) have revolutionized the field of cancer genetics, but the causal links between increased genetic risk and onset/progression of disease processes remain to be identified. Here we report the first step in such an endeavor for prostate cancer. We provide a comprehensive annotation of the 77 known risk loci, based upon highly correlated variants in biologically relevant chromatin annotations— we identified 727 such potentially functional SNPs. We also provide a detailed account of possible protein disruption, microRNA target sequence disruption and regulatory response element disruption of all correlated SNPs at . 88% of the 727 SNPs fall within putative enhancers, and many alter critical residues in the response elements of transcription factors known to be involved in prostate biology. We define as risk enhancers those regions with enhancer chromatin biofeatures in prostate-derived cell lines with prostate-cancer correlated SNPs. To aid the identification of these enhancers, we performed genomewide ChIP-seq for H3K27-acetylation, a mark of actively engaged enhancers, as well as the transcription factor TCF7L2. We analyzed in depth three variants in risk enhancers, two of which show significantly altered androgen sensitivity in LNCaP cells. This includes rs4907792, that is in linkage disequilibrium () with an eQTL for NUDT11 (on the X chromosome) in prostate tissue, and rs10486567, the index SNP in intron 3 of the JAZF1 gene on chromosome 7. Rs4907792 is within a critical residue of a strong consensus androgen response element that is interrupted in the protective allele, resulting in a 56% decrease in its androgen sensitivity, whereas rs10486567 affects both NKX3-1 and FOXA-AR motifs where the risk allele results in a 39% increase in basal activity and a 28% fold-increase in androgen stimulated enhancer activity. Identification of such enhancer variants and their potential target genes represents a preliminary step in connecting risk to disease process. In the following work we provide a complete summary annotation of functional hypotheses relating to risk identified by genome wide association studies of prostate cancer. In addition, we present new genome-wide profiles for H3K27-acetylation and TCF7L2 binding in LNCaP cells. We also introduce the concept of a risk enhancer, and characterize two novel androgen-sensitive enhancers whose activity is specifically affected by prostate-cancer risk SNPs. Our findings represent a preliminary approach to systematic identification of causal variation underlying cancer risk in the prostate.
登录
查看更多内容
影响因子：
12.3
作者：
Berman BP;Pfeiffer BD;Laverty TR;Salzberg SL;Rubin GM;Eisen MB;Celniker SE
通讯作者：
Celniker SE
来自1,092个人基因组的遗传变异的综合图。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
14.9
作者：
Blahnik KR;Dou L;O'Geen H;McPhillips T;Xu X;Cao AR;Iyengar S;Nicolet CM;Ludäscher B;Korf I;Farnham PJ
通讯作者：
Farnham PJ
DOI：
10.1073/pnas.231608898
发表时间：
2002-01-22
影响因子：
11.1
作者：
Berman, BP;Nibu, Y;Eisen, MB
通讯作者：
Eisen, MB
DOI：
10.1056/nejmoa1110000
发表时间：
2012-01-12
期刊：
The New England journal of medicine
影响因子：
--
作者：
Ewing CM;Ray AM;Lange EM;Zuhlke KA;Robbins CM;Tembe WD;Wiley KE;Isaacs SD;Johng D;Wang Y;Bizon C;Yan G;Gielzak M;Partin AW;Shanmugam V;Izatt T;Sinari S;Craig DW;Zheng SL;Walsh PC;Montie JE;Xu J;Carpten JD;Isaacs WB;Cooney KA
通讯作者：
Cooney KA