Jia Li, Landan Gilad, Pomerantz Mark, Jaschek Rami, Herman Paula, Reich David, Yan Chunli, Khalid Omar, Kantoff Phil, Oh William, Manak J Robert, Berman Benjamin P, Henderson Brian E, Frenkel Baruch, Haiman Christopher A, Freedman Matthew, Tanay Amos, Coetzee Gerhard A
USC/Norris Cancer Center, Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA.
PLoS Genet. 2009 Aug;5(8):e1000597. doi: 10.1371/journal.pgen.1000597. Epub 2009 Aug 14.
Multiple discrete regions at 8q24 were recently shown to contain alleles that predispose to many cancers including prostate, breast, and colon. These regions are far from any annotated gene and their biological activities have been unknown. Here we profiled a 5-megabase chromatin segment encompassing all the risk regions for RNA expression, histone modifications, and locations occupied by RNA polymerase II and androgen receptor (AR). This led to the identification of several transcriptional enhancers, which were verified using reporter assays. Two enhancers in one risk region were occupied by AR and responded to androgen treatment; one contained a single nucleotide polymorphism (rs11986220) that resides within a FoxA1 binding site, with the prostate cancer risk allele facilitating both stronger FoxA1 binding and stronger androgen responsiveness. The study reported here exemplifies an approach that may be applied to any risk-associated allele in non-protein coding regions as it emerges from genome-wide association studies to better understand the genetic predisposition of complex diseases.
最近研究表明，位于8号染色体长臂24区（8q24）的多个离散区域包含一些等位基因，这些等位基因会增加患多种癌症的风险，包括前列腺癌、乳腺癌和结肠癌。这些区域距离任何已注释的基因都很远，其生物学活性一直未知。在此，我们对一个5兆碱基的染色质片段进行了分析，该片段涵盖了所有与RNA表达、组蛋白修饰以及RNA聚合酶II和雄激素受体（AR）占据位置相关的风险区域。这使得我们鉴定出了几个转录增强子，并通过报告基因检测进行了验证。其中一个风险区域的两个增强子被AR占据，并对雄激素治疗有反应；其中一个包含一个单核苷酸多态性（rs11986220），该多态性位于一个FoxA1结合位点内，前列腺癌风险等位基因促进了更强的FoxA1结合以及更强的雄激素反应性。本文报道的这项研究例证了一种方法，该方法可应用于全基因组关联研究中出现的非蛋白质编码区域的任何风险相关等位基因，以更好地理解复杂疾病的遗传易感性。
