Evaluation of the 8q24 prostate cancer risk locus and MYC expression.
Evaluation of the 8q24 prostate cancer risk locus and MYC expression.
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DOI：
10.1158/0008-5472.can-09-0387
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发表时间：
2009-07-01
期刊：
影响因子：
11.2
通讯作者：
Freedman ML
中科院分区：
文献类型：
--
作者：
Pomerantz MM;Beckwith CA;Regan MM;Wyman SK;Petrovics G;Chen Y;Hawksworth DJ;Schumacher FR;Mucci L;Penney KL;Stampfer MJ;Chan JA;Ardlie KG;Fritz BR;Parkin RK;Lin DW;Dyke M;Herman P;Lee S;Oh WK;Kantoff PW;Tewari M;McLeod DG;Srivastava S;Freedman ML
8q24的多态性与前列腺癌风险密切相关。风险变异位于非蛋白质编码区，其机制尚未完全阐明。为了进一步剖析该基因座的功能，我们测试了两个假设：i）未注释的microRNA在该区域中转录，以及ii）该区域是顺式作用增强子。使用下一代测序，在组织学正常的根治性乳腺癌切除术（RP）组织中询问8q24风险区域的已知和新的microRNA（miRNA）。我们还评估了风险变异与多个基因转录水平之间的关联，重点是原癌基因MYC。在280例RP标本（来自234例欧洲裔美国人和46例非洲裔美国人患者）的组织学正常和肿瘤组织中测量RNA表达，并对每个个体的配对生殖系DNA进行6个8q24风险SNP的基因分型。在8q24前列腺癌风险基因座内没有发现显著的miRNA转录的证据。同样，在组织学正常或肿瘤组织中，远端RNA表达和风险等位基因状态之间没有令人信服的关联。据我们所知，这是第一个也是最大的研究之一，直接评估该区域的miRNA，并系统地测量与遗传风险变异相关的前列腺组织中MYC表达水平。这些数据将有助于指导未来的研究这一风险位点。
Polymorphisms at 8q24 are robustly associated with prostate cancer risk. The risk variants are located in non-protein coding regions and their mechanism has not been fully elucidated. To further dissect the function of this locus, we tested two hypotheses: i) unannotated microRNAs are transcribed in the region, and that ii) this region is a cis-acting enhancer. Using next generation sequencing, 8q24 risk regions were interrogated for known and novel microRNAs (miRNAs) in histologically normal radical prostatectomy (RP) tissue. We also evaluated the association between the risk variants and transcript levels of multiple genes, focusing on the proto-oncogene, MYC. RNA expression was measured in histologically normal and tumor tissue from 280 RP specimens (from 234 European American and 46 African American patients), and paired germline DNA from each individual was genotyped for six 8q24 risk SNPs. No evidence was found for significant miRNA transcription within 8q24 prostate cancer risk loci. Likewise, no convincing association between distal RNA expression and risk allele status was detected in either histologically normal or tumor tissue. To our knowledge, this is one of the first and largest studies to directly assess miRNA in this region and to systematically measure MYC expression levels in prostate tissue in relation to inherited risk variants. These data will help to direct the future study of this risk locus.