Segedi Maja, Anderson Laura N, Espin-Garcia Osvaldo, Borgida Ayelet, Bianco Teresa, Cheng Dangxiao, Chen Zhuo, Patel Devalben, Brown M Catherine, Xu Wei, Reisman David, Gallinger Steven, Cotterchio Michelle, Hung Rayjean, Liu Geoffrey, Cleary Sean P
Department of Surgery, University of British Columbia, Vancouver, BC, Canada.
Princess Margaret Cancer Centre-University Health Network-Ontario Cancer Institute, University of Toronto, Toronto, ON, Canada.
Int J Cancer. 2016 Dec 1;139(11):2474-81. doi: 10.1002/ijc.30369. Epub 2016 Aug 18.
Variant alleles of two promoter polymorphisms in the BRM gene (BRM-741, BRM-1321), create MEF2D transcription binding sites that lead to epigenetic silencing of BRM, the key catalytic component of the SWI/SNF chromatin remodeling complex. BRM suppression can be reversed pharmacologically.(1) Our group and others have reported associations with lung, head and neck, hepatocellular cancer risk,(1-3) and with lung and esophageal cancer prognosis (ASCO 2013; abstract 11057 & 4077). Herein, we assessed risk and survival associations with pancreatic cancer. A provincial population-based case-control study was conducted with 623 histologically confirmed pancreatic adenocarcinoma cases and 1,192 age/gender distribution-matched controls.(4) Survival of cases was obtained through the Ontario Cancer Registry. Logistic and Cox proportional hazard regression models were fitted, adjusting for relevant covariates. Median age was 65 y; 52% were male; Stage I (8%), II (55%), III (14%), IV (23%); 53% after curative resection, 79% after chemotherapy; and 83% had died. In the risk analysis, adjusted odds ratios (aOR) were 1.01 (95% CI: 0.1-2.0) and 0.96 (95% CI: 0.7-1.3) for the homozygotes of BRM-741 and BRM-1321, respectively; aOR of double-homozygotes was 1.11 (95% CI: 0.80-1.53), compared to the double-wildtype. For the survival analysis, adjusted hazard ratios (aHR) were 2.19 (95% CI: 1.9-2.5) for BRM-741 and 1.94 (95% CI: 1.7-2.2) for BRM-1321, per unit increase in variant alleles. Compared with the double-wildtype, aHR for carrying no, one, and two double-homozygotes were 2.14 (95% CI: 1.6-2.8), 4.17 (95% CI: 3.0-5.7), 8.03 (95% CI: 5.7-11.4), respectively. In conclusion, two functional promoter BRM polymorphisms were not associated with pancreatic adenocarcinoma risk, but are strongly associated with survival.
BRM基因中两个启动子多态性（BRM - 741、BRM - 1321）的变异等位基因会产生MEF2D转录结合位点，导致BRM基因发生表观遗传沉默，BRM是SWI/SNF染色质重塑复合体的关键催化成分。BRM的抑制作用可通过药物逆转。（1）我们团队及其他研究团队已报道这些多态性与肺癌、头颈癌、肝细胞癌风险相关，（1 - 3）也与肺癌和食管癌的预后相关（美国临床肿瘤学会2013年会议；摘要11057及4077）。在此，我们评估了其与胰腺癌的风险及生存关联。我们开展了一项基于省级人群的病例对照研究，纳入623例经组织学确诊的胰腺腺癌病例和1192例年龄/性别分布匹配的对照。（4）病例的生存信息通过安大略癌症登记处获取。我们拟合了逻辑回归模型和Cox比例风险回归模型，并对相关协变量进行了调整。病例的中位年龄为65岁；52%为男性；I期（8%）、II期（55%）、III期（14%）、IV期（23%）；53%接受了根治性切除，79%接受了化疗；83%已死亡。在风险分析中，BRM - 741和BRM - 1321纯合子的校正比值比（aOR）分别为1.01（95%置信区间：0.1 - 2.0）和0.96（95%置信区间：0.7 - 1.3）；与双野生型相比，双纯合子的aOR为1.11（95%置信区间：0.80 - 1.53）。在生存分析中，BRM - 741每增加一个变异等位基因，校正风险比（aHR）为2.19（95%置信区间：1.9 - 2.5），BRM - 1321为1.94（95%置信区间：1.7 - 2.2）。与双野生型相比，携带无、一个和两个双纯合子的aHR分别为2.14（95%置信区间：1.6 - 2.8）、4.17（95%置信区间：3.0 - 5.7）、8.03（95%置信区间：5.7 - 11.4）。总之，BRM基因的两个功能性启动子多态性与胰腺腺癌风险无关，但与生存密切相关。
