Pasic Ivan, Wong Kit M, Lee Jonghun J, Espin-Garcia Osvaldo, Brhane Yonathan, Cheng Dangxiao, Chen Zhuo, Patel Devalben, Brown Catherine, Bucur Roxana, Reisman David, Knox Jennifer J, Xu Wei, Hung Rayjean J, Liu Geoffrey, Cleary Sean P
Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
University of Toronto, Toronto, Canada.
Mol Carcinog. 2018 Jan;57(1):106-113. doi: 10.1002/mc.22736. Epub 2017 Oct 9.
Polymorphisms in the promoter of the BRM gene, a critical subunit of the chromatin remodeling SWI/SNF complex, have previously been implicated in risk and prognosis in Caucasian-predominant lung, head and neck, esophageal, and pancreatic cancers, and in hepatocellular cancers in Asians. We investigated the role of these polymorphisms in hepatocellular carcinoma (HCC) risk and prognosis. HCC cases were recruited in a comprehensive cancer center while the matched controls were recruited from family practice units from the same catchment area. For risk analyses, unconditional logistic regression analyses were performed in HCC patients and matched healthy controls. Overall survival analyses were performed using Cox proportional hazard models, Kaplan-Meier curves, and log-rank tests. In 266 HCC cases and 536 controls, no association between either BRM promoter polymorphism (BRM-741 or BRM-1321) and risk of HCC was identified (P > 0.10 for all comparisons). There was significant worsening of overall survival as the number of variant alleles increased: BRM-741 per variant allele adjusted hazards ratio (aHR) 5.77, 95% confidence interval (CI) 2.89-11.54 and BRM-1321 per variant allele aHR 4.09, 95%CI 2.22-7.51. The effects of these two polymorphisms were at least additive, where individuals who were double homozygotes for the variant alleles had a 45-fold increase in risk of death when compared to those who were double wild-type for the two polymorphisms. Two BRM promoter polymorphisms were strongly associated with HCC prognosis but were not associated with increased HCC susceptibility. The association was strongest in double homozygotes for the allele variants.
BRM基因是染色质重塑SWI/SNF复合物的关键亚基，其启动子多态性先前已被认为与以白种人为主的肺癌、头颈癌、食管癌和胰腺癌以及亚洲人的肝细胞癌的风险和预后有关。我们研究了这些多态性在肝细胞癌（HCC）风险和预后中的作用。HCC病例在一个综合癌症中心招募，而匹配的对照则从同一集水区的家庭医疗单位招募。对于风险分析，在HCC患者和匹配的健康对照中进行无条件逻辑回归分析。使用Cox比例风险模型、Kaplan-Meier曲线和对数秩检验进行总生存分析。在266例HCC病例和536例对照中，未发现BRM启动子多态性（BRM-741或BRM-1321）与HCC风险之间存在关联（所有比较的P>0.10）。随着变异等位基因数量的增加，总生存期显著恶化：BRM-741每个变异等位基因调整后的风险比（aHR）为5.77，95%置信区间（CI）为2.89-11.54；BRM-1321每个变异等位基因aHR为4.09，95%CI为2.22-7.51。这两种多态性的影响至少是相加的，与两种多态性均为双野生型的个体相比，变异等位基因双纯合子个体的死亡风险增加了45倍。两种BRM启动子多态性与HCC预后密切相关，但与HCC易感性增加无关。这种关联在等位基因变异的双纯合子中最强。
