BRM promoter insertion/deletion polymorphisms in hepatocellular carcinoma risk and survival.

Abstract

225 Background: MEF2D and HDAC9 regulate the expression of BRM, the catalytic subunit of SWI/SNF (chromatin remodeling complex). MEF2D binding sites are created in the BRM promoter by two germline insertion/deletion polymorphisms (BRM-741, BRM-1321), which mediate epigenetic silencing. We recently identified BRM as a potential drug target and a susceptibility gene for lung and head and neck cancers, while others reported its association with HCC risk in Asians. BRM also correlates with prognosis in lung and esophageal cancers (ASCO 2013; abstracts 11057, 4077). In this analysis, we assessed the effects of the BRM promoter variants on risk and overall survival (OS) in HCC from a North American centre (Toronto). Methods: We conducted a case-control study with 266 histologically confirmed HCC cases and 536 age/sex distribution-matched healthy controls. Survival of the cases was obtained from medical records. Association between the BRM polymorphisms and HCC risk was analyzed by multivariate logistic regression adjusted for age, sex, race, smoking and BMI; their impact on OS was evaluated by Cox proportional hazard regression adjusted for age, sex, treatment intent and Hepatitis B status. Results: Median age was 62 years; 83% were male. Hepatitis B and C infections affected 34% and 31% of cases, respectively. 83% of patients were Child Pugh A at diagnosis, and 66% received initial curative therapy (surgical resection rate 32%). There were 13% deaths at a median follow-up of 24.1 months. There was no significant association between BRM polymorphisms and HCC risk: the adjusted risk odds ratios of the homozygous BRM variants, relative to wild-type, were 0.87 (95% CI: 0.53-1.45; BRM-741) and 1.01 (95% CI: 0.78-1.29; BRM-1321), and 0.94 (95% CI: 0.48-1.86) for the double homozygotes vs. double wild-type. The adjusted hazard ratios for OS were 5.77 (95% CI: 2.9-11.5; BRM-741) and 4.09 (95% CI: 2.2-7.5; BRM-1321) for each variant allele; the double homozygotes were also highly associated with OS compared to double wild-type (p<0.0001). Conclusions: Two functional BRM promoter polymorphisms did not increase the risk of HCC. However, they were strongly associated with OS despite short median follow-up. SPC and RH are co-senior authors.