Functional BRM promoter polymorphisms, pancreatic adenocarcinoma risk, and survival.
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222 Background: 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 (PMID:23524580). BRM suppression can be reversed pharmacologically (PMID: 21478905). Our group and others have reported associations with lung, head and neck, and hepatocellular cancer risk (PMIDs: 21478907, 23322154, 23359823). We have also reported associations with lung and esophageal cancer prognosis (ASCO 2013; abstr 11057 and 4077). In this analysis, we assessed risk and survival associations with pancreatic cancer. Methods: A population-based case-control study was conducted in Ontario with 623 histologically-confirmed pancreatic adenocarcinoma cases and 1192 age/gender distribution-matched controls (PMID: 23908141). Survival of cases was obtained through the Ontario Cancer Registry. Logistic and Cox proportional hazard regression models were fitted, adjusting for relevant covariates. Results: Median age was 65 years; 52% were male; 53% had received a curative resection; Stage I (8%), II (55%), III (14%), IV (23%); 79% received chemotherapy; 83% had died. In the risk analysis, the adjusted odds ratios were 1.01 (95%CI:0.1-2.0) and 0.96 (95%CI:0.7-1.3) for the homozygous variants of BRM-741 and BRM-1321, respectively, when each was compared to wildtype; adjusted odds ratio of double-homozygotes was 1.11 (95%CI:0.80-1.53) when compared to the double-wildtype. In contrast for the survival analysis, the hazard ratios (adjusted for age, stage, receipt of curative surgery, receipt of chemotherapy, and packyears) 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 each unit increase in variant alleles. Compared with the double-wildtype, the adjusted hazard ratio for carrying no, one, and two homozygous (double-homozygous) variants were 2.14 (95%CI:1.6-2.8), 4.17 (95%CI:3.0-5.7), and 8.03 (95%CI: 5.7-11.4), respectively. Conclusions: Two functional promoter BRM polymorphisms were not associated with pancreatic adenocarcinoma risk, but are strongly associated with survival.
