BRM polymorphisms, pancreatic cancer risk and survival

Abstract

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 Promoter Polymorphisms and Survival of Advanced Non–Small Cell Lung Cancer Patients in the Princess Margaret Cohort and CCTG BR.24 Trial

“…Thirdly, the interplay between EGFR, ALK, and other somatic changes with BRM on prognosis is unknown; we had too few patients with these molecular alterations to perform molecular-specific analyses of BRM relationships. We also acknowledge that the dual roles of BRM polymorphisms on risk and prognosis may not be consistent: in other tumours and settings, a risk association may not translate into a survival association, and vice versa; evaluation in each specific cancer disease site is necessary 51 . We did not have the power or tumor samples to explore the effect of these polymorphisms in difference milieu (e.g.…”

Association of two BRM promoter polymorphisms and smoking status with malignant pleural mesothelioma risk and prognosis

“…Recently, several mechanisms by which BRM polymorphisms are linked to various cancer risks and prognosis have been proposed . Homozygous 6 to 7 bp insertion variants at BRM‐741 and BRM‐1321 produce the MEF2D binding site .…”

“…The loss of BRM expression has been linked to epigenetic regulation. Specifically, germline homozygous variants of two insertion‐deletion (indel) polymorphisms in the BRM promoter region (9p23‐24) that recruit MEF2 and histone deacetylases, BRM‐741 and BRM‐ 1321, have been implicated either as susceptibility factors or as poor prognostic factors in patients across a spectrum of solid tumors (Figure S1 for information regarding polymorphism sequences) . However, in liver and pancreatic tumors, BRM polymorphisms were not associated with risk, suggesting the role of BRM may differ between tumor types .…”

“…Specifically, germline homozygous variants of two insertion‐deletion (indel) polymorphisms in the BRM promoter region (9p23‐24) that recruit MEF2 and histone deacetylases, BRM‐741 and BRM‐ 1321, have been implicated either as susceptibility factors or as poor prognostic factors in patients across a spectrum of solid tumors (Figure S1 for information regarding polymorphism sequences) . However, in liver and pancreatic tumors, BRM polymorphisms were not associated with risk, suggesting the role of BRM may differ between tumor types . In efforts to explain the molecular basis of BRM polymorphisms on malignancies, in vitro studies revealed increases in MEF2D binding and five‐fold decreases in luciferase reporter gene activity in cancer cell lines in the presence of the promoter insertion variant .…”

Alterations of Epigenetic Regulators in Pancreatic Cancer and Their Clinical Implications

“…Putative DNA binding subunits ARID1A , ARID1B , and PBRM1 , enzymatic subunits SMARCA2 and SMARCA4 , and ARID2 have been shown to be mutated in pancreatic cancer [1,82,83]. Promoter polymorphisms in the SMARCA2 gene are strongly associated with pancreatic cancer patient survival [84]. BRM expression was shown to be related to tumor size, lymphatic invasion, and tumor stage [85].…”