Two BRM promoter polymorphisms predict poor survival in patients with hepatocellular carcinoma

Abstract

Funding informationThe Alan B. Brown Chair in Molecular Genomics; The Posluns Family Fund 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. K E Y W O R D S

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

“…In assessing our patient sample, we did not find an association between BRM polymorphisms and risk of developing MPM, consistent with liver, pancreatic, and colorectal cancer but in contrast to upper aerodigestive (head and neck and lung cancer), suggesting heterogeneity in mechanism and cancer‐site specificity . This is the first study, however, to identify an effect modification by smoking.…”

“…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 .…”

“…However, two exploratory analysis, one restricted to Caucasian males (which allowed for improved matching between cases and controls) and one restricted to occupationally‐exposed individuals both yielded ORs similar to the entire sample, including the differential effect by smoking status. Differential effect by disease sites raises concerns about technical differences in genotyping; however, we utilized an identical genotyping technique by the same technician, in similarly processed samples, as with our other studies . In our study, we did not explore BAP1, a widely studied susceptibility and prognostic marker for MPM .…”

“…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 .…”