BRM promoter polymorphisms and survival of advanced non-small cell lung cancer patients in the princess Margaret cohort and CCTG BR.24 trial

Geoffrey Liu, Sinead Cuffe, Shermi Liang, Abul Kalam Azad, Lu Cheng, Yonathan Brhane, Xin Qiu, David W. Cescon, Jeffrey Bruce, Zhuo Chen, Dangxiao Cheng, Devalben Patel, Brandon C. Tse, Scott A. Laurie, Glenwood Goss, Natasha B. Leighl, Rayjean Hung, Penelope A. Bradbury, Lesley Seymour, Frances A. ShepherdMing Sound Tsao, Bingshu E. Chen, Wei Xu, David N. Reisman

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


Introduction: BRM, a key catalytic subunit of the SWI/SNF chromatin remodeling complex, is a putative tumor susceptibility gene that is silenced in 15% of non-small cell lung cancer (NSCLC). Two novel BRM promoter polymorphisms (BRM-741 and BRM-1321) are associated with reversible epigenetic silencing of BRM protein expression. Experimental Design: Advanced NSCLC patients from the Princess Margaret (PM) cohort study and from the CCTG BR.24 clinical trial were genotyped for BRM promoter polymorphisms. Associations of BRM variants with survival were assessed using log-rank tests, the method of Kaplan and Meier, and Cox proportional hazards models. Promoter swap, luciferase assays, and chromatin immunoprecipitation (ChIP) experiments evaluated polymorphism function. In silico analysis of publicly available gene expression datasets with outcome were performed. Results: Carrying the homozygous variants of both polymorphisms ("double homozygotes", DH) when compared with those carrying the double wild-type was associated with worse overall survival, with an adjusted hazard ratios (aHR) of 2.74 (95% CI, 1.9-4.0). This was confirmed in the BR.24 trial (aHR, 8.97; 95% CI, 3.3-18.5). Lower BRM gene expression (by RNA-Seq or microarray) was associated with worse outcome (P < 0.04). ChIP and promoter swap experiments confirmed binding of MEF2D and HDAC9 only to homozygotes of each polymorphism, associated with reduced promoter activity in the DH. Conclusions: Epigenetic regulatory molecules bind to two BRM promoter sequence variants but not to their wild-type sequences. These variants are associated with adverse overall and progression-free survival. Decreased BRM gene expression, seen with these variants, is also associated with worse overall survival.

Original languageEnglish (US)
Pages (from-to)2460-2470
Number of pages11
JournalClinical Cancer Research
Issue number10
StatePublished - May 15 2017
Externally publishedYes

ASJC Scopus subject areas

  • General Medicine


Dive into the research topics of 'BRM promoter polymorphisms and survival of advanced non-small cell lung cancer patients in the princess Margaret cohort and CCTG BR.24 trial'. Together they form a unique fingerprint.

Cite this