Abstract
ABSTRACT Background BRM, an ATPase subunit of the SWI/SNF chromatin remodeling complex, is a putative tumor susceptibility gene that is silenced in 15% of lung cancers. Two BRM promoter insertion variants (BRM-741 and BRM-1321) result in epigenetic silencing of BRM through recruitment of histone deacetylases. The presence of double homozygous BRM variants is associated with loss of BRM expression, and double the risk of lung cancer. Recently, pharmacological reversal of the epigenetic changes of BRM has been shown to be a potentially viable therapeutic strategy. We investigated the association between BRM promoter variants and survival outcomes in advanced NSCLC patients. Methods 313 stage IV NSCLC patients treated in Princess Margaret Hospital from 2006-2010 were genotyped for the BRM promoter variants using TaqMan. Association of BRM variants and overall (OS) and progression free survival (PFS) were assessed using multivariate Cox proportional hazards models. Results 71% were Caucasian; 71%, adenoca; median age, 63 yrs; Median OS, 1.1 yrs; median follow up, 1.8 yrs. The frequency of homozygosity was: BRM-741 25%; BRM-1321 21%; both 12%. Homozygous variants of BRM-741 were strongly associated with worse OS (adjusted HR [aHR] 3.5 [95% CI: 2.4-5.0; p = 1x10E-11]) and PFS (aHR 2.3 [95% CI: 1.6-3.1; p = 8x10E-7]), compared to the wildtypes. Similar findings were observed for the BRM-1321 homozygous variants (aHR for OS of 2.5 [95% CI: 1.7-3.5; p = 1.1x10E-6]; aHR for PFS of 1.9 [95% CI: 1.3-2.6; p = .0004]). Finally, the presence of double homozygous BRM-741 and BRM-1321 variants was strongly associated with substantially worse OS (aHR 4.4 [95% CI: 2.7-7.1, p = 1x10E-9]) and PFS (aHR 3.6 [95% CI: 2.3-5.6, p = 2x10E-8]). Conclusion The same two homozygous BRM promoter variants that are associated with increased risk of lung cancer are also strongly associated with adverse OS and PFS in this cohort of stage IV NSCLC patients. Validation of the results in prospective clinical trials is underway and will better elucidate whether these BRM promoter variants are prognostic or predictive. Disclosure All authors have declared no conflicts of interest.
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
