The effect of two BRM promoter variants on the risk of stage I/II upper aerodigestive tract cancers.

Abstract

10522 Background: BRM is a key subunit of the chromatin remodeling complex SWI/SNF and a putative tumor suppressor gene that is silenced in 15-20% of many solid tumors (PMID 15722796). Evidence suggests that it is epigenetically regulated, as two BRM promoter insertion variants (BRM-741 and BRM-1321) may lead to gene silencing by recruiting histone deacetylases. The presence of both homozygous BRM-741 and BRM-1321 highly correlate with loss of BRM expression and function in lung tumors, while increasing smoking-related lung cancer by two-fold (PMID 21478907). Also, the pharmacologic reversal of epigenetic changes of BRM offers a potential novel therapeutic approach (PMID 21478905). We assessed whether these BRM variants are associated with the risk of upper aerodigestive tract cancers, focusing on Stage I/II tumors that would most benefit from new screening and prevention strategies. Methods: BRM was genotyped by qPCR using TaqMan probes. 1,008 controls were matched to 595 cases by frequency distribution based on age, gender and smoking status. Multivariate logistic regression generated adjusted odds ratios (aOR). Results: The 595 cases were: 115 esophageal, 278 lung, and 202 head and neck cancers. 51% were adenocarcinomas; 60% were Stage I. The frequency of homozygozity was: BRM-741, 26%; BRM-1321, 23%; both variants, 15%. In the combined analysis, there was significant correlation between malignancy and homozygous BRM-741 (aOR 1.91 (95%CI 1.3-2.4); p=0.001) or BRM-1321 (aOR 1.94 (95%CI 1.4-2.7; p=3x10E-4). Being homozygous for both BRM variants carried an even greater risk (aOR 2.45 (95%CI 1.6-3.9); p=1x10E-5). This correlation was similar for adenocarcinomas (aOR 2.53 (95%CI 1.4-4.2); p=6x10E-4) and squamous cell carcinomas (aOR 2.33 (95%CI 1.3-4.4); p=8x10E-4). The increased cancer risk was also similar between these subgroups: head and neck, esophageal and lung cancers; Stage I and II patients; smokers and non-smokers. Conclusions: The two homozygous BRM variants increase the risk of early stage upper aerodigestive tumors by more than two-fold independent of smoking status. BRM promoter variants and their potential epigenetic effect may be early events in the evolution of these cancers.