Association of BRM promoter polymorphisms and esophageal adenocarcinoma outcome

// Grzegorz J. Korpanty 1, 2, * , Lawson Eng 1, * , Xin Qiu 3, * , Olusola Olusesan Faluyi 1 , Daniel J. Renouf 4 , Dangxiao Cheng 5 , Devalben Patel 5 , Zhuo Chen 5 , Brandon C. Tse 5 , Jennifer J. Knox 1 , Lorin Dodbiba 1 , Jennifer Teichman 1 , Abul Kalam Azad 1 , Rebecca Wong 6 , Gail Darling 7 , David Reisman 8 , Sinead Cuffe 1, # , Geoffrey Liu 1, 5, 9, # , Wei Xu 3, # 1 Princess Margaret Cancer Centre, Department of Medicine, University Health Network, Toronto, ON, Canada 2 Canadian Cancer Trials Group, Department of Medicine, Queens University, Kingston, ON, Canada 3 Princess Margaret Cancer Centre, Department of Biostatistics, University Health Network, Toronto, ON, Canada 4 Department of Medical Oncology, University of British Columbia and British Columbia Cancer Agency, Vancouver, BC, Canada 5 Princess Margaret Cancer Centre, Department of Medical Biophysics, University Health Network, Toronto, ON, Canada 6 Princess Margaret Cancer Centre, Radiation Medicine Program, University Health Network, Toronto, ON, Canada 7 Department of Surgery, Division of Thoracic Surgery, Toronto General Hospital, University Health Network, Toronto, ON, Canada 8 Department of Medicine in the College of Medicine, Division of Hematology and Oncology, University of Florida, Gainesville, FL, USA 9 Department of Epidemiology, Dalla Lana School of Pubic Health, Toronto, ON, Canada * Co-first authors # Co-senior authors Correspondence to: Geoffrey Liu, email: Geoffrey.Liu@uhn.on.ca Keywords: chromatin remodeling, polymorphism, cancer prognosis, esophageal cancer, brahma Received: October 20, 2016      Accepted: February 22, 2017      Published: March 03, 2017 ABSTRACT Purpose: Brahma (BRM) is a critical catalytic subunit of the SWI/SNF chromatin remodeling complex; expression of BRM is commonly lost in various cancer types. BRM promoter polymorphisms (BRM-741; BRM-1321) are associated with loss of BRM expression, and with cancer risk/survival. We evaluated these two polymorphisms in the overall survival (OS) of esophageal adenocarcinoma (EAC) patients. Results: Of 270 patients, 37% were stage IV. Minor allele frequencies were 47−49%; 15% were double-homozygotes. When compared to the wild-type genotype, the homozygous variant of BRM-741 carried an adjusted OS hazard ratio (aHR) of 1.64 (95% CI:1.1−2.4); for BRM-1321, the aHR was 2.09 (95% CI:1.4−3.0). Compared to the double wild-type, carrying homozygous variants of both promoter polymorphisms (double-homozygote) yielded an aHR of 2.21 (95% CI:1.4−3.6). Directions/magnitudes of associations were similar in subsets by age, gender, smoking status, use of platinum agents, and disease stage, and for progression-free survival. Materials and Methods: In a cohort of EAC patients of all stages (84% male; median age of 64 years), two BRM polymorphisms were genotyped. Cox proportional hazards models, adjusted for known prognostic variables, estimated the association of polymorphisms with OS. Conclusions: BRM polymorphisms were associated with OS in EAC in this study. Validation studies are warranted.