Promoter polymorphisms of the SWI/SNF chromatin remodeling complex molecule, BRM and esophageal adenocarcinoma outcome Grzegorz Korpanty1, Xin Qiu1, Lawson.

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Promoter polymorphisms of the SWI/SNF chromatin remodeling complex molecule, BRM and esophageal adenocarcinoma outcome Grzegorz Korpanty1, Xin Qiu1, Lawson Eng1, Olusola Olusesan Faluyi1, Dangxiao Cheng1, Daniel John Renouf2, Jennifer J. Knox1, Rebecca Wong1, Gail Darling1, Wei Xu1, Lorin Dodbiba1, Abul Kalam Azad1, David Reisman3, Sinead Cuffe1, Geoffrey Liu1 1Princess Margaret Hospital, University Health Network, Toronto, ON, Canada; 2 British Columbia Cancer Agency, Vancouver, BC, Canada; 3University of Florida, FL, USA Abstract Results Background: The SWI/SNF chromatin remodeling complex is an important regulator of gene expression that has been linked to cancer development and outcome. Expression of Brahma (BRM), a critical catalytic subunit of SWI/SNF is lost in a variety of solid tumors. Two novel BRM promoter polymorphisms (BRM-741 and BRM-1321) have been correlated with BRM loss and elevated cancer risk in upper aerodigestive and lung cancer outcome. Objectives: We evaluated BRM polymorphisms and their role in the survival of esophageal cancer patients. Methods: 270 histologically-confirmed esophageal adenocarcinoma patients of all stages were evaluated. The two BRM polymorphisms utilized Taqman genotyping. Cox proportional hazards models adjusted for clinical prognostic variables and determined the association of polymorphisms with overall survival (OS) and progression free survival (PFS). Adjusted hazard ratio (aHR) and 95% confidence intervals (CI) were calculated. Results: Among our patients, 85% were male; the mean age was 63 years. 37% had stage IV advanced tumors. The median PFS was 12.9 months, while median OS was 20.8 months. After adjustment for known prognostic clinical variables, carrying homozygous variants of both BRM polymorphisms (double homozygotes) was associated with a worse outcome: aHR 2.207 (1.36-3.58, p=0.0014) for OS and aHR 2.467 (1.527-3.983, p=0.0002) for PFS. Conclusions: We report the initial association of BRM polymorphisms with survival in esophageal cancer. We plan to explore additional relationships and validate these findings in other datasets. Patient Demographics No. of Patients (%) n=270 Ethnicity Caucasian 235 (87) Non-Caucasian 20 (7) Other/Unknown 15 (6) Sex Male 228 (84.4) Female 42 (15.6) Age Median, range (years) 64.1 (29.1 - 87.6) Body Mass Index at diagnosis 28.6 (17.7 – 58.5) Smoking status Never-smokers 71 (26.3) Ex-Smokers 137 (50.7) Current Smokers 59 (21.9) Unknown 3 (1.1) Alcohol intake (ever) Yes 220 (81.5) No 49 (18.1) 1 (0.4) Performance status (ECOG) 58 (21.5) 1 196 (72.6) 2-3 16 (5.9) Presence of weight loss at diagnosis < 10% 147 (54.4) ≥ 10% 122 (45.2) TNM stage 29 (10.8) 2 73 (27.1) 3 4 94 (34.9) Tumour location Upper 1/3 of esophagus Middle 1/3 of esophagus 6 (2.2) Lower 1/3 of esophagus 113 (41.9) Gastro-esophageal junction 61 (22.6) Not specified 47 (17.4) Other 42 (15.5) Presence of Barrett’s esophagus 45 (16.6) 224 (83) Treated with surgery 172 (63.7) 98 (36.3) Treated with chemotherapy 178 (65.9) 92 (34.1) Treated with cisplatin chemotherapy 167 (61.9) 103 (38.1) Treated with radiotherapy 152 (56.3) 118 (43.7) Univariate Analysis PFS OS Variables HR 95% CI p BRM-741 Polymorphism Heterozygous Homozygous 1.073 1.69 0.77-1.495 1.175-2.454 0.676 0.0049 1.116 1.87 0.795-1.566 1.299-2.701 0.527 0.0008 BRM-1321 Polymorphism 1.357 2.253 0.974-1.889 1.561-3.251 0.071 1.44x10-5 1.377 2.405 0.983-1.929 1.66-3.485 0.0632 3.51x10-6 BRM-741 & BRM-1321 Polymorphism None homozygous One homozygous Two homozygous 1.324 1.638 2.839 0.89-1.971 1.047-2.562 1.768-4.56 0.167 0.0307 1.58x10-5 1.379 1.984 2.973 0.915-2.078 1.267-3.109 1.842-4.798 0.125 0.0028 8.18x10-6 Weight loss <10% 0.661 0.505-0.866 0.0026 0.614 0.468-0.806 0.0004 Barrett’s esophagus 0.568 0.381-0.847 0.0056 0.665 0.454-0.976 0.037 ECOG 2-3 1.023-3.42 0.042 2.194 1.199-4.014 0.0108 Stage 2 1.94 1.09-3.456 0.0243 1.942 1.09-3.46 Stage 3 3.6 2.037-6.364 1.04x10-5 3.514 1.984-6.23 1.66x10-5 Stage 4 5.476 3.119-9.615 3.21x10-9 5.311 3.016-9.352 7.27x10-9 Surgical resection 0.255 0.192-0.34 1.28x10-20 0.258 0.194-0.344 2.2x10-20 Multivariate Analysis* PFS OS Variables HR 95% CI p BRM-741 Polymorphism Heterozygous Homozygous 1.063 1.647 0.759-1.488 1.134-2.391 0.7214 0.0088 1.068 1.635 0.758-1.504 1.127-2.372 0.706 0.0096 BRM-1321 Polymorphism 1.518 2.288 1.078-2.138 1.564-3.347 0.0168 1.98x10-5 1.369 2.085 0.969-1.935 1.433-3.035 0.075 0.0001 BRM-741 & BRM-1321 Polymorphism None homozygous One homozygous Two homozygous 1.281 1.642 2.467 0.858-1.913 1.032-2.611 1.527-3.983 0.225 0.0362 0.0002 1.245 1.823 2.207 0.824-1.881 1.147-2.899 1.36-3.581 0.297 0.0111 0.0014 Background The SWI/SNF chromatin remodeling complex is an important gene expression regulator associated with carcinogenesis. Expression of Brahma (BRM), a critical ATPasa catalytic subunit of SWI/SNF, is lost in a variety of solid tumors. Two novel BRM promoter polymorphisms (BRM -741 and BRM -1321) have been correlated with loss of BRM expression and increased risk of head and neck and lung cancer 1,2. * After adjustment to variables included in clinical base model (age, ECOG, weight loss (%), TNM Stage and surgical resection) Two BRM insertion promoter sequence variants (BRM-741 and BRM-1321) result in epigenetic silencing of BRM through recruitment of histone deacetylases2 (Figure 1). Recently, pharmacological reversal of the epigenetic changes of BRM has been shown to be a potentially viable therapeutic strategy3. We investigated the association between BRM promoter variants and survival outcomes in patients with esophageal cancer. We investigated the association between BRM promoter variants and survival outcomes in patients with esophageal cancer Overall Survival by BRM-741 Genotype Overall Survival by BRM-1321 Genotype Figure 1. The location and sequence of BRM-1321 and BRM-741. The polymorphic sites are located at 1321 and 741 bp upstream of the transcriptional start site. BRM-1321 and BRM-741 are insertion variants of 6 and 7 bp in length, respectively. Methods The study population consisted of 270 patients with histologically confirmed esophageal adenocarcinoma of all TNM stages treated in Princess Margaret Hospital, Toronto from 2003 to 2013. Clinico-pathological and treatment data were extracted from the patients’ medical records and survival data were obtained from the Ontario Cancer Registry. Genotyping for the BRM promoter variants was performed using Taqman probes. Association of the polymorphisms with overall (OS) & progression free survival (PFS) were assessed using multivariate Cox proportional hazards models. Variables included in the multivariate model were: age, gender, ECOG performance status, presence of weight loss at diagnosis, Body Mass Index (BMI), alcohol use, TNM stage, presence of Barrett’s esophagus, type of received treatment (surgery, cisplatin-based chemotherapy, radiation) Progression Free (A) and Overall (B) Survival by Number of Homozygous Variants of BRM-741 and BRM-1321 A B Results 270 patients with esophageal adenocarcinoma had available blood samples for genotyping and were eligible for inclusion in this study. After a median follow up of 58.5 months, median OS time was 20.8 months with 95% CI (17.4-26.2) and median PFS time 12.9 months with 95% CI (10.7-15.9). Homozygous variants of BRM-741 were strongly associated with worse OS (adjusted HR [aHR] 1.873 [95% CI: 1.3-2.7; p=0.0008]) and PFS (aHR 1.698 [95% CI: 1.2-2.5; p=0.005]), compared to the wild types. Similar findings were observed for the BRM-1321 homozygous variants (aHR for OS of 2.405 [95% CI: 1.7-3.5; p=3.5x10-6]; aHR for PFS of 2.252 [95% CI: 1.7-3.3; p=1.4x10-5]). The presence of double homozygous BRM-741 and BRM-1321 variants was strongly associated with substantially worse OS (aHR 2.973 [95% CI: 1.8-4.8, p=8.2x10-6]) and PFS (aHR 2.839 [95% CI: 1.8-4.6, p=1.6x10-5]) Conclusions Two homozygous BRM promoter polymorphisms (BRM-741 and BRM 1321) are associated with adverse progression and overall survival in patients with esophageal adenocarcinoma. We plan to explore additional relationships and validate these findings in other datasets. References Wang JR et al. Association of two BRM promoter polymorphisms with head and neck squamous cell carcinoma risk. Carcinogenesis 2013;34(5):1012-1017 Liu G et al. Two novel BRM insertion promoter sequence variants are associated with loss of BRM expression and lung cancer risk. Oncogen 2011;30(29):3295-3304. Gramling S et al. Pharmacologic reversal of epigenetic silencing of the anticancer protein BRM: a novel targeted treatment strategy. Oncogene. 2011 Jul 21;30(29):3289-94. .