BAF250a (ARID1A) Loss Is Frequent in High-Grade Gastric Adenocarcinomas and Is Associated with Mismatch Repair Protein Loss
David F Schaeffer, Kimberly C Wiegand, Maggie Cheang, Aalok Kumar, Howard J Lim, David G Huntsman. Mount Sinai Hospital - University of Toronto, Toronto, ON, Canada; BC Cancer Agency, Vancouver, BC, Canada
Background: BAF250a, the protein encoded by the tumor suppressor gene AT-rich interactive domian1A gene (ARID1A), a subunit of the SWI/SNF chromatin remodeling complex, is considered to be an essential part of early tumorigenesis. We reported frequent mutations of ARID1A in clear cell and endometrioid ovarian carcinomas and loss of the corresponding protein BAF250a by immunohistochemistry (IHC). These finding have generated interest in assessing the mutation and loss of ARID1A in other malignancies. Our group recently reported that BAF250a is also frequently lost in endometrial cancers with loss observed in 29% (29/101) of grade 1 or 2 and 39% (44/113) of grade 3 endometrioid carcinomas of the endometrium. In preliminary studies gastric cancer has also displayed an increased frequency of BAF250a loss and we now report a series of gastric carcinomas with associated clinical follow-up.
Design: The study cohort consisted of 222 gastric carcinomas (mean age 63.5 y; m:f 163:59) from patients referred for treatment at the BCCA. A tissue microarray (duplicate 0.6 mm cores) was immunostained for BAF250a (Anti-ARID1A, HPA005456, Sigma), MLH1 (ES05, Leica), MSH2 (25d12, Leica), MSH6 (44/MSH6, BD Biosc.) and PMS2 (A16-4, BD Biosc.). Immunoreactivity was considered positive in tissue cores that contained any positive tumor cell nuclear staining, regardless of intensity. Negatively scored tissue cores were ones that showed completely absent tumor cell nuclear staining, as well as positive non-neoplastic cell nuclear staining. The significant association of BAF250a with biomarkers and survival were determined by Fisher's exact test and Kaplan Meier plot and log rank tests respectively.
Results: Overall, loss of BAF250a expression as measured by IHC was observed in 32.9 % (n=49) of gastric adenocarcinomas. This was preferentially seen in higher-grade tumors (G3: 52%, G2: 43%) than in low-grade lesions (G1: 4.2%) and was significantly associated with absent expression of at least one mismatch repair (MMR) protein (p<0.0001). Whereas loss of MMR protein expression was correlated with better overall survival (p<0.001), BAF250a was not.
Conclusions: Loss of BAF250a expression, and thus mutation of ARID1A, is relatively common in high-grade gastric adenocarcinomas and significantly correlates with loss of expression of mismatch repair proteins offering a potential therapeutic approach for these cancers.
Monday, March 19, 2012 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 115, Monday Morning