Pathway-Dependent Roles of ARID1A Expression Loss in Gastric Cancer: Relationships with Epstein-Barr Virus Infection and Microsatellite Instability
Hiroyuki Abe, Daichi Maeda, Tsunekazu Hishima, Yoshiaki Iwasaki, Masashi Fukayama. Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan; Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Bunkyo-ku, Tokyo, Japan
Background: The AT-rich interactive domain 1A gene (ARID1A), which encodes one of the subunits in the Switch/Sucrose Nonfermentable (SWI/SNF) chromatin remodeling complex, is occasionally mutated and is responsible for loss of protein expression in gastric carcinoma (GC), particularly with Epstein–Barr virus (EBV) infection and microsatellite instability-high (MSI-H) phenotype. However, the clinicopathological significance of ARID1A loss and the relationship with EBV infection or MSI-H were unknown.
Design: We applied immunohistochemistry of ARID1A to the tissue microarray of 857 GCs, including 67 EBV(+) and 136 MLH1-lost (corresponding to MSI-H phenotype) GCs. Whole sections of some GC cases were also stained to assess the distribution of ARID1A-lost carcinoma cells. In order to compare with gastric carcinoma, eight nasopharyngeal carcinomas, 15 lymphomas with EBV infection, and 173 colorectal carcinomas were also examined.
Results: Loss of ARID1A expression was significantly more frequent in EBV(+) (23/67; 34%) and MLH1-lost (40/136; 29%) GCs than in EBV(−)MLH1-preserved (32/657; 5%) GCs (P<0.01). Loss of ARID1A correlated with larger tumor size, advanced invasion depth, lymph node metastasis and poor prognosis in EBV(−)MLH1-preserved GC. A correlation was found only with tumor size and diffuse-type histology in MLH1-lost GC, and no correlation was observed in EBV(+) GC. Loss of ARID1A expression in EBV(+) GC was highly frequent in the early stage of GC. In whole section staining, all of 14 EBV(+) GCs with ARID1A loss were totally negative for ARID1A in the entire lesion. However, 7 of 17 MLH1-lost GCs with ARID1A loss showed regional expression loss (p=0.02). EBV(+) nasopharyngeal carcinomas and lymphomas failed to show loss of ARID1A. In 173 colorectal carcinomas, only four cases showed ARID1A-loss, and these were also MLH1-lost.
Conclusions: ARID1A expression loss may be an early change in carcinogenesis of EBV(+) GC. It specifically occurs in gastric epithelial cells but not in EBV-infection in nasal epithelial cells or lymphocytes. Loss of ARID1A is also frequent in MLH1-lost GC, but it is a late stage event. ARID1A-loss is infrequent, but is related with poor prognosis in EBV-negative and MLH1-preservedGC. ARID1A expression loss has different and pathway-dependent roles in GC.
Wednesday, March 6, 2013 1:00 PM
Poster Session VI # 90, Wednesday Afternoon