ARID1A expression loss in gastric cancer: pathway-dependent roles with and without Epstein–Barr virus infection and microsatellite instability

Abstract

The AT-rich interactive domain 1A gene (ARID1A), which encodes one of the subunits in the Switch/Sucrose Nonfermentable chromatin remodeling complex, carries mutations and is responsible for loss of protein expression in gastric carcinoma, particularly with Epstein-Barr virus (EBV) infection and a microsatellite instability-high phenotype. We used immunohistochemistry to investigate the significance of ARID1A loss in 857 gastric carcinoma cases, including 67 EBV(+) and 136 MLH1-lost gastric carcinomas (corresponding to a microsatellite instability-high phenotype). Loss of ARID1A expression was significantly more frequent in EBV(+) (23/67; 34 %) and MLH1-lost (40/136; 29 %) gastric carcinomas than in EBV(-)MLH1-preserved (32/657; 5 %) gastric carcinomas (P < 0.01). Loss of ARID1A correlated with larger tumor size, advanced invasion depth, lymph node metastasis, and poor prognosis in EBV(-)MLH1-preserved gastric carcinoma. A correlation was found only with tumor size and diffuse-type histology in MLH1-lost gastric carcinoma, but no correlation was observed in EBV(+) gastric carcinoma. Loss of ARID1A expression in EBV(+) gastric carcinoma was highly frequent in the early stage of gastric carcinoma, although EBV infection did not cause downregulation of ARID1A: EBV-positive nasopharyngeal carcinomas (n = 8) and lymphomas (n = 15) failed to show loss of ARID1A, and EBV infection did not cause loss of ARID1A in gastric carcinoma cell lines. Taken together, loss of ARID1A may be an early change in carcinogenesis and may precede EBV infection in gastric epithelial cells, while loss of ARID1A promotes cancer progression in gastric cancer cells without EBV infection or loss of MLH1 expression. Loss of ARID1A has different and pathway-dependent roles in gastric carcinoma.

The emerging roles of ARID1A in tumor suppression

“…46 Wang et al found ARID1A mutation in 47% of EBVinfected, microsatellite stable gastric cancer samples, which was substantially higher than in microsatellite stable gastric cancers without EBV infection (10%). 43 Abe et al observed that loss of ARID1A expression was prevalent in EBV-associated (34%) and MLH1-lost (29%) gastric cancer, but rare in gastric cancer without EBV infection and MLH1 loss (5%).…”

“…ARID1A mutation has been associated with MSI in gastric and colorectal cancers. 43,47 Similarly, loss of ARID1A protein expression is associated with loss of expression of mismatch repair proteins and/or MSI in gastric carcinoma 46 and uterine endometrioid carcinoma. 88,89 However, controversy remains as to whether loss of ARID1A is the cause or result of MMR deficiency.…”

“…43 Abe et al observed that loss of ARID1A expression was prevalent in EBV-associated (34%) and MLH1-lost (29%) gastric cancer, but rare in gastric cancer without EBV infection and MLH1 loss (5%). 46 Histologically, EBVassociated gastric cancer is characterized by an intense infiltrate of lymphocytes within tumors, 91 which is also a histological feature of colorectal and gastric cancers with MSI. 92,93 Interestingly, an RNAi screen revealed that knockdown of ARID1A rendered Jurkat leukemia cells resistant to Fas (CD95)-mediated apoptosis, 94 a killing mechanism used by T cells and NK cells.…”

Loss of ARID1A expression and its relationship with PI3K-Akt pathway alterations, TP53 and microsatellite instability in endometrial cancer

“…In gastric cancer, an association has been described between MSI and mutations in ARID1A. 12,[14][15][16] As the rate of somatic ARID1A mutations in MSI cases was 12-to 61-fold higher than the global background mutation rate, it was suggested that the ARID1A gene is particularly targeted by MSI. 12 A possible association between ARID1A loss and MSI, as has been reported for gastric cancer, has not been studied in endometrial cancer.…”

Molecular Pathogenesis of Gastric Adenocarcinoma

“…EBVaGC occurs in the upper and middle stomach in the majority. Fukayama et al indicated the tumor distribution in the stomach, with the proportion that 58% in the cardia, 33% in the body, and 9% in the antrum [20,21]. They also depicted the appearance of EBVaGC as ulcerated or saucer-like, with obvious thickened gastric wall.…”