ARID1A Mutations in Gastric Cancer: A Review with Focus on Clinicopathological Features, Molecular Background and Diagnostic Interpretation

Abstract

AT-rich interaction domain 1 (ARID1A) is a pivotal gene with a significant role in gastrointestinal tumors which encodes a protein referred to as BAF250a or SMARCF1, an integral component of the SWI/SNF (SWItch/sucrose non-fermentable) chromatin remodeling complex. This complex is instrumental in regulating gene expression by modifying the structure of chromatin to affect the accessibility of DNA. Mutations in ARID1A have been identified in various gastrointestinal cancers, including colorectal, gastric, and pancreatic cancers. These mutations have the potential to disrupt normal SWI/SNF complex function, resulting in aberrant gene expression and potentially contributing to the initiation and progression of these malignancies. ARID1A mutations are relatively common in gastric cancer, particularly in specific adenocarcinoma subtypes. Moreover, such mutations are more frequently observed in specific molecular subtypes, such as microsatellite stable (MSS) cancers and those with a diffuse histological subtype. Understanding the presence and implications of ARID1A mutations in GC is of paramount importance for tailoring personalized treatment strategies and assessing prognosis, particularly given their potential in predicting patient response to novel treatment strategies including immunotherapy, poly(ADP) ribose polymerase (PARP) inhibitors, mammalian target of rapamycin (mTOR) inhibitors, and enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) inhibitors.

Keywords: ARID1A; PARP inhibitors; PD-L1; SWI/SNF complex; gastric cancer; microsatellite instability.

Figure 1

This image illustrates the role of ARID1A in the SWI/SNF complex, highlighting its role in chromatin remodeling and gene expression.

Figure 2

Immunohistochemical staining patterns of ARID1A (images taken from author’s pathological archives): (A,B) Diffuse nuclear staining for ARID1A in a case of intestinal-type tubular adenocarcinoma of the stomach is depicted. (C) Diffuse nuclear staining in a diffuse-type gastric carcinoma (poorly cohesive carcinoma). These stainings are considered positive. (D,E) Another example of tubular adenocarcinoma of the stomach showing negative staining for ARID1A is depicted. Positive ARID1A staining, observed in the stromal cells as well as non-neoplastic glands, served as a positive internal control.