SMARCA4 and SMARCE1 in gastric cancer: Correlation with ARID1A, and microsatellite stability, and SMARCE1/ERBB2 co-amplification

Abstract

Background: Recent studies have shown an association between certain subunits of the SWI/SNF complex with specific tumor characteristics in gastric cancer (GC). In an earlier study, we applied multiregional whole exome sequencing on multiple primary tumor samples and found alterations of the SWI/SNF complex in 78% of the cases. ERBB2, which encodes for Her2/neu, is a well-known predictive biomarker used to guide the treatment of GC in the palliative setting. SMARCE1, which encodes for a subunit of the SWI/SNF complex, is localized in close genetic proximity to ERBB2.

Aim: As little is known about the significance of the SWI/SNF complex in GC biology and the potential relationship between ERBB2 and SMARCE1 upregulation, we examined the expression patterns of SMARCA4 and SMARCE1, two mutually exclusive catalytic ATPase subunits of the SWI/SNF complex, in a well characterized GC cohort.

Materials and methods: The expression of SMARCA4 and SMARCE1 was studied by immunohistochemistry in connection with clinicopathological patient characteristics in a cohort of 468 GCs. Digital droplet polymerase chain reaction was performed for amplification analysis on ERBB2 and SMARCE1.

Results: Immunohistochemical staining of whole-mount tissue sections found a diffusely "gray scale" expression of SMARCA4 in 446 (95.2%) GCs and of SMARCE1 in 463 (98.8%) GCs. The expression of SMARCA4 and SMARCE1 correlated significantly with ARID1A, p53, and microsatellite status. No correlation was found with the patient prognosis. The amplification analysis of SMARCE1 showed amplification in 4 of 34 cases. In 3 of 34 cases, SMARCE1 was co-amplified with ERBB2. We also found a co-expression of SMARCE1 and Her2/neu in a subset of patients.

Conclusion: While the effect of a co-amplification is currently unknown, synergistic effects of SMARCE1 and Her2/neu overexpression should be explored in future studies, holding potential for an improved treatment of GC.

Keywords: MSI; SMARCA4; SMARCE1; gastric carcinoma; heterogeneity; immunohistochemistry.