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Updated: Dec 23, 2025
Genome-Wide Analysis of DNA Methylation in Gastrointestinal Cancer
Published on: September 18, 2020
The clinicopathological and molecular analysis of gastric cancer with altered SMARCA4 expression
Shih-Chiang Huang1,2, Kwai-Fong Ng1, Ta-Sen Yeh3
1Department of Anatomic Pathology, College of Medicine, Linkou Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan.
Aims:
In this study, we examine the clinicopathological and molecular features of gastric cancer (GC) with SMARCA4 alterations.
Methods And Results:
We screened SMARCA4 alterations using immunohistochemistry on 1199 surgically resected GCs with information on Epstein-Barr virus (EBV), microsatellite instability (MSI) and other SWI/SNF subunits. SMARCA4, SMARCA2 and ARID1A mutations were investigated by targeted sequencing. The clinicopathological significance was determined by statistical analysis. Twenty-seven cases (2%) with altered SMARCA4 expression were identified, exhibiting completely lost (six), reduced (nine) or heterogeneous (12) patterns. Frequent concomitant alterations of other SWI/SNF subunits were noted with an unusual discordant spatial heterogeneity. In comparison with SMARCA4-retained GCs, SMARCA4-lost GCs were observed more frequently in the non-EBV/MSI subgroup (five of six) and reduced or heterogeneous SMARCA4 expression mainly occurred in EBV- or MSI-associated cases (six of nine and six of 12, respectively; P < 0.001). Histologically, SMARCA4-altered GC, irrespective of expression pattern, demonstrated divergent histomorphology, spanning tubular, poorly cohesive or mixed, neuroendocrine to solid and undifferentiated carcinoma, with a predilection to the latter two (P < 0.001). De-differentiation-like transition and rhabdoid features were noted in a minority of cases. For overall survival, altered SMARCA4 expression was an unfavourable prognostic factor in stage III, EBV-associated GC and non-EBV/MSI intestinal subtype (P ≤ 0.001). SMARCA4 or ARID1A mutations were detected mainly in SMARCA4-lost or reduced GC, respectively.
Conclusions:
SMARCA4-altered GCs are rare and have intratumoral heterogeneity, histomorphological diversity, conditional prognostic significance and various genetic drivers. SMARCA4-lost GC may represent a genuine SMARCA4-deficient neoplasm, but most SMARCA4-reduced/heterogeneous cases are secondary to ARID1A collapse or associated with different genotypes.
Insights
Gastric cancer (GC) with SMARCA4 alterations are rare and show diverse features. Altered SMARCA4 expression is linked to poor prognosis in specific GC subtypes.
Area of Science:
- Oncology
- Molecular Pathology
- Genetics
Background:
- Gastric cancer (GC) is a heterogeneous disease with diverse molecular subtypes.
- Alterations in SWI/SNF chromatin remodeling complex subunits, including SMARCA4, are implicated in various cancers.
- Understanding the clinicopathological and molecular spectrum of SMARCA4 alterations in GC is crucial for diagnosis and treatment.
Purpose of the Study:
- To investigate the clinicopathological and molecular characteristics of gastric cancer (GC) with SMARCA4 alterations.
- To correlate SMARCA4 alterations with Epstein-Barr virus (EBV) status, microsatellite instability (MSI), and other SWI/SNF subunit alterations.
- To determine the prognostic significance of SMARCA4 alterations in GC.
Main Methods:
- Immunohistochemistry was used to screen SMARCA4 alterations in 1199 surgically resected GCs.
- Targeted sequencing was employed to investigate mutations in SMARCA4, SMARCA2, and ARID1A.
- Clinicopathological data, including EBV status and MSI, were analyzed alongside SMARCA4 expression patterns.
Main Results:
- SMARCA4 alterations were identified in 2% of GCs, presenting as complete loss, reduction, or heterogeneous expression.
- SMARCA4-lost GCs were more frequent in the non-EBV/MSI subgroup, while reduced/heterogeneous expression was associated with EBV or MSI.
- Altered SMARCA4 expression correlated with diverse histomorphology and served as an unfavorable prognostic factor in specific GC subtypes.
Conclusions:
- SMARCA4-altered GCs are rare, exhibiting intratumoral heterogeneity and histomorphological diversity.
- SMARCA4-lost GC may represent a distinct SMARCA4-deficient neoplasm.
- Most SMARCA4-reduced/heterogeneous cases are secondary to ARID1A alterations or associated with different genetic profiles.
