The clinicopathological and molecular analysis of gastric cancer with altered SMARCA4 expression

Abstract

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.

Comprehensive Immunohistochemical Study of the SWI/SNF Complex Expression Status in Gastric Cancer Reveals an Adverse Prognosis of SWI/SNF Deficiency in Genomically Stable Gastric Carcinomas

“…We observed a loss of SMARCA4 expression in three cases (0.6%). Similar frequencies have been observed in other studies in gastric, esophageal, and lung carcinomas [22,24,30,38]. All three tumors with SMARCA4 deficiency showed very similar, specific histopathologic features and were located at the gastroesophageal junction (AEGII).…”

“…Additionally, they showed very adverse clinical characteristics and poor survival. The specific growth pattern and clinical significance have been described by Agaimy et al [21] in two cases and Huang et al [22] in six cases. As described by Agaimy et al [21] the expression pattern of cytokeratins was different among the SMARCA4-deficient cases.…”

“…To the best of our knowledge, no study has evaluated the clinical relevance of the SWI/SNF complex in a large Western cohort of gastric cancer patients [21][22][23][24]36].…”

“…Mutations or deficiencies of one or more subunits can have an oncogenic effect and influence the development, progression, and eventual therapy resistance of tumor diseases [18][19][20]. A few studies have also already demonstrated loss or heterogeneous expression patterns of these subunits in gastric carcinoma, which could make them potential starting points for new therapeutic concepts [21][22][23][24][25].…”

Molecular profiles of response to neoadjuvant chemoradiotherapy in oesophageal cancers to develop personalized treatment strategies

“…Beyond the need to validate these associations in additional larger cohorts to determine its reproducibility, it is not clear whether these genes are really associated with CRT resistance or sensitivity or whether these genes are mere innocent bystanders. SMARCA4 mutation and SMURF1 amplification have been associated with a poor prognosis in gastro‐oesophageal adenocarcinoma before, potentially confirming a more aggressive phenotype, but the same accounts for ETV4 amplification and CSMD1 deletion [18–22]. Furthermore, inactivation of SMARCA4, the catalytic subunit of the SWI/SNF chromatin remodelling complex, has been linked to impaired nucleotide excision repair (NER) [23] and loss of Rb activity [24], and thereby increased platinum sensitivity in HNSCC and NSCLC cell lines [23] and NSCLC patients [25], which contrasts our findings of resistance to platinum‐containing CRT.…”