SMARCA4 Mutations in Carcinomas of the Esophagus, Esophagogastric Junction, and Stomach

Abstract

Deficiency of SMARCA4, a member of the SWI/SNF chromatin remodeling complex, has been described in a subset of undifferentiated gastroesophageal carcinomas with an aggressive clinical course. The full spectrum and frequency of SMARCA4 mutations in gastroesophageal cancer are unknown. We interrogated our institutional database and identified patients with gastroesophageal carcinomas who underwent cancer next-generation sequencing. We classified SMARCA4 mutations, assessed histologic features, and correlated SMARCA4 mutations with SMARCA4 protein expression by immunohistochemistry. SMARCA4 mutations were identified in gastroesophageal carcinomas from 107 (9.1%) of 1174 patients. Forty-nine SMARCA4 mutations, including 26 missense variants and 23 protein-truncating variants, were interpreted as pathogenic in 42 (3.6%) of 1174 patients. Thirty (71%) of 42 cancers with pathogenic SMARCA4 mutations were located in the esophagus or esophagogastric junction, and 12 cancers (29%) were located in the stomach. Sixty-four percent of carcinomas with pathogenic truncating SMARCA4 variants were poorly differentiated or undifferentiated compared with 25% of carcinomas with pathogenic missense variants. Eight of 12 carcinomas with truncating SMARCA4 variants and none of the 7 carcinomas with pathogenic SMARCA4 missense variants showed loss of SMARCA4 expression by immunohistochemistry. Four carcinomas with pathogenic truncating SMARCA4 variants were associated with Barrett esophagus. SMARCA4-mutated gastroesophageal cancers were enriched for APC (31%) and CTNNB1 (14%) mutations and exhibited similar frequency of TP53 (76%) and ARID1A (31%) mutations compared with gastroesophageal cancers without pathogenic SMARCA4 mutations. The median overall survival was 13.6 months for patients who presented with metastasis at diagnosis and 22.7 months for patients without metastasis. Overall, SMARCA4-mutated gastroesophageal cancers exhibit a spectrum of histologic grade, an association with Barrett esophagus, and a concurrent mutational pattern similar to SMARCA4-wild-type gastroesophageal adenocarcinomas. Although SMARCA4-deficient gastroesophageal carcinomas are associated with poorly differentiated and undifferentiated histology, the spectrum of histologic and molecular features suggests overlapping pathogenic pathways with conventional gastroesophageal adenocarcinomas.

Keywords: SMARCA4; adenocarcinoma; gastroesophageal cancer; gastrointestinal pathology; immunohistochemistry; molecular pathology; next-generation sequencing; undifferentiated.