Clinicopathological and prognostic significance of SWI/SNF complex subunits in undifferentiated gastric carcinoma

Abstract

Background The switch/sucrose nonfermentable (SWI/SNF) complex is an evolutionarily conserved chromatin remodeling complex that displays dysfunction in many tumors, especially undifferentiated carcinoma. Cancer stem cells (CSC), a special type of undifferentiated cancer cells with stem cell-like properties, play an essential role in tumor cell proliferation, invasion, and metastasis. In undifferentiated gastric carcinomas, the association of SWI/SNF complexes with clinicopathological features, CSC phenotype, and the prognosis is not fully understood. Methods We collected a cohort of 21 patients with undifferentiated/dedifferentiated gastric carcinoma. We next performed immunohistochemistry staining for the five subunits of the SWI/SNF complex (ARID1A, ARID1B, SMARCA2, SMARCA4, and SMARCB1), and four mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6), as well as other markers such as p53, PD-L1, and cancer stem cell (CSC) markers (SOX2, SALL4). Then, we investigated the correlation of SWI/SNF complex subunits with clinicopathological characters and performed prognostic analysis. Results We observed SMARCA2 loss in 12 cases (57.14%), followed by ARID1A (5 cases, 23.81%) and SMARCA4 (3 cases, 14.29%). Fourteen cases (66.67%) lost any one of the SWI/SNF complex subunits, including 3 cases with SMARCA2 and ARID1A co-loss, and 3 cases with SMARCA2 and SMARCA4 co-loss. Correlation analysis revealed that the CSC phenotype occurred more frequently in the SWI/SNF complex deficient group (P = 0.0158). Survival analysis revealed that SWI/WNF complex deficiency, undifferentiated status, CSC phenotype, and the loss of SMARCA2 and SMARCA4 resulted in worse survival. Univariate and multivariate Cox regression analyses screened out three independent factors associated with worse prognosis: undifferentiated status, SWI/SNF complex deficiency, and lymph node metastasis. Conclusions The SWI/SNF complex deficiency was more likely to result in a CSC phenotype and worse survival and was an independent prognostic factor in undifferentiated/dedifferentiated gastric carcinoma.

Gastric SMARCA4-deficient undifferentiated tumor (SMARCA4-UT): a clinicopathological analysis of four rare cases

“…SMARCA4 is associated with progression and poor prognosis in gastric cancer [ 7 , 25 ]. Inactivation of SMARCA4 rarely occurs in classic glandular gastric cancer as a driver molecular event and is more likely to occur in gastric cancer with solid and poorly differentiated and undifferentiated morphology [ 6 , 13 , 16 , 26 ], and loss of SMARCA4 is associated with adverse clinical characteristics [ 11 , 12 ].…”

SMARCA4(BRG1)-deficient carcinoma invading the skull base: report of two cases and literature review

“…It was easy to invade the adjacent orbital wall and anterior cranial base with an invasive bony reaction, consistent with the image manifestation of case 1 in this paper.SMARCB1 (INI1) and SMARCA4 were in the SWI/SNF complex. The pathogenic mechanism of these tumors is that the gene inactivation mutations or deletions lead to the deletion of the corresponding gene products 10 – 13 . Schaefer and colleagues suggested that all genes of the SWI/SNF complex, except SMARCB1 and SWI/SNF subunits other than SMARCA4, are rarely involved in head and neck malignancies, and SMARCA4-deficient sinus carcinomas have demographic and clinical features similar to those of SMARCB1-deficient sinus carcinomas.…”