Switch/sucrose‐non‐fermentable (SWI/SNF) complex (SMARCA4, SMARCA2, INI1/SMARCB1)‐deficient colorectal carcinomas are strongly associated with microsatellite instability: an incidence study in 4508 colorectal carcinomas

Abstract

Aims Loss of expression of mammalian switch/sucrose‐non‐fermentable (SWI/SNF) [BRG1/BRM‐associated factor (BAF)] complex subunits, including SMARCA4, SMARCA2 and INI1/SMARCB1 (termed SWI/SNF complex deficiency), has been reported in colorectal carcinomas (CRCs) but its frequency and clinical significance are uncertain. Methods and results We performed immunohistochemistry for SMARCA4, SMARCA2 and SMARCB1 on 4508 consecutive resected CRCs. Loss of SMARCA4 expression was found in 13 cases (0.3%), loss of SMARCA2 expression was found in 59 cases (1.3%), and loss of SMARCB1 expression was found in 21 cases (0.4%). Some CRCs showed loss of expression of more than one subunit, so that 84 CRCs (1.7%) were deficient for at least one component. SWI/SNF complex deficiency was associated with higher grade, a right‐sided location, mismatch repair deficiency, and BRAF V600E mutation (P < 0.05); 5.8% of mismatch repair‐deficient (MMRd) cases and 5.4% of BRAF V600E‐mutant cases were SWI/SNF complex‐deficient, as compared with 0.9% and 0.4% of mismatch repair‐proficient and BRAF‐wild‐type cases (P < 0.001). Any loss of SMARCB1 expression and global loss of SMARCA2 expression were associated with statistically significant worse overall survival, whereas SMARCA4‐deficient cases showed a trend only towards poor overall survival (P = 0.121). In multivariate analysis, any loss of SMARCA4 expression and global loss of SMARCA2 expression were associated with worse survival [odds ratio (OR) 3.33, P = 0.019; and OR 3.39, P < 0.001]. Of particular note, among the subgroup of cases that were MMRd and BRAF V600E‐mutated (otherwise considered to be a good prognostic group), loss of SMARCA4 expression was associated with much worse median survival (10.5 months versus 110.9 months; P = 0.003). Conclusions SWI/SNF complex deficiency is rare in CRC but is enriched in MMRd cases. Identifying these cases has morphological associations and prognostic significance, and in the future may have potential therapeutic implications.

Large cell neuroendocrine carcinoma with discohesive growth pattern of the sigmoid colon resembling undifferentiated carcinoma

“…UC frequently shows a loss of SWI/SNF complex proteins, including SMARCB1, SMARCA4, SMARCA2, and ARID1A, which are rarely found in conventional adenocarcinoma. 1,5 Immunohistochemically, we did not detect any loss of SMARCB1, SMARCA4, or ARID1A, and loss of SMARCB1 was also not demonstrated in the previously reported case. 2 The antibody for SMARCA2 was not available in our institutions.…”

Fetal gut cell-like differentiation in esophageal adenocarcinoma defines a rare tumor subtype with therapeutically relevant claudin-6 positivity and SWI/SNF gene alteration

“…However, an underlying oncogenic mechanism of SWI/SNF alteration remains unclear. Currently, an increased prevalence of genetic instability resulting from impaired DNA repair mechanisms, lineage-specific, epigenetic modifications and an association with distinct, oncogenic signalling pathways are being discussed 20 – 25 . Various early phase clinical trials are currently investigating the therapeutic potential of the suspected effects of SWI/SNF alterations, for example, by using poly(ADP-ribose)-polymerase (PARP) inhibitors in order to address impaired DNA repair mechanisms or Enhancer of zeste homolog 2 (EZH2) inhibitors to modulate certain epigenetic signatures 16 .…”

Treatment of Thoracic SMARCA4-Deficient Undifferentiated Tumors: Where We Are and Where We Will Go

“…BRG1 is elevated during myofibroblast maturation, while HSC-specific deletion of BRG1 inhibits liver fibrosis [31]. Concerning the role of SMARCA4 in cancer, BRG1 deficiency is implicated in th velopment of several malignancies, such as small-cell carcinoma of the ovary hyperc mic type (SCCOHT), SMARCA4-deficient thoracic sarcoma, colorectal cancer, and e metrial stromal sarcomas [32][33][34][35][36]. Reisman et al first described the involvement of B deficiency in lung cancer development [37].…”