SMARCA4

Overview

SMARCA4 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator of Chromatin, Subfamily A, Member 4), also known as BRG1, encodes the catalytic ATPase subunit of the SWI/SNF chromatin-remodeling complex. SMARCA4 is a tumor suppressor mutated or deleted across multiple cancer types; its loss leads to altered nucleosome positioning and dysregulated transcription. Tumors with SMARCA4 loss are often sensitive to EZH2 inhibitors due to synthetic lethality between SWI/SNF and PRC2 complexes.

Alterations observed in the corpus

  • SMARCA4 R1192C missense mutation identified in a hepatic rhabdoid tumor (MRTL) in the PIPseq pediatric precision sequencing program (n=101, Columbia University); designated as an EZH2-inhibitor target. PMID:28007021
  • Significantly mutated in both EAC (ESCA) and ESCC in the TCGA esophageal carcinoma cohort (stes_tcga_pub, n=164); more frequently altered in EAC than in CIN gastric cancer. SMARCA4 mutation defines the ESCC3 molecular subtype. PMID:28052061
  • SMARCA4 mutation is enriched in EAC versus CIN gastric adenocarcinoma. PMID:28052061
  • SMARCA4 (BRG1) protein expression retained by IHC in an EWSR1::BEND2 fusion sarcoma of the urinary bladder, used to rule out SWI/SNF-deficient differential diagnoses PMID:28199314.
  • G1232S hotspot missense mutation in 1/19 sequenced oligodendroglioma tumors; classified as unknown therapeutic implication PMID:28472509
  • SWI/SNF subunit mutated collectively with ARID1A and ARID2 in 33% of WNT medulloblastomas; provides rationale for PRC2 inhibitors (trial NCT02601937) PMID:28726821
  • BRG1 (SMARCA4) knockout in A704 ccRCC cells phenocopies several BAF180-null (PBRM1-null) transcriptional changes, including immune and cytokine signaling enrichment, supporting a PBAF-complex-wide immune-priming mechanism. PMID:29301960

Cancer types (linked)

  • MRTL: SMARCA4 R1192C in a pediatric hepatic rhabdoid tumor; EZH2-inhibitor targeted on the basis of SWI/SNF loss. PMID:28007021
  • ESCA (EAC subtype): SMARCA4 is a significantly mutated gene in EAC; enrichment over CIN gastric supports its role in esophageal-specific oncogenesis. PMID:28052061
  • ESCC: SMARCA4 mutation defines the ESCC3 molecular subtype (PI3K-activated, SMARCA4/KMT2D mutant); all ESCC3 tumors had PI3K-pathway activating alterations. PMID:28052061

Co-occurrence and mutual exclusivity

Therapeutic relevance

  • EZH2 inhibitor therapy is proposed for SMARCA4-deficient tumors based on synthetic lethality between SWI/SNF and PRC2 complexes; designated as a therapeutic target in a pediatric hepatic rhabdoid tumor. PMID:28007021
  • PI3K-pathway inhibition is supported for ESCC3 (SMARCA4-mutant subtype) given universal PI3K-pathway activation in this subtype. PMID:28052061

Open questions

  • EAC-versus-CIN-gastric distinction for SMARCA4-enriched cases (whether subtle subgroup differences define a clinically meaningful entity) requires additional samples. PMID:28052061
  • Optimal EZH2-inhibitor regimen in pediatric rhabdoid tumors with SMARCA4 mutation requires clinical trial validation. PMID:28007021

Sources

This page was processed by entity-page-writer on 2026-05-15. - PMID:28199314

This page was processed by wiki-cli on 2026-05-14. - PMID:28472509

This page was processed by wiki-cli on 2026-05-15. - PMID:28726821

This page was processed by wiki-cli on 2026-05-15. - PMID:29301960

This page was processed by entity-page-writer on 2026-05-15.