SMAD4

Overview

SMAD4 (SMAD Family Member 4) is a central mediator of TGF-beta signaling, acting as a shared co-SMAD required for transduction of signals from TGF-beta, BMP, and activin receptors. As a tumor suppressor, SMAD4 is frequently inactivated by mutation or deletion in gastrointestinal cancers, including pancreatic ductal adenocarcinoma, colorectal cancer, and esophageal adenocarcinoma (EAC). Loss of SMAD4 disrupts TGF-beta-mediated growth inhibition.

Alterations observed in the corpus

  • Significantly mutated in EAC (ESCA) in the TCGA esophageal and gastroesophageal junction carcinoma cohort (stes_tcga_pub, n=164 esophageal + 359 gastric); also deleted at 18q21.2 in EAC. PMID:28052061
  • SMAD4 alteration is more frequent in EAC than in esophageal squamous cell carcinoma (ESCC). PMID:28052061
  • Mutations associated with elevated structural variant burden in cholangiocarcinoma (q < 0.1) PMID:28667006
  • Mutated in 16% of mCRC cases with right-sided enrichment; TGF-beta pathway loss in microsatellite-stable colorectal tumors. PMID:29316426

Cancer types (linked)

  • ESCA (EAC subtype): SMAD4 is a significantly mutated gene enriched in EAC; 18q21.2 deletion is a recurrent copy-number event in this histology. PMID:28052061

Co-occurrence and mutual exclusivity

  • In EAC, SMAD4 alteration co-occurs with other SWI/SNF complex (ARID1A, SMARCA4, PBRM1) and PI3K-pathway alterations as part of the broader EAC genomic landscape. PMID:28052061

Therapeutic relevance

  • No direct targeted therapy for SMAD4-mutant esophageal cancer is described in the corpus; SMAD4 loss is a context for considering TGF-beta pathway inhibitors in future trials.

Open questions

  • Whether SMAD4 loss in EAC confers differential sensitivity to chemotherapy or immunotherapy compared to SMAD4-intact EAC requires prospective evaluation. PMID:28052061

Sources

This page was processed by entity-page-writer on 2026-05-15. - PMID:28667006

This page was processed by wiki-cli on 2026-05-15. - PMID:29316426

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