# SMAD4

Source: https://onco.cc/targets/smad4/  
OnCo record `smad4` (Target). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

SMAD4 (SMAD family member 4) is a protein that switches other genes on and off. The public catalogues list it as a drug target, an oncogene driver, a tumour suppressor and a biomarker, and clinical evidence ties its variants to diagnosis, prognosis or drug response. Tied to Colorectal cancer, Gastric & gastro-oesophageal junction cancer, Oesophageal cancer and 5 more.

## Summary

In muscle physiology, plays a central role in the balance between atrophy and hypertrophy. When recruited by MSTN, promotes atrophy response via phosphorylated SMAD2/4. MSTN decrease causes SMAD4 release and subsequent recruitment by the BMP pathway to promote hypertrophy via phosphorylated SMAD1/5/8.

CIViC holds 31 clinical evidence items and 0 assertions across 20 variants, naming Cetuximab, Trametinib, Bevacizumab and Panitumumab and others. Open Targets scores its association with cancer at 0.87 (direct and indirect evidence; datatypes genetic literature 0.56, affected pathway 0.61, literature 0.99, genetic association 0.89, somatic mutation 0.97, animal model 0.85). IntOGen calls it a driver in 37 cohorts (10 activating, 27 loss-of-function), covering Invasive Breast Carcinoma, Cervical Squamous Cell Carcinoma, Cholangiocarcinoma, Colon Adenocarcinoma, Colorectal Adenocarcinoma, Oesophageal Adenocarcinoma and others.

## Fields

- Kind: Target
- Last checked: 2026-09-23
- Also known as: SMAD family member 4; DPC4; MADH4
- Tags: cancer-genes-wave
- Symbol: SMAD4
- Class: transcription
- Biology: In muscle physiology, plays a central role in the balance between atrophy and hypertrophy. When recruited by MSTN, promotes atrophy response via phosphorylated SMAD2/4. MSTN decrease causes SMAD4 release and subsequent recruitment by the BMP pathway to promote hypertrophy via phosphorylated SMAD1/5/8. Acts synergistically with SMAD1 and YY1 in bone morphogenetic protein (BMP)-mediated cardiac-specific gene expression. Binds to SMAD binding elements (SBEs) (5'-GTCT/AGAC-3') within BMP response element (BMPRE) of cardiac activating regions. Common SMAD (co-SMAD) is the coactivator and mediator of signal transduction by TGF-beta (transforming growth factor). Location: Cytoplasm; Nucleus (UniProt). Locus 18q21.2 (HGNC).
- Where found: Colorectal cancer: Open Targets association 0.79 with colorectal cancer (MONDO_0005575); CIViC evidence names this disease; Gastric & gastro-oesophageal junction cancer: Open Targets association 0.62 with gastric cancer (MONDO_0001056); IntOGen driver in 5 cohorts (STAD, STOMACH); Oesophageal cancer: Open Targets association 0.65 with oesophageal cancer (MONDO_0007576); IntOGen driver in 5 cohorts (ESCA, ESCC); Pancreatic ductal adenocarcinoma: CIViC evidence names this disease; IntOGen driver in 8 cohorts (PAAD, PANCREAS); Biliary tract cancer: Open Targets association 0.63 with biliary tract cancer (MONDO_0003060); Prostate cancer: CIViC evidence names this disease; IntOGen driver in 2 cohorts (PRAD, PROSTATE); Pancreatic ductal adenocarcinoma: mutation or deep deletion 17-33%; Colorectal cancer: mutation or deep deletion (18q loss) 12-16%; Gallbladder cancer: mutation or deletion 21-38%

## Notes

- Written by scripts/fetch-cancer-genes.ts from CIViC, Open Targets, IntOGen, HGNC and UniProt; the function text is UniProt's, condensed and in UK spelling. Roles: CIViC lists 11 therapies; IntOGen calls it an activating (Act) driver in 10 cohorts; IntOGen calls it a loss-of-function (LoF) driver in 27 cohorts; CIViC holds 31 clinical evidence items on its variants. Evidence tier "clinical-evidence" is the strongest of those signals.
- Prevalence not recorded: none of the sources gives a positivity rate.
- Diseases the sources name that have no OnCo cancer page yet, so they are not linked: Juvenile Polyposis Syndrome.
- Pancreatic ductal adenocarcinoma: lost in 17 to 33% (cBioPortal). Loss is the marker of the metastatic pattern of failure: at autopsy Dpc4 loss went with widespread metastasis and intact Dpc4 with locally destructive disease (Iacobuzio-Donahue 2009), and intact Smad4 on diagnostic cytology predicted local-dominant progression in locally advanced patients (Crane 2011). SMAD4 and TGFBR2 mutations mark the invasive step in cyst progression (Noe 2020) but did not predict survival after resection (Qian 2018).
- Colorectal cancer: lost by mutation or 18q deep deletion in 12 to 16%. The 18q event was the third step of the classical sequence, present in 73% of carcinomas and 47% of advanced adenomas against 11 to 13% of earlier adenomas (Vogelstein 1988). It is a chromosomal-instability event, so it is rare in the hypermutated classes (11.8% against 15.2%; cBioPortal), and SMAD2 and SMAD3 are deleted alongside it.
- Gallbladder cancer: SMAD4 mutation was found at similar rates in Chile (38%), Japan (36%) and the United States (27%) and went with shorter survival, 10 versus 25 months (Narayan 2019); independently associated with reduced survival in metastatic disease (Giraldo 2022).

## Sources

- HGNC HGNC:6770: https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:6770
- UniProt Q13485: https://www.uniprot.org/uniprotkb/Q13485/entry
- NCBI Gene 4089: https://www.ncbi.nlm.nih.gov/gene/4089
- Ensembl ENSG00000141646: https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000141646

## Connected records

- collections: [CIViC](https://onco.cc/collections/civic/), [IntOGen](https://onco.cc/collections/intogen/), [Open Targets Platform](https://onco.cc/collections/open-targets/)
- cancers: [Biliary tract cancer (all types)](https://onco.cc/cancers/biliary-tract-cancer/), [Breast cancer (all types)](https://onco.cc/cancers/breast-cancer/), [Colorectal cancer](https://onco.cc/cancers/colorectal/), [Gallbladder cancer](https://onco.cc/cancers/gallbladder/), [Gastric & gastro-oesophageal junction cancer](https://onco.cc/cancers/gastric/), [Head and neck squamous cell carcinoma](https://onco.cc/cancers/head-and-neck/), [Invasive carcinoma arising in an intraductal papillary mucinous neoplasm (IPMN-associated carcinoma)](https://onco.cc/cancers/ipmn-associated-carcinoma/), [Oesophageal cancer](https://onco.cc/cancers/esophageal/), [Pancreatic ductal adenocarcinoma](https://onco.cc/cancers/pancreatic/), [Prostate cancer](https://onco.cc/cancers/prostate/)
- pathways: [Colorectal cancer (KEGG map)](https://onco.cc/pathways/colorectal-cancer-signalling/), [Pancreatic cancer (KEGG map)](https://onco.cc/pathways/pancreatic-cancer-signalling/), [TGF-β signalling](https://onco.cc/pathways/tgf-beta/)
- key papers: [A combination of molecular markers and clinical features improve the classification of pancreatic cysts](https://onco.cc/key-papers/paper-springer-pancreatic-cyst-molecular-classification-gastroenterology-2015/), [A genetic model for colorectal tumorigenesis](https://onco.cc/key-papers/paper-fearon-cell/), [A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns](https://onco.cc/key-papers/paper-notta-punctuated-evolution-pancreatic-nature-2016/), [Association of alterations in main driver genes with outcomes of patients with resected pancreatic ductal adenocarcinoma](https://onco.cc/key-papers/paper-qian-driver-genes-outcomes-resected-pancreatic-jama-oncol-2018/), [Biliary cancer: utility of next-generation sequencing for clinical management](https://onco.cc/key-papers/paper-javle-biliary-ngs-cancer-2016/), [Classifying colorectal cancer by tumor location rather than sidedness highlights a continuum in mutation profiles and consensus molecular subtypes](https://onco.cc/key-papers/paper-loree-tumour-location-continuum-colorectal-ccr-2018/), [Clinical sequencing defines the genomic landscape of metastatic colorectal cancer](https://onco.cc/key-papers/paper-yaeger-metastatic-colorectal-genomic-landscape-cancer-cell-2018/), [Comprehensive molecular characterization of gallbladder carcinoma and potential targets for intervention](https://onco.cc/key-papers/paper-giraldo-gallbladder-msk-impact-ccr-2022/), [Comprehensive molecular characterization of human colon and rectal cancer](https://onco.cc/key-papers/paper-tcga-colorectal-comprehensive-characterization-nature-2012/), [Core signaling pathways in human pancreatic cancers revealed by global genomic analyses](https://onco.cc/key-papers/paper-jones-pancreatic-core-pathways-science-2008/), [DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer](https://onco.cc/key-papers/paper-iacobuzio-donahue-dpc4-failure-pattern-autopsy-jco-2009/), [Genetic alterations during colorectal-tumor development](https://onco.cc/key-papers/paper-vogelstein-genetic-alterations-colorectal-tumor-development-nejm-1988/), [Genomic analyses identify molecular subtypes of pancreatic cancer](https://onco.cc/key-papers/paper-bailey-molecular-subtypes-pancreatic-nature-2016/), [Genomic characterization of biliary tract cancers identifies driver genes and predisposing mutations](https://onco.cc/key-papers/paper-wardell-biliary-drivers-germline-j-hepatol-2018/), [Genomic characterization of malignant progression in neoplastic pancreatic cysts](https://onco.cc/key-papers/paper-noe-cyst-malignant-progression-genomics-nat-commun-2020/), [Genomic profiling of Indian gallbladder carcinoma: mutational insights in a high-incidence population](https://onco.cc/key-papers/paper-suryavanshi-indian-gallbladder-genomics-jco-go-2025/), [Integrated genomic characterization of pancreatic ductal adenocarcinoma](https://onco.cc/key-papers/paper-tcga-pancreatic-integrated-characterisation-cancer-cell-2017/), [IPMNs with co-occurring invasive cancers: neighbours but not always relatives](https://onco.cc/key-papers/paper-felsenstein-ipmn-cooccurring-cancer-relatedness-gut-2018/), [Molecular and clinical determinants of targeted therapy treatment in biliary tract cancer](https://onco.cc/key-papers/paper-cowzer-biliary-targeted-therapy-determinants-ccr-2026/), [Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes](https://onco.cc/key-papers/paper-biankin-pancreatic-exomes-axon-guidance-nature-2012/), [Pathways of progression from intraductal papillary mucinous neoplasm to pancreatic ductal adenocarcinoma based on molecular features](https://onco.cc/key-papers/paper-omori-ipmn-progression-pathways-gastroenterology-2019/), [Phase II trial of cetuximab, gemcitabine, and oxaliplatin followed by chemoradiation with cetuximab for locally advanced (T4) pancreatic adenocarcinoma: correlation of Smad4(Dpc4) immunostaining with pattern of disease progression](https://onco.cc/key-papers/paper-crane-smad4-progression-pattern-locally-advanced-jco-2011/), [Population-Specific Immunogenomic Alterations in Gallbladder Cancer and Prognostic Significance](https://onco.cc/key-papers/paper-zhu-population-specific-immunogenomics-gallbladder-cancer-mod-pathol-2025/), [Real-time targeted genome profile analysis of pancreatic ductal adenocarcinomas identifies genetic alterations that might be targeted with existing drugs or used as biomarkers](https://onco.cc/key-papers/paper-singhi-targeted-genome-profiling-3594-pdac-gastroenterology-2019/), [Regional differences in gallbladder cancer pathogenesis: insights from a multi-institutional comparison of tumor mutations](https://onco.cc/key-papers/paper-narayan-gallbladder-regional-mutations-cancer-2019/), [TGF-beta drives immune evasion in genetically reconstituted colon cancer metastasis](https://onco.cc/key-papers/paper-tauriello-tgfbeta-immune-evasion-colorectal-nature-2018/), [Whole genomes redefine the mutational landscape of pancreatic cancer](https://onco.cc/key-papers/paper-waddell-whole-genomes-pancreatic-nature-2015/)
- terms: [Pancreatic intraepithelial neoplasia (PanIN), the microscopic precursor of pancreatic cancer](https://onco.cc/terms/panin/)

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JSON: https://onco.cc/api/v1/entities/smad4.json