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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.
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.
In plain words · 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.
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.
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.
No product in this corpus aims at SMAD4 yet. Transcription factors have no pocket to plug, so drugs either degrade them or block the partner protein they need to dock on DNA.
Tumour-specific alteration: the catalogues call it an oncogene driver (IntOGen cohort analysis finds it activated more often than chance) and a tumour suppressor (IntOGen finds it knocked out more often than chance), so the direction differs between cohorts but the alteration is somatic either way; what a medicine would aim at or exploit is the altered form or its loss, absent from normal cells; no corpus medicine is aimed at it yet. HPA SMAD4: RNA low tissue specificity; high antibody staining in 7 normal tissues; highest cancer staining carcinoid (1 of 4 high). Distribution: 8 cancer families in the corpus carry a prevalence row, label threshold or catalogue link for it (Biliary tract cancer (all types), Colorectal cancer, Gastric & gastro-oesophageal junction cancer, Oesophageal cancer, Pancreatic ductal adenocarcinoma, Prostate cancer, Head and neck squamous cell carcinoma and more); Open Targets associates it with 9 specific cancer types at or above 0.5 (juvenile polyposis syndrome, juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, generalized juvenile polyposis/juvenile polyposis coli, familial pancreatic carcinoma, colorectal adenocarcinoma, pancreatic adenocarcinoma and more). (Rule 6 of scripts/fetch-target-specificity.ts.)
Sources: UniProt Q13485; CIViC gene SMAD4; IntOGen SMAD4; Human Protein Atlas SMAD4 tissue; Open Targets ENSG00000141646 associations
First described 1996. Earliest sequence paper UniProt cites for the protein: Hahn S.A. et al, Science, 1996, "DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1". Source.
Sources: HGNC HGNC:6770 (approved symbol, name, aliases, locus and cross-references (hgnc_complete_set.txt)); UniProt Q13485 (protein name, function text, keywords and locations (REST API)); CIViC gene SMAD4 (31 evidence items, 0 assertions, 20 variants; diseases: Pancreatic Cancer, Colorectal Cancer, Prostate Cancer, Juvenile Polyposis Syndrome, Lung Non-small Cell Carcinoma and 3 more (GraphQL API, CC0)); Open Targets ENSG00000141646 (association with cancer (MONDO_0004992) 0.87; per-cancer scores at or above 0.5: non-small cell lung carcinoma 0.50, colorectal cancer 0.79, gastric cancer 0.62, oesophageal cancer 0.65, gallbladder cancer 0.50, lung cancer 0.56 (GraphQL API, CC0)); IntOGen SMAD4 (driver in 37 cohorts (Act 10, LoF 27); Compendium_Cancer_Genes.tsv release 20240920, CC0 1.0)
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).
RNA: low tissue specificity, detected in all normal tissues.
Medium: Adrenal gland, Bone marrow, Breast, Bronchus, Cervix, Endometrium, Esophagus, Fallopian tube.
Medium only: breast cancer, cervical cancer, colorectal cancer, endometrial cancer.
Human Protein Atlas version 25.1, antibody staining at reliability approved, enhanced or supported; used under CC BY-SA 3.0. Staining counts are patients per level in the atlas cohort, not population prevalence.
| Cancer | Prevalence | Measure | Note | Source |
|---|---|---|---|---|
| Gallbladder cancer | 21-38% | Mutation or deletion | 38% in Chile, 36% in Japan and 27% in the United States among 81 patients, with worse survival (10 versus 25 months; Narayan 2019); mutation in 52 of 244 samples, 21.3%, and deep deletion in 11 of 244, 4.5%, in cBioPortal gbc_mskcc_2022; 26.2% of 103 in gbc_msk_2018; 7% of 376 Indian patients (Suryavanshi 2025); independently associated with reduced survival in metastatic disease (Giraldo 2022) and with inferior outcomes in ERBB2-driven tumours (Cowzer 2026). | doi.org |
| Pancreatic ductal adenocarcinoma | 17-33% | Mutation or deep deletion | cBioPortal: mutation in 512 of 2,336, 21.9%, and deep deletion in 102, 4.4%, in pdac_msk_2024 (R361H 30, R361C 26, R445* 15); 86 of 383, 22.5%, in paad_qcmg_uq_2016; mutation 37 of 179, 20.7%, and deep deletion 23 of 183, 12.6%, in paad_tcga_pan_can_atlas_2018; mutation 21 and deep deletion 32 of 109 in paad_utsw_2015; 68 of 395, 17.2%, plus 10 deletions in pancreas_msk_2024; 24 of 140, 17.1%, in paad_cptac_2021. TGFBR2 mutation in 91 of 2,336, 3.9%, and 18 of 383, 4.7%; TGFBR1 64 of 2,336; ACVR1B 11 of 383 (cBioPortal). SMAD4 and TGFBR2 mutations were largely restricted to the invasive carcinoma in cyst progression (Noe 2020). | cBioPortal (TCGA) |
| Colorectal cancer | 12-16% | Mutation or deep deletion (18q loss) | cBioPortal: mutation in 1,078 of 7,237, 14.9%, plus deep deletion in 205, in crc_msk_2026; 173 of 1,134, 15.3%, plus 42 deletions, in crc_msk_2017; 238 of 1,516, 15.7%, plus 46 deletions, in crc_eo_2020; 68 of 534, 12.7%, plus 28 deletions of 592, in coadread_tcga_pan_can_atlas_2018; 73 of 619, 11.8%, in coadread_dfci_2016. SMAD2 and SMAD3 are deleted alongside it (74 and 49 deep deletions in crc_msk_2026). A specific region of chromosome 18 was lost in 73% of carcinomas and 47% of advanced adenomas but only 11 to 13% of early adenomas, which is how 18q entered the model (Vogelstein 1988). | cBioPortal (TCGA) |
Approximate, population-level figures; the measure column says what was counted. Ranges show the midpoint as a bar.
For gallbladder cancer the points that matter are that HER2 can disappear under HER2-directed pressure, that SMAD4 co-mutation predicts a worse response, and that sequencing at progression, not just at diagnosis, may be needed to guide the next line.
HER2 is as frequent in India as in the West, so HER2 testing pays off in the highest-incidence population, while tumour-agnostic immunotherapy markers will rarely apply. The paper also shows plasma testing is feasible where tissue is scarce.
Evidence that the immune environment of gallbladder cancer differs by population even when the mutations do not; a reason to report gallbladder cancer and its regions separately in immunotherapy trials rather than as one biliary subgroup.
The reference Western cohort for gallbladder cancer frequencies, deposited on cBioPortal as gbc_mskcc_2022, where the per-gene sample counts on OnCo were read. It supports panel testing at diagnosis: one patient in three has a targetable finding.
It gives surveillance a target and a timetable: catch high-grade dysplasia and there are about three years before invasion, and TGF-beta pathway loss is the event to detect.
A cancer next to a cyst is not necessarily from the cyst, so removing the cyst does not always remove the risk, and surveillance must cover the whole gland.
It fixed the working numbers for a comprehensive panel in pancreatic cancer: a hit worth acting on in about one patient in six, most of it in repair genes and the KRAS wild-type minority.
Regional biology is real but partial: exposures and age differ, some genes differ, and SMAD4 loss emerges as the shared bad-prognosis marker. It is the paper behind the MSK 2018 gallbladder study on cBioPortal (gbc_msk_2018).
Query for this target: (TITLE:"SMAD4" OR ABSTRACT:"SMAD4" OR TITLE:"SMAD family member 4" OR ABSTRACT:"SMAD family member 4" OR TITLE:"DPC4" OR ABSTRACT:"DPC4" OR TITLE:"MADH4" OR ABSTRACT:"MADH4") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about SMAD4, not a curated reading list.
Shares Regional differences in gallbladder cancer pathogenesis: insights from a multi-institutional comparison of tumor mutations, Genomic characterization of biliary tract cancers identifies driver genes and predisposing mutations, Biliary cancer: utility of next-generation sequencing for clinical management, Genomic profiling of Indian gallbladder carcinoma: mutational insights in a high-incidence population.
Shares Pancreatic intraepithelial neoplasia (PanIN), the microscopic precursor of pancreatic cancer, A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns, Association of alterations in main driver genes with outcomes of patients with resected pancreatic ductal adenocarcinoma, Molecular and clinical determinants of targeted therapy treatment in biliary tract cancer.
Shares Pathways of progression from intraductal papillary mucinous neoplasm to pancreatic ductal adenocarcinoma based on molecular features, IPMNs with co-occurring invasive cancers: neighbours but not always relatives, Classifying colorectal cancer by tumor location rather than sidedness highlights a continuum in mutation profiles and consensus molecular subtypes, A combination of molecular markers and clinical features improve the classification of pancreatic cysts.
Shares IPMNs with co-occurring invasive cancers: neighbours but not always relatives, Genomic characterization of malignant progression in neoplastic pancreatic cysts, A combination of molecular markers and clinical features improve the classification of pancreatic cysts, Clinical sequencing defines the genomic landscape of metastatic colorectal cancer.
Shares Genomic characterization of malignant progression in neoplastic pancreatic cysts, Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes, Integrated genomic characterization of pancreatic ductal adenocarcinoma, TGF-β signalling.
Shares TGF-beta drives immune evasion in genetically reconstituted colon cancer metastasis, A genetic model for colorectal tumorigenesis, Clinical sequencing defines the genomic landscape of metastatic colorectal cancer, Genetic alterations during colorectal-tumor development.
Shares Classifying colorectal cancer by tumor location rather than sidedness highlights a continuum in mutation profiles and consensus molecular subtypes, A combination of molecular markers and clinical features improve the classification of pancreatic cysts, Clinical sequencing defines the genomic landscape of metastatic colorectal cancer, Integrated genomic characterization of pancreatic ductal adenocarcinoma.
Shares Whole genomes redefine the mutational landscape of pancreatic cancer, Genomic analyses identify molecular subtypes of pancreatic cancer, Oesophageal cancer, CIViC.