{"entity":{"id":"smad4","kind":"target","name":"SMAD4","aka":["SMAD family member 4","DPC4","MADH4"],"tldr":"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.\n\nCIViC 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.","asOf":"2026-09-23","links":[{"label":"HGNC HGNC:6770","url":"https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:6770"},{"label":"UniProt Q13485","url":"https://www.uniprot.org/uniprotkb/Q13485/entry"},{"label":"NCBI Gene 4089","url":"https://www.ncbi.nlm.nih.gov/gene/4089"},{"label":"Ensembl ENSG00000141646","url":"https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000141646"}],"tags":["cancer-genes-wave"],"related":["civic","open-targets","intogen"],"cancers":["colorectal","gastric","esophageal","pancreatic","biliary-tract-cancer","prostate","head-and-neck","breast-cancer","gallbladder"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":["colorectal-cancer-signalling","pancreatic-cancer-signalling","tgf-beta"],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-noe-cyst-malignant-progression-genomics-nat-commun-2020","paper-iacobuzio-donahue-dpc4-failure-pattern-autopsy-jco-2009","paper-crane-smad4-progression-pattern-locally-advanced-jco-2011","paper-qian-driver-genes-outcomes-resected-pancreatic-jama-oncol-2018","paper-vogelstein-genetic-alterations-colorectal-tumor-development-nejm-1988","paper-narayan-gallbladder-regional-mutations-cancer-2019","paper-suryavanshi-indian-gallbladder-genomics-jco-go-2025","paper-giraldo-gallbladder-msk-impact-ccr-2022","paper-cowzer-biliary-targeted-therapy-determinants-ccr-2026"],"journals":[],"dependsOn":[],"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)."],"provenance":{"editedBy":"scripts/fetch-cancer-genes.ts (CIViC, Open Targets, IntOGen, HGNC, UniProt)","editedOn":"2026-09-23"},"symbol":"SMAD4","role":["drug-target","oncogene-driver","tumour-suppressor","biomarker"],"evidenceTier":"clinical-evidence","sources":[{"label":"HGNC HGNC:6770","url":"https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:6770","note":"approved symbol, name, aliases, locus and cross-references (hgnc_complete_set.txt)"},{"label":"UniProt Q13485","url":"https://www.uniprot.org/uniprotkb/Q13485/entry","note":"protein name, function text, keywords and locations (REST API)"},{"label":"CIViC gene SMAD4","url":"https://civicdb.org/features/77","note":"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)"},{"label":"Open Targets ENSG00000141646","url":"https://platform.opentargets.org/target/ENSG00000141646/associations","note":"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)"},{"label":"IntOGen SMAD4","url":"https://www.intogen.org/search?gene=SMAD4","note":"driver in 37 cohorts (Act 10, LoF 27); Compendium_Cancer_Genes.tsv release 20240920, CC0 1.0"}],"specificity":"tumour-specific","distribution":"many-types","specificityNote":"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.)","specificitySources":[{"label":"UniProt Q13485","url":"https://www.uniprot.org/uniprotkb/Q13485/entry","note":"protein name, function text, keywords and locations (REST API)"},{"label":"CIViC gene SMAD4","url":"https://civicdb.org/features/77","note":"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)"},{"label":"IntOGen SMAD4","url":"https://www.intogen.org/search?gene=SMAD4","note":"driver in 37 cohorts (Act 10, LoF 27); Compendium_Cancer_Genes.tsv release 20240920, CC0 1.0"},{"label":"Human Protein Atlas SMAD4 tissue","url":"https://www.proteinatlas.org/ENSG00000141646-SMAD4/tissue","note":"RNA tissue and blood lineage specificity, normal tissue antibody staining (version 25.1, CC BY-SA 3.0)"},{"label":"Open Targets ENSG00000141646 associations","url":"https://platform.opentargets.org/target/ENSG00000141646/associations","note":"cancer associations at or above 0.5 (CC0)"}],"hgnc":"HGNC:6770","ensembl":"ENSG00000141646","uniprot":"Q13485","entrez":"4089","firstDescribed":1996,"firstDescribedBasis":"sequence","firstDescribedNote":"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\".","firstDescribedSource":"https://pubmed.ncbi.nlm.nih.gov/8553070/","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).","whereFound":["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%"],"targetClass":"transcription","prevalence":[{"cancerId":"pancreatic","pct":"17-33","measure":"Mutation or deep deletion","source":"https://www.cbioportal.org/study/summary?id=pdac_msk_2024","note":"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)."},{"cancerId":"colorectal","pct":"12-16","measure":"Mutation or deep deletion (18q loss)","source":"https://www.cbioportal.org/study/summary?id=crc_msk_2026","note":"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)."},{"cancerId":"gallbladder","pct":"21-38","measure":"Mutation or deletion","source":"https://doi.org/10.1002/cncr.31850","note":"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)."}]},"route":"/targets/smad4/","neighbours":{"collection":[{"id":"civic","kind":"collection","name":"CIViC","route":"/collections/civic/"},{"id":"intogen","kind":"collection","name":"IntOGen","route":"/collections/intogen/"},{"id":"open-targets","kind":"collection","name":"Open Targets Platform","route":"/collections/open-targets/"}],"cancer":[{"id":"biliary-tract-cancer","kind":"cancer","name":"Biliary tract cancer (all types)","route":"/cancers/biliary-tract-cancer/"},{"id":"breast-cancer","kind":"cancer","name":"Breast cancer (all types)","route":"/cancers/breast-cancer/"},{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"},{"id":"gallbladder","kind":"cancer","name":"Gallbladder cancer","route":"/cancers/gallbladder/"},{"id":"gastric","kind":"cancer","name":"Gastric & gastro-oesophageal junction cancer","route":"/cancers/gastric/"},{"id":"head-and-neck","kind":"cancer","name":"Head and neck squamous cell carcinoma","route":"/cancers/head-and-neck/"},{"id":"ipmn-associated-carcinoma","kind":"cancer","name":"Invasive carcinoma arising in an intraductal papillary mucinous neoplasm (IPMN-associated carcinoma)","route":"/cancers/ipmn-associated-carcinoma/"},{"id":"esophageal","kind":"cancer","name":"Oesophageal cancer","route":"/cancers/esophageal/"},{"id":"pancreatic","kind":"cancer","name":"Pancreatic ductal adenocarcinoma","route":"/cancers/pancreatic/"},{"id":"prostate","kind":"cancer","name":"Prostate cancer","route":"/cancers/prostate/"}],"pathway":[{"id":"colorectal-cancer-signalling","kind":"pathway","name":"Colorectal cancer (KEGG map)","route":"/pathways/colorectal-cancer-signalling/"},{"id":"pancreatic-cancer-signalling","kind":"pathway","name":"Pancreatic cancer (KEGG map)","route":"/pathways/pancreatic-cancer-signalling/"},{"id":"tgf-beta","kind":"pathway","name":"TGF-β signalling","route":"/pathways/tgf-beta/"}],"paper":[{"id":"paper-springer-pancreatic-cyst-molecular-classification-gastroenterology-2015","kind":"paper","name":"A combination of molecular markers and clinical features improve the classification of pancreatic cysts","route":"/key-papers/paper-springer-pancreatic-cyst-molecular-classification-gastroenterology-2015/"},{"id":"paper-fearon-cell","kind":"paper","name":"A genetic model for colorectal tumorigenesis","route":"/key-papers/paper-fearon-cell/"},{"id":"paper-notta-punctuated-evolution-pancreatic-nature-2016","kind":"paper","name":"A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns","route":"/key-papers/paper-notta-punctuated-evolution-pancreatic-nature-2016/"},{"id":"paper-qian-driver-genes-outcomes-resected-pancreatic-jama-oncol-2018","kind":"paper","name":"Association of alterations in main driver genes with outcomes of patients with resected pancreatic ductal adenocarcinoma","route":"/key-papers/paper-qian-driver-genes-outcomes-resected-pancreatic-jama-oncol-2018/"},{"id":"paper-javle-biliary-ngs-cancer-2016","kind":"paper","name":"Biliary cancer: utility of next-generation sequencing for clinical management","route":"/key-papers/paper-javle-biliary-ngs-cancer-2016/"},{"id":"paper-loree-tumour-location-continuum-colorectal-ccr-2018","kind":"paper","name":"Classifying colorectal cancer by tumor location rather than sidedness highlights a continuum in mutation profiles and consensus molecular subtypes","route":"/key-papers/paper-loree-tumour-location-continuum-colorectal-ccr-2018/"},{"id":"paper-yaeger-metastatic-colorectal-genomic-landscape-cancer-cell-2018","kind":"paper","name":"Clinical sequencing defines the genomic landscape of metastatic colorectal cancer","route":"/key-papers/paper-yaeger-metastatic-colorectal-genomic-landscape-cancer-cell-2018/"},{"id":"paper-giraldo-gallbladder-msk-impact-ccr-2022","kind":"paper","name":"Comprehensive molecular characterization of gallbladder carcinoma and potential targets for intervention","route":"/key-papers/paper-giraldo-gallbladder-msk-impact-ccr-2022/"},{"id":"paper-tcga-colorectal-comprehensive-characterization-nature-2012","kind":"paper","name":"Comprehensive molecular characterization of human colon and rectal cancer","route":"/key-papers/paper-tcga-colorectal-comprehensive-characterization-nature-2012/"},{"id":"paper-jones-pancreatic-core-pathways-science-2008","kind":"paper","name":"Core signaling pathways in human pancreatic cancers revealed by global genomic analyses","route":"/key-papers/paper-jones-pancreatic-core-pathways-science-2008/"},{"id":"paper-iacobuzio-donahue-dpc4-failure-pattern-autopsy-jco-2009","kind":"paper","name":"DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer","route":"/key-papers/paper-iacobuzio-donahue-dpc4-failure-pattern-autopsy-jco-2009/"},{"id":"paper-vogelstein-genetic-alterations-colorectal-tumor-development-nejm-1988","kind":"paper","name":"Genetic alterations during colorectal-tumor development","route":"/key-papers/paper-vogelstein-genetic-alterations-colorectal-tumor-development-nejm-1988/"},{"id":"paper-bailey-molecular-subtypes-pancreatic-nature-2016","kind":"paper","name":"Genomic analyses identify molecular subtypes of pancreatic cancer","route":"/key-papers/paper-bailey-molecular-subtypes-pancreatic-nature-2016/"},{"id":"paper-wardell-biliary-drivers-germline-j-hepatol-2018","kind":"paper","name":"Genomic characterization of biliary tract cancers identifies driver genes and predisposing mutations","route":"/key-papers/paper-wardell-biliary-drivers-germline-j-hepatol-2018/"},{"id":"paper-noe-cyst-malignant-progression-genomics-nat-commun-2020","kind":"paper","name":"Genomic characterization of malignant progression in neoplastic pancreatic cysts","route":"/key-papers/paper-noe-cyst-malignant-progression-genomics-nat-commun-2020/"},{"id":"paper-suryavanshi-indian-gallbladder-genomics-jco-go-2025","kind":"paper","name":"Genomic profiling of Indian gallbladder carcinoma: mutational insights in a high-incidence population","route":"/key-papers/paper-suryavanshi-indian-gallbladder-genomics-jco-go-2025/"},{"id":"paper-tcga-pancreatic-integrated-characterisation-cancer-cell-2017","kind":"paper","name":"Integrated genomic characterization of pancreatic ductal adenocarcinoma","route":"/key-papers/paper-tcga-pancreatic-integrated-characterisation-cancer-cell-2017/"},{"id":"paper-felsenstein-ipmn-cooccurring-cancer-relatedness-gut-2018","kind":"paper","name":"IPMNs with co-occurring invasive cancers: neighbours but not always relatives","route":"/key-papers/paper-felsenstein-ipmn-cooccurring-cancer-relatedness-gut-2018/"},{"id":"paper-cowzer-biliary-targeted-therapy-determinants-ccr-2026","kind":"paper","name":"Molecular and clinical determinants of targeted therapy treatment in biliary tract cancer","route":"/key-papers/paper-cowzer-biliary-targeted-therapy-determinants-ccr-2026/"},{"id":"paper-biankin-pancreatic-exomes-axon-guidance-nature-2012","kind":"paper","name":"Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes","route":"/key-papers/paper-biankin-pancreatic-exomes-axon-guidance-nature-2012/"},{"id":"paper-omori-ipmn-progression-pathways-gastroenterology-2019","kind":"paper","name":"Pathways of progression from intraductal papillary mucinous neoplasm to pancreatic ductal adenocarcinoma based on molecular features","route":"/key-papers/paper-omori-ipmn-progression-pathways-gastroenterology-2019/"},{"id":"paper-crane-smad4-progression-pattern-locally-advanced-jco-2011","kind":"paper","name":"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","route":"/key-papers/paper-crane-smad4-progression-pattern-locally-advanced-jco-2011/"},{"id":"paper-zhu-population-specific-immunogenomics-gallbladder-cancer-mod-pathol-2025","kind":"paper","name":"Population-Specific Immunogenomic Alterations in Gallbladder Cancer and Prognostic Significance","route":"/key-papers/paper-zhu-population-specific-immunogenomics-gallbladder-cancer-mod-pathol-2025/"},{"id":"paper-singhi-targeted-genome-profiling-3594-pdac-gastroenterology-2019","kind":"paper","name":"Real-time targeted genome profile analysis of pancreatic ductal adenocarcinomas identifies genetic alterations that might be targeted with existing drugs or used as biomarkers","route":"/key-papers/paper-singhi-targeted-genome-profiling-3594-pdac-gastroenterology-2019/"},{"id":"paper-narayan-gallbladder-regional-mutations-cancer-2019","kind":"paper","name":"Regional differences in gallbladder cancer pathogenesis: insights from a multi-institutional comparison of tumor mutations","route":"/key-papers/paper-narayan-gallbladder-regional-mutations-cancer-2019/"},{"id":"paper-tauriello-tgfbeta-immune-evasion-colorectal-nature-2018","kind":"paper","name":"TGF-beta drives immune evasion in genetically reconstituted colon cancer metastasis","route":"/key-papers/paper-tauriello-tgfbeta-immune-evasion-colorectal-nature-2018/"},{"id":"paper-waddell-whole-genomes-pancreatic-nature-2015","kind":"paper","name":"Whole genomes redefine the mutational landscape of pancreatic cancer","route":"/key-papers/paper-waddell-whole-genomes-pancreatic-nature-2015/"}],"term":[{"id":"panin","kind":"term","name":"Pancreatic intraepithelial neoplasia (PanIN), the microscopic precursor of pancreatic cancer","route":"/terms/panin/"}]}}