{"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"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":["colorectal-cancer-signalling","pancreatic-cancer-signalling","tgf-beta"],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"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."],"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"}],"hgnc":"HGNC:6770","ensembl":"ENSG00000141646","uniprot":"Q13485","entrez":"4089","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)"],"targetClass":"transcription","prevalence":[]},"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":"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":"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/"}]}}