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NOTCH1 (Neurogenic locus notch homolog protein 1) 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 Leukaemia, Non-Hodgkin lymphoma, Head and neck squamous cell carcinoma and 5 more.
Functions as a receptor for membrane-bound ligands Jagged-1 (JAG1), Jagged-2 (JAG2) and Delta-1 (DLL1) to regulate cell-fate determination. Upon ligand activation through the released notch intracellular domain (NICD) it forms a transcriptional activator complex with RBPJ/RBPSUH and activates genes of the enhancer of split locus. Affects the implementation of differentiation, proliferation and apoptotic programs.
CIViC holds 33 clinical evidence items and 0 assertions across 33 variants, naming Prednisone, Porcupine Inhibitor WNT974, Nirogacestat and NOTCH1 Antibody (PF-06293622) and others. Open Targets scores its association with cancer at 0.85 (direct and indirect evidence; datatypes clinical 0.08, affected pathway 0.97, literature 1.00, genetic association 0.00, somatic mutation 0.95, animal model 0.43). IntOGen calls it a driver in 39 cohorts (10 activating, 29 loss-of-function), covering Acute Lymphoblastic Leukaemia, Angiosarcoma, Basal Cell Carcinoma, Bladder Urothelial Carcinoma, Invasive Breast Carcinoma, Cervical Squamous Cell Carcinoma and others.
In plain words · NOTCH1 (Neurogenic locus notch homolog protein 1) 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 Leukaemia, Non-Hodgkin lymphoma, Head and neck squamous cell carcinoma and 5 more.
NOTCH1 (Neurogenic locus notch homolog protein 1) 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 Leukaemia, Non-Hodgkin lymphoma, Head and neck squamous cell carcinoma and 5 more.
Functions as a receptor for membrane-bound ligands Jagged-1 (JAG1), Jagged-2 (JAG2) and Delta-1 (DLL1) to regulate cell-fate determination.
No product in this corpus aims at NOTCH1 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 NOTCH1: RNA low tissue specificity; high antibody staining in 8 normal tissues; highest cancer staining colorectal cancer (12 of 12 high). Distribution: 8 cancer families in the corpus carry a prevalence row, label threshold or catalogue link for it (Leukaemia, Lymphoma, Head and neck squamous cell carcinoma, Lung cancer (all types), Oesophageal cancer, Salivary gland cancers, Colorectal cancer and more); Open Targets associates it with 4 specific cancer types at or above 0.5 (B-cell chronic lymphocytic leukemia, head and neck squamous cell carcinoma, lymphoid leukemia, squamous cell lung carcinoma). (Rule 6 of scripts/fetch-target-specificity.ts.)
Sources: UniProt P46531; CIViC gene NOTCH1; IntOGen NOTCH1; Human Protein Atlas NOTCH1 tissue; Open Targets ENSG00000148400 associations
First described 1991. Earliest sequence paper UniProt cites for the protein: Ellisen L.W. et al, Cell, 1991, "TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms". Source.
Sources: HGNC HGNC:7881 (approved symbol, name, aliases, locus and cross-references (hgnc_complete_set.txt)); UniProt P46531 (protein name, function text, keywords and locations (REST API)); CIViC gene NOTCH1 (33 evidence items, 0 assertions, 33 variants; diseases: T-cell Acute Lymphoblastic Leukaemia, Chronic Lymphocytic Leukaemia, Lung Non-small Cell Carcinoma, Mantle Cell Lymphoma, Colorectal Cancer and 3 more (GraphQL API, CC0)); Open Targets ENSG00000148400 (association with cancer (MONDO_0004992) 0.85; per-cancer scores at or above 0.5: oesophageal cancer 0.56, cervical cancer 0.53, head and neck squamous cell carcinoma 0.69, acute lymphoblastic leukaemia 0.79, B-cell chronic lymphocytic leukaemia 0.74, non-Hodgkin lymphoma 0.81 (GraphQL API, CC0)); IntOGen NOTCH1 (driver in 39 cohorts (Act 10, LoF 29); Compendium_Cancer_Genes.tsv release 20240920, CC0 1.0)
Functions as a receptor for membrane-bound ligands Jagged-1 (JAG1), Jagged-2 (JAG2) and Delta-1 (DLL1) to regulate cell-fate determination. Upon ligand activation through the released notch intracellular domain (NICD) it forms a transcriptional activator complex with RBPJ/RBPSUH and activates genes of the enhancer of split locus. Affects the implementation of differentiation, proliferation and apoptotic programs. Involved in angiogenesis; negatively regulates endothelial cell proliferation and migration and angiogenic sprouting. Involved in the maturation of both CD4(+) and CD8(+) cells in the thymus. Important for follicular differentiation and possibly cell fate selection within the follicle. Location: Cell membrane; Late endosome membrane; Nucleus (UniProt). Locus 9q34.3 (HGNC).
RNA: low tissue specificity, detected in many normal tissues.
Medium: Adipose tissue, Bone marrow, Breast, Bronchus, Caudate, Cerebral cortex, Cervix, Duodenum.
Medium only: breast cancer, carcinoid, liver cancer, lymphoma.
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 |
|---|---|---|---|---|
| Small-cell lung cancer | 13-25% | Inactivating mutation | cBioPortal: NOTCH1 mutated in 16 of 120, 13.3%, in sclc_ucologne_2015. Inactivating mutations across the NOTCH family were found in 25% of the sequenced tumours, and activating Notch signalling in a mouse model strikingly reduced tumour number, extended survival and abolished neuroendocrine gene expression (George 2015). | cBioPortal (TCGA) |
| Triple-negative breast cancer | 5-9% | Activating rearrangement, PEST-domain mutation or amplification | NOTCH1 and NOTCH2 rearrangements causing constitutive activation in 6 of 66 TNBCs, 9%, and in no other solid tumour type (Stoeck 2014); PEST-domain mutations of NOTCH1, NOTCH2 and NOTCH3 and focal NOTCH2/NOTCH3 amplifications significantly enriched in the TNBC subset of TCGA (Wang 2015); cBioPortal: NOTCH1 mutation in 16 of 299, 5.4%, in brca_metabric and 9 of 176, 5.1%, in breast_msk_2018; NOTCH2 amplification in 21 of 119, 17.6%, in brca_tcga_pan_can_atlas_2018. | doi.org |
Approximate, population-level figures; the measure column says what was counted. Ranges show the midpoint as a bar.
Chile has the world's highest gallbladder cancer mortality and until this paper almost no tumour genomics; the lower TP53 rate and high TSC2 and NOTCH1 hint at a different mutational grammar, but the panel and sample size mean the figures need replication.
The piece that turns a research classification into something a trial can use on one person's biopsy, with a probability attached rather than a flat label. It is the reason genetics-directed lymphoma trials became possible at all.
The genetic nosology that precision-medicine trials in diffuse large B-cell lymphoma now use to pick patients. It gives a mechanism, not just a label: two of the four subtypes point at a drug class that already exists.
Why small-cell lung cancer has no targeted therapy in the conventional sense: it is built from the loss of TP53 and RB1, and the drugs that transformed non-small-cell disease inhibit gains rather than restore losses. The NOTCH result pointed at DLL3 and, eventually, at tarlatamab.
It widens the NOTCH driver segment beyond rearrangements to PEST mutations that ordinary DNA panels can report, the finding that fed NOTCH-mutant cohorts into basket trials.
NOTCH is a real but small driver segment in TNBC with a receptor-specific drug response, which is why NOTCH-directed trials require rearrangement or N1-ICD testing rather than treating all TNBC.
It explained why squamous lung cancer has no equivalent of an EGFR inhibitor: its commonest alterations are a transcription factor amplicon, a tumour suppressor deletion and an antioxidant switch, none of which is a drug target in the way a mutant kinase is.
Query for this target: (TITLE:"NOTCH1" OR ABSTRACT:"NOTCH1" OR TITLE:"notch receptor 1" OR ABSTRACT:"notch receptor 1" OR TITLE:"Neurogenic locus notch homolog protein 1" OR ABSTRACT:"Neurogenic locus notch homolog protein 1" OR TITLE:"TAN1" OR ABSTRACT:"TAN1") 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 NOTCH1, not a curated reading list.
Shares LymphGen and the genetic clusters of large B-cell lymphoma, A probabilistic classification tool for genetic subtypes of diffuse large B cell lymphoma with therapeutic implications, Genetics and pathogenesis of diffuse large B-cell lymphoma, Salivary gland cancers.
Shares Comprehensive genomic characterization of squamous cell lung cancers, Leukaemia (all types), Cervical cancer, IntOGen.
Shares LymphGen and the genetic clusters of large B-cell lymphoma, A probabilistic classification tool for genetic subtypes of diffuse large B cell lymphoma with therapeutic implications, Genetics and pathogenesis of diffuse large B-cell lymphoma, Lymphoma roadmap: from a jaw tumour in Uganda and the first human cancer virus to gene-expression subtypes, PET-adapted chemotherapy, CAR-T cells, bispecific antibodies and the genetics-directed trials now recruiting.
Shares Comprehensive genomic profiles of small cell lung cancer, Oesophageal cancer, Cervical cancer, CIViC.
Shares Leukaemia (all types), CIViC, IntOGen, Head and neck squamous cell carcinoma.
Shares Leukaemia (all types), Oesophageal cancer, Cervical cancer, CIViC.
Shares LymphGen and the genetic clusters of large B-cell lymphoma, A probabilistic classification tool for genetic subtypes of diffuse large B cell lymphoma with therapeutic implications, Genetics and pathogenesis of diffuse large B-cell lymphoma, Leukaemia (all types).
Shares Leukaemia (all types), Cervical cancer, IntOGen, Lung cancer (all types).