NOTCH1

Overview

NOTCH1 is a canonical CLL driver. In the corpus it is one of the four cardinal CLL drivers in the 1,148-patient CLL map.

Alterations observed in the corpus

  • Mutated in 12.3% of CLL patients in the CLL map; a cardinal known CLL driver PMID:35927489.
  • Temporally intermediate in both M-CLL and U-CLL subtypes by PhylogicNDT ordering PMID:35927489.
  • Negatively regulated by ZFP36L1, which is disrupted by the recurrent 37-Mb chr14 deletion in U-CLL PMID:35927489.
  • Recurrent SNVs identified by SeqSig analysis in anaplastic thyroid carcinoma (ATC) PMID:38412093.
  • Loss-of-function mutations frequent in normal keratinocyte clones; typically early/trunk events in cutaneous squamous cell carcinoma (cSCC) evolution; induce stem/progenitor cell state PMID:39091884.
  • NOTCH1 pathway alterations higher in GBC carcinomas with squamous differentiation (26% vs 8% in adenocarcinoma, q=0.07) PMID:36228155
  • Recurrently mutated in HNSCC across 74 tumor-normal pairs by whole-exome sequencing; tumor suppressor role proposed (Broad cohort) PMID:21798893
  • Recurrently mutated in HNSCC across 32 primary tumors by whole-exome sequencing (Johns Hopkins cohort) PMID:21798897
  • NOTCH1 somatic mutations were recurrently detected in diffuse large B-cell lymphoma by whole-exome sequencing of 55 tumors PMID:22343534
  • NOTCH1 mutations identified in SCLC (JHU WES/WGS, 36 tumors) PMID:22941189
  • NOTCH1 truncating mutations (8/17 loss-of-function) in lung squamous cell carcinoma (TCGA, 178 tumors); part of 44% squamous differentiation pathway alteration rate PMID:22960745
  • Recurrently mutated CLL driver gene identified in CLL WES of 160 tumors (Broad) PMID:23415222
  • Mutated in 9% of OSCC primary tumors and in 16/44 HNSCC cell lines (frameshift, nonsense, missense); functions as tumor suppressor — activated NOTCH1 (ICN1) induced G1 arrest, p21 induction, senescence, and inhibited xenograft growth in 5 HNSCC cell lines (40-tumor MD Anderson cohort) PMID:23619168
  • NOTCH1 missense (3) and nonsense (1) mutations detected in 5% of ACC cases; Notch-pathway activation supported by GSEA trend PMID:23685749
  • NOTCH1 missense p.F1702S and frameshift p.Y550fs*81 detected in ACC exome sequencing; functional direction (activating vs. loss-of-function per HNSCC) unresolved from mutation pattern alone PMID:23778141
  • PEST-truncating mutations in 8/172 (4.6%) MCL plus MINO and REC-1 cell lines; enriched in blastoid/pleomorphic morphology; shorter 3-year OS (33% vs 60%, P=0.026); combined NOTCH1/2 mutations in 9.5% mark aggressive MCL (3-y OS 24% vs 63%, P=3.4×10⁻⁴) PMID:24145436
  • Mutated in 3/21 (14%) sequenced sinonasal adenoid cystic carcinomas — truncating variants including p.Ser2467Ter and p.Ala1908SerfsTer72; co-occurring with canonical MYB::NFIB fusion in all 3 cases; associated with solid/basaloid and metatypical morphology and poor outcome (2/3 dead of disease) PMID:24418857
  • NOTCH1 is mutated in ESCC as part of the canonical genomic landscape cited in a review of oral microbiome associations with ESCC PMID:24670651
  • NOTCH1 is recurrently mutated in ESCC, confirming prior reports of Notch pathway dysregulation in this cancer type PMID:24686850
  • Mutated in 59.0% of 39 aggressive cSCC cases; inactivating pattern (missense in EGF-like repeats, truncating throughout); significant by all four driver-detection methods PMID:25303977
  • NOTCH1 inactivated in 24% of metastatic cSCC (truncating/COSMIC mutations); up to 69% if all nonsynonymous SNVs included; truncating NOTCH1 and EP300 events are mutually exclusive. PMID:25589618
  • NOTCH1 inactivating mutations in 19% of HNSC (MutSigCV q<0.1, TCGA n=279); NOTCH2 9% and NOTCH3 5% non-significant; convergent with FAT1 and AJUBA on β-catenin signalling; basal mRNA subtype enriched for NOTCH1 inactivation. PMID:25631445
  • In pancreatic ductal adenocarcinoma (PAAD), NOTCH1 alterations were present in 10% of cases, contributing to the NOTCH pathway total of ~31% alteration frequency (amplification/mutation); γ-secretase inhibitor (MK0752) is nominated as a therapeutic candidate. PMID:25855536
  • Inactivating mutations (often in the extracellular domain) observed as part of pan-NOTCH inactivation in 25% of human SCLC; mouse models confirm Notch activation suppresses SCLC initiation and prolongs survival. PMID:26168399
  • Somatic mutations enriched in adenoid cystic carcinoma (ACC) tumors lacking both MYB and MYBL1 fusions (~33% of 102-tumor cohort); raises possibility of NOTCH-targeted therapy substratification in fusion-negative ACC PMID:26631609
  • Activated by point mutations or structural alterations (tandem duplication of 3′ enhancers; 5′ partial deletion) in grade-3 ACC; intracellular NOTCH1 (ICN1) marks luminal epithelial cells PMID:26829750
  • Most-frequently mutated gene in ACC cohort: 4 mutations in 3/25 tumors (nonsense, missense, frameshift, in-frame deletion) — 12% frequency PMID:26862087
  • NOTCH1 was mutated in anaplastic thyroid carcinoma (ATC) as part of a finding that all four NOTCH family members (NOTCH1–NOTCH4) were mutated in ATC; part of low-frequency hits in a 341-gene panel sequencing study PMID:26878173
  • NOTCH1 significantly mutated in lung squamous cell carcinoma but not other cancer types (excluding HNSC, BLCA) in pan-lung cancer TCGA analysis (n=1144) PMID:27158780
  • Altered in 33% of adenoid cystic carcinoma (ACYC) with activating mutations/amplifications in 22.2% (8.3-fold enriched versus primary ACYC); recurrent S2467 truncating events; nominates gamma-secretase inhibitors as a therapeutic strategy PMID:27442865
  • Significantly mutated in ESCC (enriched in the ESCC2 subtype); modulator of squamous cell maturation PMID:28052061
  • Mutated in 6/19 (32%) of 1p/19q-codeleted anaplastic oligodendroglioma; specific alterations include A1701S, F357del, P1443Afs36, T633Dfs12, V324Qfs*6; not predictive of PFS or OS in this small NGS subset PMID:28472509

Cancer types (linked)

  • Chronic lymphocytic leukemia (CLLSLL) — 12.3% mutation frequency PMID:35927489.
  • Anaplastic thyroid carcinoma (ATC) — recurrent SNVs PMID:38412093.
  • Cutaneous squamous cell carcinoma (cSCC) — loss-of-function mutations are early/trunk events during AK-to-cSCC evolution; induce stem/progenitor cell state PMID:39091884.

Co-occurrence and mutual exclusivity

Therapeutic relevance

  • No direct therapeutic link reported in the corpus.

Open questions

  • Relationship of NOTCH1 mutation status to expression clusters and epitype PMID:35927489.

Sources

This page was processed by entity-page-writer on 2026-05-15.