NOTCH4

Overview

NOTCH4 is one of four mammalian NOTCH receptors, members of the evolutionarily conserved NOTCH signaling pathway governing cell fate, differentiation, and proliferation. In squamous epithelium, NOTCH signaling promotes differentiation; loss-of-function NOTCH mutations are therefore associated with squamous cell carcinomas across multiple anatomical sites.

Alterations observed in the corpus

  • NOTCH4 inactivated as part of the NOTCH1/2/4 inactivation pattern in metastatic cSCC: 24% of samples (7/29) with truncating or COSMIC-annotated mutations, rising to 69% if all nonsynonymous SNVs of unknown significance are included. Truncating NOTCH and EP300 events are mutually exclusive across samples. PMID:25589618
  • In PAAD, NOTCH4 was altered in 9% of cases within the TGF-β/NOTCH pathway analysis of the 109-case microdissected exome cohort. 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
  • NOTCH4 was mutated in ATC as part of a finding that all four NOTCH family members (NOTCH1–NOTCH4) were mutated; part of low-frequency hits in a 341-gene panel sequencing study of thyroid cancers PMID:26878173

Cancer types (linked)

  • CSCC: NOTCH4 inactivation is part of the broad NOTCH pathway loss of function in cutaneous SCC; squamous differentiation alterations (TP53, CDKN2A, TP63, NOTCH1/2) did not correlate independently with prognosis in metastatic cSCC (n=29). PMID:25589618

Co-occurrence and mutual exclusivity

  • Mutually exclusive with EP300 truncating mutations across metastatic cSCC samples; co-occurs with NOTCH1 and NOTCH2 inactivation as convergent loss of NOTCH pathway function. PMID:25589618

Therapeutic relevance

  • No therapeutic associations reported; NOTCH pathway alterations in cSCC do not independently predict prognosis in this cohort. PMID:25589618

Open questions

  • Whether NOTCH4 loss contributes independently to metastatic cSCC phenotype or is functionally redundant with NOTCH1/2 inactivation is unresolved. PMID:25589618

Sources

This page was processed by crosslinker on 2026-05-14. - PMID:25855536

This page was processed by crosslinker on 2026-05-14. - PMID:26168399

This page was processed by crosslinker on 2026-05-14. - PMID:26878173

This page was processed by wiki-cli on 2026-05-14.