NOTCH2

Overview

NOTCH2 is a receptor in the Notch signaling pathway. In the context of normal skin and cutaneous squamous cell carcinoma (cSCC) evolution, NOTCH2 loss-of-function mutations are secondary hits to the Notch pathway, accumulating on phylogenetic branches during the actinic keratosis (AK) to cSCC progression.

Alterations observed in the corpus

Loss-of-function mutations observed in actinic keratosis (AK) lesions; secondary hits to the Notch pathway on phylogenetic branches during AK-to-cSCC evolution PMID:39091884.
Identified as a significantly mutated gene in HNSCC whole-exome sequencing of 74 tumor-normal pairs (Broad cohort) PMID:21798893
NOTCH2 mutations identified in lung squamous cell carcinoma (TCGA, 178 tumors) PMID:22960745
NOTCH2 compound heterozygous truncating mutations p.Q2308fs5 and p.E2420 in ACC (PD3189), co-occurring with SPEN truncations; reminiscent of activating mutations in Hajdu-Cheney syndrome PMID:23778141
PEST-truncating mutations in 9/172 (5.2%) MCL; mutually exclusive with NOTCH1 (only 1/16 carried both); dismal 3-year OS (0% vs 62%, P=2.5×10⁻⁴); independent OS risk factor (HR 3.5; 95% CI 1.3–9.5; P=0.017); enriched in blastoid/pleomorphic morphology (66% vs 18%, P=0.001) PMID:24145436
Referenced as a Notch-pathway co-actor in AdCC based on literature; no specific mutations reported in this cohort but implicated in Notch pathway oncogenesis in adenoid cystic carcinoma PMID:24418857
Mutated in 51.3% of 39 aggressive cSCC cases; inactivating pattern paralleling NOTCH1; novel candidate tumor suppressor; mutation associated with perineural invasion (70% mutant vs 33% WT, p=0.04) and scalp/periorbital primary site (p=0.04) PMID:25303977
NOTCH2 inactivated in metastatic cSCC (n=29); part of the NOTCH1/2/4 inactivation pattern (24% with truncating/COSMIC mutations, up to 69% with missense included). PMID:25589618
In PAAD, NOTCH2 alterations were present in 6% of cases as part of a broadly altered NOTCH pathway (31% total), nominating γ-secretase inhibitors. 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
Non-synonymous substitution in one ACC tumor PMID:26862087
NOTCH2 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
NOTCH2 mutation found uniquely in the plasmacytoid component of a mixed plasmacytoid/urothelial NOS bladder tumor (multi-region sequencing); functional consequence not dissected PMID:26901067
Recurrent mutation in 5% of unclassified RCC (uRCC) in the MSK-IMPACT 230-gene panel cohort (n=62) PMID:27713405
Mutated in 5/19 (26%) of 1p/19q-codeleted anaplastic oligodendroglioma; not predictive of PFS or OS in this small NGS subset PMID:28472509
NOTCH2 was identified as a DLBCL driver gene; however, CRISPR-based knockout of NOTCH2 did not significantly impair growth of DLBCL cell lines, suggesting NOTCH2 may play a role in early pathogenesis rather than being a direct therapeutic target in established DLBCL PMID:28985567

Cancer types (linked)

Cutaneous squamous cell carcinoma (cSCC) — NOTCH2 LoF mutations accumulate in AK as secondary Notch pathway hits; contribute to the mutational landscape driving AK-to-cSCC transformation PMID:39091884.

Co-occurrence and mutual exclusivity

Co-occurs with NOTCH1 LoF mutations in the Notch pathway inactivation during cSCC evolution; NOTCH2 mutations are typically on branches while NOTCH1 mutations are on trunks PMID:39091884.

Therapeutic relevance

No direct therapeutic link reported in the corpus.

Open questions

Whether NOTCH2 LoF contributes independently to the stem/progenitor phenotype induced by NOTCH1 loss in keratinocytes is not determined.

Sources

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