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Updated: May 1, 2026

Cell Population Analyses During Skin Carcinogenesis
06:53

Cell Population Analyses During Skin Carcinogenesis

Published on: August 21, 2013

15.5K

NOTCH1 mutations occur early during cutaneous squamous cell carcinogenesis

Andrew P South1, Karin J Purdie2, Stephen A Watt1

  • 1Division of Cancer Research, University of Dundee, Dundee, UK.

The Journal of Investigative Dermatology
|March 26, 2014
PubMed

Insights

NOTCH1 mutations are early events in squamous cell carcinogenesis, acting as a gatekeeper in cutaneous SCC (cSCC). This common skin cancer can arise from multiple cell origins, even in patients treated with kinase inhibitors.

Area of Science:

  • Oncology
  • Dermatology
  • Genetics

Background:

  • Cutaneous squamous cell carcinoma (cSCC) is a prevalent skin cancer with metastatic potential.
  • cSCC can rapidly develop in patients undergoing systemic kinase inhibitor therapy.
  • NOTCH1 mutations are implicated in various cancers, but their role in cSCC initiation is not fully understood.

Purpose of the Study:

  • To investigate the role of NOTCH1 mutations in the early stages of squamous cell carcinogenesis.
  • To identify genetic alterations in sporadic cSCC and vemurafenib-induced cSCC.
  • To determine if NOTCH1 functions as a tumor suppressor in cSCC development.

Main Methods:

  • Massively parallel exome and targeted sequencing of 132 sporadic cSCCs, 39 squamoproliferative lesions/cSCCs from vemurafenib-treated patients, and 10 normal skin samples.
  • Immunohistochemical analysis for nuclear NOTCH1.
  • Analysis of lesion heterogeneity and mutation status.

Main Results:

  • NOTCH1 mutations were identified as an early event in squamous cell carcinogenesis.
  • Vemurafenib-induced cSCCs exhibited heterogeneity, with distinct HRAS and NOTCH1 mutations in different halves of the same lesion, suggesting polyclonal origin.
  • Loss or downregulation of nuclear NOTCH1 was frequently observed in normal-looking skin and correlated with mutation status in sporadic cSCCs.

Conclusions:

  • NOTCH1 acts as a critical gatekeeper in human cSCC development.
  • The findings suggest that NOTCH1 loss-of-function is a key step in cSCC initiation.
  • Understanding NOTCH1's role may inform therapeutic strategies for cSCC.

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