NOTCH1 mutations occur early during cutaneous squamous cell carcinogenesis

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.