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J Invest Dermatol. 2014 Oct;134(10):2630-2638. doi: 10.1038/jid.2014.154. Epub 2014 Mar 24.

NOTCH1 mutations occur early during cutaneous squamous cell carcinogenesis.

Author information

1
Division of Cancer Research, University of Dundee, Dundee, UK.
2
Centre for Cutaneous Research, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
3
Eastern Sequence and Informatics Hub (EASIH), University of Cambridge, Laboratory Block Addenbrooke's Hospital, Cambridge, UK.
4
Department of Dermatology, University of California, San Francisco, CA, USA.
5
Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
6
Department of Cellular Pathology, Barts Health NHS Trust, London, UK.
#
Contributed equally

Abstract

Cutaneous SCC (cSCC) is the most frequently occuring skin cancer with metastatic potential and can manifest rapidly as a common side effect in patients receiving systemic kinase inhibitors. Here, we use massively parallel exome and targeted level sequencing of 132 sporadic cSCCs and of 39 squamoproliferative lesions and cSCCs arising in patients receiving the BRAF inhibitor vemurafenib, as well as 10 normal skin samples, to identify NOTCH1 mutation as an early event in squamous cell carcinogenesis. Bisected vemurafenib-induced lesions revealed surprising heterogeneity with different activating HRAS and NOTCH1 mutations identified in two halves of the same cSCC, suggesting polyclonal origin. Immunohistochemical analysis using an antibody specific to nuclear NOTCH1 correlates with mutation status in sporadic cSCCs, and regions of NOTCH1 loss or downregulation are frequently observed in normal-looking skin. Our data indicate that NOTCH1 acts as a gatekeeper in human cSCC.

PMID:
24662767
PMCID:
PMC4753672
DOI:
10.1038/jid.2014.154
[Indexed for MEDLINE]
Free PMC Article

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