NOTCH1 mutations occur early during cutaneous squamous cell carcinogenesis

Andrew P. South (Lead / Corresponding author), Karin J. Purdie, Stephen A. Watt, Sam Haldenby, Nicoline den Breems, Michelle Dimon, Sarah T. Arron, Michael J. Kluk, Jon C. Aster, Angela McHugh, Dylan J. Xue, Jasbani H. S. Dayal, Kim S. Robinson, S. M. Hasan Rizvi, Charlotte M. Proby, Catherine A. Harwood, Irene M. Leigh

Research output: Contribution to journalArticlepeer-review

275 Citations (Scopus)


Cutaneous SCC (cSCC) is the most frequent 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 132 sporadic cSCC, 39 squamoproliferative lesions and cSCC arising in patients receiving the BRAF inhibitor vemurafenib, as well as 10 normal skin samples to identify significant 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 cSCC and regions of NOTCH1 loss or down-regulation are frequently observed in normal looking skin. Our data indicate that NOTCH1 acts as a gatekeeper in human cSCC.Journal of Investigative Dermatology accepted article preview online, 24 March 2014; doi:10.1038/jid.2014.154.
Original languageEnglish
Pages (from-to)2630-2638
Number of pages9
JournalJournal of Investigative Dermatology
Issue number10
Early online date17 Apr 2014
Publication statusPublished - Oct 2014


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