NOTCH1 Mutations Occur Early During Cutaneous Squamous Cell Carcinogenesis

Overview

Journal J Invest Dermatol

Publisher Elsevier

Specialty Dermatology

Date 2014 Mar 26

PMID 24662767

Citations 157

Authors

Andrew P South

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 Hs Dayal

Kim S Robinson

Sm Hasan Rizvi

Charlotte M Proby

Catherine A Harwood

Irene M Leigh

Affiliations

Soon will be listed here.

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.

Citing Articles

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