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NOTCH1 Mutations Occur Early during Cutaneous Squamous Cell Carcinogenesis
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NOTCH1 Mutations Occur Early during Cutaneous Squamous Cell Carcinogenesis
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NOTCH1 Mutations Occur Early during Cutaneous Squamous Cell Carcinogenesis
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Journal Article
NOTCH1 Mutations Occur Early during Cutaneous Squamous Cell Carcinogenesis
2014
Overview
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.
Publisher
Elsevier Inc,Elsevier Limited
Subject
/ Biopsy
/ Carcinoma, Squamous Cell - genetics
/ Carcinoma, Squamous Cell - metabolism
/ Carcinoma, Squamous Cell - pathology
/ Female
/ Humans
/ Male
/ Proto-Oncogene Proteins B-raf - antagonists & inhibitors
/ Proto-Oncogene Proteins p21(ras) - genetics
/ Proto-Oncogene Proteins p21(ras) - metabolism
/ Receptor, Notch1 - metabolism
/ Receptors, Notch - metabolism
/ Signal Transduction - genetics
/ Signal Transduction - physiology
/ Skin Diseases - drug therapy
