title: NOTCH1 mutations occur early during cutaneous squamous cell carcinogenesis.
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.
authors.affiliation: Division of Cancer Research, University of Dundee, Dundee, UK.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: South
authors.affiliation: Centre for Cutaneous Research, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Karin J
authors.initials: KJ
authors.lastname: Purdie
authors.affiliation: Division of Cancer Research, University of Dundee, Dundee, UK.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Watt
authors.affiliation: Eastern Sequence and Informatics Hub (EASIH), University of Cambridge, Laboratory Block Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Sam
authors.initials: S
authors.lastname: Haldenby
authors.affiliation: Division of Cancer Research, University of Dundee, Dundee, UK.
authors.forename: Nicoline
authors.initials: N
authors.lastname: den Breems
authors.affiliation: Department of Dermatology, University of California, San Francisco, CA, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Dimon
authors.affiliation: Department of Dermatology, University of California, San Francisco, CA, USA.
authors.forename: Sarah T
authors.initials: ST
authors.lastname: Arron
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Kluk
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Jon C
authors.initials: JC
authors.lastname: Aster
authors.affiliation: Division of Cancer Research, University of Dundee, Dundee, UK.
authors.forename: Angela
authors.initials: A
authors.lastname: McHugh
authors.affiliation: Division of Cancer Research, University of Dundee, Dundee, UK.
authors.forename: Dylan J
authors.initials: DJ
authors.lastname: Xue
authors.affiliation: Division of Cancer Research, University of Dundee, Dundee, UK.
authors.forename: Jasbani Hs
authors.initials: JH
authors.lastname: Dayal
authors.affiliation: Division of Cancer Research, University of Dundee, Dundee, UK.
authors.forename: Kim S
authors.initials: KS
authors.lastname: Robinson
authors.affiliation: Department of Cellular Pathology, Barts Health NHS Trust, London, UK.
authors.forename: Sm Hasan
authors.initials: SH
authors.lastname: Rizvi
authors.affiliation: Division of Cancer Research, University of Dundee, Dundee, UK.
authors.forename: Charlotte M
authors.initials: CM
authors.lastname: Proby
authors.affiliation: Centre for Cutaneous Research, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Harwood
authors.affiliation: Division of Cancer Research, University of Dundee, Dundee, UK.|Centre for Cutaneous Research, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Irene M
authors.initials: IM
authors.lastname: Leigh
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001706:Biopsy; D063646:Carcinogenesis / Q000235:genetics* / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D015536:Down-Regulation; D005260:Female; D006801:Humans; D007211:Indoles / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D051881:Receptor, Notch1 / Q000235:genetics* / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics* / Q000502:physiology; D012867:Skin / Q000378:metabolism / Q000473:pathology; D012871:Skin Diseases / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D013449:Sulfonamides / Q000627:therapeutic use; D000077484:Vemurafenib
chemical_list: D007211:Indoles; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D051880:Receptors, Notch; D013449:Sulfonamides; D000077484:Vemurafenib; D048493:Proto-Oncogene Proteins B-raf; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)