title: Mutational Analysis of BRAF Inhibitor-Associated Squamoproliferative Lesions.
abstract: In recent years, there has been increasing use of BRAF-inhibiting drugs for the treatment of various malignancies, including melanoma. However, these agents are associated with the development of other nonmelanoma skin lesions, in particular squamoproliferative lesions such as keratoacanthomas (KAs), squamous cell carcinomas, and BRAF inhibitor-associated verrucous keratoses. The molecular pathogenesis of these lesions is of interest, not only for therapeutic reasons, but also for the insight it might provide into the development of similar lesions in a sporadic setting. We used next-generation sequencing to compare the mutational profiles of lesions after treatment with a BRAF inhibitor, with similar lesions arising sporadically. HRAS mutations were common among the BRAF inhibitor-induced lesions, being identified in 56%, compared with 14% of lesions in the sporadic group (P = 0.002). Thus, despite similar histomorphological appearances, the underlying molecular mechanisms may be different. In addition, within the BRAF inhibitor-associated group, the lesions designated as KAs and BRAF inhibitor-associated verrucous keratoses had a similar mutational profile (mutations in PIK3CA, APC, and HRAS), which was distinct to that seen in squamous cell carcinomas (FGFR3, CDKN2A, and STK11). We have previously noted histological overlap between KAs and BRAF inhibitor-associated verrucous keratoses, and this finding supports the notion that they may represent morphological or temporal variants of a single lesion type.
authors: Translational Cancer Pathology Laboratory, School of Pathology and Laboratory Medicine, The University of Western Australia, Crawley, Western Australia, Australia.
authors: Britt
authors: B
authors: Clynick
authors: Translational Cancer Pathology Laboratory, School of Pathology and Laboratory Medicine, The University of Western Australia, Crawley, Western Australia, Australia.
authors: Tania
authors: T
authors: Tabone
authors: Translational Cancer Pathology Laboratory, School of Pathology and Laboratory Medicine, The University of Western Australia, Crawley, Western Australia, Australia.
authors: Kathryn
authors: K
authors: Fuller
authors: Translational Cancer Pathology Laboratory, School of Pathology and Laboratory Medicine, The University of Western Australia, Crawley, Western Australia, Australia.
authors: Wendy
authors: W
authors: Erber
authors: Translational Cancer Pathology Laboratory, School of Pathology and Laboratory Medicine, The University of Western Australia, Crawley, Western Australia, Australia.
authors: Katie
authors: K
authors: Meehan
authors: Department of Medical Oncology, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia; School of Medicine and Pharmacology, The University of Western Australia, Crawley, Western Australia, Australia.
authors: Michael
authors: M
authors: Millward
authors: Translational Cancer Pathology Laboratory, School of Pathology and Laboratory Medicine, The University of Western Australia, Crawley, Western Australia, Australia; Department of Anatomical Pathology, PathWest Laboratory Medicine, QEII Medical Centre, Nedlands, Western Australia, Australia.
authors: Benjamin A
authors: BA
authors: Wood
authors: Translational Cancer Pathology Laboratory, School of Pathology and Laboratory Medicine, The University of Western Australia, Crawley, Western Australia, Australia; Department of Anatomical Pathology, PathWest Laboratory Medicine, QEII Medical Centre, Nedlands, Western Australia, Australia. Electronic address: nathan.harvey@health.wa.gov.au.
authors: Nathan T
authors: NT
authors: Harvey
mesh_terms: D000328:Adult; D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D006801:Humans; D007636:Keratoacanthoma / Q000235:genetics*; D007642:Keratosis / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics*
chemical_list: C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf