title: Cutaneous epithelial tumors induced by vemurafenib involve the MAPK and Pi3KCA pathways but not HPV nor HPyV viral infection.
abstract: The inhibitors of mutant BRAF that are used to treat metastatic melanoma induce squamoproliferative lesions. We conducted a prospective histopathological and molecular study on 27 skin lesions from 12 patients treated with vemurafenib. Mutation hot spots in HRAS, NRAS, KRAS, BRAF, and Pi3KCA were screened. HPV and HPyV infection status were also determined. The lesions consisted of 19 verrucal papillomas, 1 keratoacanthoma and 7 squamous cell carcinomas. No mutations were found within BRAF and NRAS. KRAS, HRAS, and Pi3KCA oncogenic mutations were found in 10 (83.3%), 7 (58.3%), and 4 (33.3%) patients respectively; however, these mutations were not consistent within all tumors of a given patient. Pi3KCA mutation was always associated with a mutation in HRAS. Finally, no correlation was found between the mutated gene or type of mutation and the type of cutaneous tumor or clinical response to vemurafenib. P16 protein level was not indicative of HPV infection. HPV was detected in only two lesions. Two cases had MCPyV, and one had HPyV7. In conclusion, neither HPV nor HPyV seem to be involved in the development of squamoproliferative lesions induced by verumafenib. By contrast, HRAS and KRAS play a predominant role in the physiopathology of these tumors.
authors.affiliation: Department of Biopathology, CHU Montpellier, Montpellier, France; University of Montpellier I, Montpellier, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Frouin
authors.affiliation: University of Montpellier I, Montpellier, France; Department of Dermatology, CHU Montpellier, Montpellier, France; U1058, INSERM, University of Montpellier I, Montpellier, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Guillot
authors.affiliation: Department of Biopathology, CHU Montpellier, Montpellier, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Larrieux
authors.affiliation: Department of Biopathology, CHU Montpellier, Montpellier, France.
authors.forename: Ariane
authors.initials: A
authors.lastname: Tempier
authors.affiliation: Department of Biopathology, CHU Montpellier, Montpellier, France; University of Montpellier I, Montpellier, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Boulle
authors.affiliation: University of Montpellier I, Montpellier, France; U1058, INSERM, University of Montpellier I, Montpellier, France; Department of Virology, CHU Montpellier, Montpellier, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Foulongne
authors.affiliation: University of Montpellier I, Montpellier, France; Department of Dermatology, CHU Montpellier, Montpellier, France; U1058, INSERM, University of Montpellier I, Montpellier, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Girard
authors.affiliation: Department of Biopathology, CHU Montpellier, Montpellier, France; University of Montpellier I, Montpellier, France; U1058, INSERM, University of Montpellier I, Montpellier, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Costes
authors.affiliation: Department of Biopathology, CHU Montpellier, Montpellier, France; University of Montpellier I, Montpellier, France; Department of Clinical Oncoproteomics, Montpellier Cancer Institute (ICM), Montpellier, France.
authors.forename: Jérome
authors.initials: J
authors.lastname: Solassol
mesh_terms: D006801:Humans; D007211:Indoles / Q000009:adverse effects* / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D027383:Papillomaviridae / Q000502:physiology; D011120:Polyomavirus / Q000502:physiology; D011446:Prospective Studies; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects*; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000473:pathology / Q000821:virology; D013449:Sulfonamides / Q000009:adverse effects* / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism*; D000077484:Vemurafenib
chemical_list: D007211:Indoles; D009687:Nuclear Proteins; C503859:PI3KCA protein, human; D013449:Sulfonamides; D014157:Transcription Factors; D000077484:Vemurafenib; D048493:Proto-Oncogene Proteins B-raf; D020928:Mitogen-Activated Protein Kinases