title: Association of CDK4 germline and BRAF somatic mutations in a patient with multiple primary melanomas and BRAF inhibitor resistance.
abstract: Many genetic alterations, including predisposing or somatic mutations, may contribute toward the development of melanoma. Although CDKN2A and CDK4 are high-penetrance genes for melanoma, MC1R is a low-penetrance gene that has been associated most consistently with the disease. Moreover, BRAF is the most frequently somatically altered oncogene and is a validated therapeutic target in melanoma. This paper reports a case of multiple primary melanoma with germline CDK4 mutation, MC1R variant, and somatic BRAF mutation in nine out of 10 melanomas, indicating that a common pathogenesis, because of a predisposing genetic background, may be shared among distinct subsequent melanomas of probable clonal origin. After 3 months of targeted therapy with BRAF inhibitor, our patient developed resistance with rapid progression of the disease leading to death. This is the first case in which early resistance to BRAF inhibitor has been reported in a patient with CDK4 germline mutation.
authors.affiliation: Departments of aPlastic and Reconstructive Surgery bPathological Anatomy cMedicine, Section of Dermatology, Azienda Ospedaliera Universitaria Integrata, Verona dUnit of Immunology and Molecular Oncology, Veneto Institute of Oncology, IOV-IRCCS eDepartment of Surgery, Oncology and Gastroenterology, Section of Oncology and Immunology, University of Padova, Padova, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Governa
authors.forename: Evelina
authors.initials: E
authors.lastname: Caprarella
authors.forename: Edoardo
authors.initials: E
authors.lastname: Dalla Pozza
authors.forename: Enrico
authors.initials: E
authors.lastname: Vigato
authors.forename: Monia
authors.initials: M
authors.lastname: Maritan
authors.forename: Glenda G
authors.initials: GG
authors.lastname: Caputo
authors.forename: Marina
authors.initials: M
authors.lastname: Zannoni
authors.forename: Paolo
authors.initials: P
authors.lastname: Rosina
authors.forename: Lisa
authors.initials: L
authors.lastname: Elefanti
authors.forename: Camilla
authors.initials: C
authors.lastname: Stagni
authors.forename: Chiara
authors.initials: C
authors.lastname: Menin
mesh_terms: D000328:Adult; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D017809:Fatal Outcome; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D007211:Indoles / Q000627:therapeutic use; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics*; D009378:Neoplasms, Multiple Primary / Q000188:drug therapy / Q000235:genetics*; D017354:Point Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics*; D012878:Skin Neoplasms / Q000188:drug therapy / Q000235:genetics*; D013449:Sulfonamides / Q000627:therapeutic use; D000077484:Vemurafenib
chemical_list: D007211:Indoles; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4