title: BRAF alterations are associated with complex mutational profiles in malignant melanoma.
abstract: To evaluate the mutational profiles associated with BRAF mutations in human melanoma, we have studied BRAF, RAS, PTEN, TP53, CDKN2A and CDK4 genes and their expression in melanoma lesions. Owing to the lack of sufficient material from fresh specimens, we employed short-term cell lines obtained from melanoma biopsies. In all, 41 melanoma obtained from eight primary lesions, 20 nodal, 11 cutaneous and two visceral metastases from patients with sporadic (n=31), familial (n=4) and multiple melanoma (n=2) were analysed. The results revealed novel missense mutations in the BRAF, PTEN, CDKN2A and CDK4 genes. Overall, activating mutations of BRAF and loss of functional p16 and ARF were detected in the majority of melanomas (29/41, 36/41 and 29/41, respectively), while PTEN alterations/loss, NRAS and TP53 mutations occurred less frequently (6/41, 6/41 and 10/41, respectively). In the resulting 12 mutational profiles, p16/ARF loss associated with mutated BRAFV599E was the most represented (n=15). In addition, TP53 and PTEN mutations were always accompanied with BRAF alterations, while PTEN loss was found in association with CDKN2A or TP53 mutations in the absence of BRAF activation. The p16/ARFDelta+BRAF/RAS profile was significantly associated with a longer survival, while complex mutational profiles were detected in highly aggressive disease and poor survival. These data support the existence of several molecularly defined melanoma groups which likely reflect different clinical/biological behaviour, thus suggesting that a more extensive molecular classification of melanoma would significantly impact its clinical management.
authors.affiliation: Unit of Melanoma Genetics, Istituto Nazionale per lo Studio e la Cura dei Tumori, via Venezian 1, 20133 Milan, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Daniotti
authors.forename: Maria
authors.initials: M
authors.lastname: Oggionni
authors.forename: Tiziana
authors.initials: T
authors.lastname: Ranzani
authors.forename: Viviana
authors.initials: V
authors.lastname: Vallacchi
authors.forename: Valentina
authors.initials: V
authors.lastname: Campi
authors.forename: Delia
authors.initials: D
authors.lastname: Di Stasi
authors.forename: Gabriella Della
authors.initials: GD
authors.lastname: Torre
authors.forename: Federica
authors.initials: F
authors.lastname: Perrone
authors.forename: Chiara
authors.initials: C
authors.lastname: Luoni
authors.forename: Simona
authors.initials: S
authors.lastname: Suardi
authors.forename: Milo
authors.initials: M
authors.lastname: Frattini
authors.forename: Silvana
authors.initials: S
authors.lastname: Pilotti
authors.forename: Andrea
authors.initials: A
authors.lastname: Anichini
authors.forename: Gabrina
authors.initials: G
authors.lastname: Tragni
authors.forename: Giorgio
authors.initials: G
authors.lastname: Parmiani
authors.forename: Marco A
authors.initials: MA
authors.lastname: Pierotti
authors.forename: Monica
authors.initials: M
authors.lastname: Rodolfo
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000235:genetics; D005260:Female; D019942:Genes, p16; D016158:Genes, p53; D006801:Humans; D008297:Male; D008545:Melanoma / Q000209:etiology / Q000235:genetics* / Q000401:mortality; D008875:Middle Aged; D009154:Mutation; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human