BRAF alterations are associated with complex mutational profiles in malignant melanoma

• Published in: Oncogene Vol. 23; no. 35; pp. 5968 - 5977
• Main Authors: DANIOTTI, Maria, OGGIONNI, Maria, FRATTINI, Milo, PILOTTI, Silvana, ANICHINI, Andrea, TRAGNI, Gabrina, PARMIANI, Giorgio, PIEROTTI, Marco A, RODOLFO, Monica, RANZANI, Tiziana, VALLACCHI, Viviana, CAMPI, Valentina, DI STASI, Delia, DELLA TORRE, Gabriella, PERRONE, Federica, LUONI, Chiara, SUARDI, Simona
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 05.08.2004; Nature Publishing Group
• Subjects: Adult; Aged; Aged, 80 and over; Biological and medical sciences; Biopsy; Cell lines; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinases - genetics; Dermatology; Female; Fundamental and applied biological sciences. Psychology; Genes; Genes, p16; Genes, p53; Humans; Kinases; Male; Medical sciences; Melanoma; Melanoma - etiology; Melanoma - genetics; Melanoma - mortality; Metastases; Middle Aged; Missense mutation; Molecular and cellular biology; Mutation; p53 Protein; Phosphoric Monoester Hydrolases - genetics; Promoter Regions, Genetic; Proteins; Proto-Oncogene Proteins; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-raf - genetics; PTEN Phosphohydrolase; PTEN protein; Skin cancer; Tumor Suppressor Proteins - genetics; Tumors; Tumors of the skin and soft tissue. Premalignant lesions; Italy; NRAS; CDKN2A; C-Onc gene; Malignant melanoma; PTEN; melanoma; BRAF; Malignant tumor; Mutation; Carcinogenesis; TP53; Tumor suppressor gene
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1207780

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.