BRAF alterations are associated with complex mutational profiles in malignant melanoma

Maria Daniotti, Maria Oggionni, Tiziana Ranzani, Viviana Vallacchi, Valentina Campi, Delia Di Stasi, Gabriella Della Torre, Federica Perrone, Chiara Luoni, Simona Suardi, Milo Frattini, Silvana Pilotti, Andrea Anichini, Gabrina Tragni, Giorgio Parmiani, Marco A. Pierotti, Monica Rodolfo

Research output: Contribution to journalArticle

Abstract

To evaluate the mutational profiles associated with BRAF mutations in human melanoma, we have studied BRAF, MAS, 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/ARFΔ + 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.

Original languageEnglish
Pages (from-to)5968-5977
Number of pages10
JournalOncogene
Volume23
Issue number35
DOIs
Publication statusPublished - Aug 5 2004

Keywords

  • BRAF
  • CDKN2A
  • Melanoma
  • NRAS
  • PTEN
  • TP53

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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  • Cite this

    Daniotti, M., Oggionni, M., Ranzani, T., Vallacchi, V., Campi, V., Di Stasi, D., Della Torre, G., Perrone, F., Luoni, C., Suardi, S., Frattini, M., Pilotti, S., Anichini, A., Tragni, G., Parmiani, G., Pierotti, M. A., & Rodolfo, M. (2004). BRAF alterations are associated with complex mutational profiles in malignant melanoma. Oncogene, 23(35), 5968-5977. https://doi.org/10.1038/sj.onc.1207780