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BRAF alterations are associated with complex mutational profiles in malignant melanoma

Oncogene volume 23, pages 5968–5977 (2004)Cite this article

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/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.

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Acknowledgements

We gratefully acknowledge the contributions of Marina Castellano, Michela Sosio and Marco Asioli in p16/ARF analysis; Licia Rivoltini and Chiara Castelli for melanoma and LCL lines; Claudia Lombardo for genetic HLA typing; Donata Penso for sequence analysis; Ilaria Bersani and Barbara Vergani for histochemical stainings, Simona Frigerio for MSM analysis, Graziella Pasquini for TP53 sequencing and Grazia Barp for editorial assistance. This study was supported by Italian Association for Cancer Research (AIRC, Milan), CNR-MIUR ‘Progetto Strategico Oncologia’ (02.00385.ST97 to M.A. Pierotti) and the Cariplo Foundation (Milan).

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Authors and Affiliations

  1. Unit of Melanoma Genetics, Istituto Nazionale per lo Studio e la Cura dei Tumori, via Venezian 1, Milan, 20133, Italy

    Maria Daniotti, Tiziana Ranzani, Viviana Vallacchi, Valentina Campi, Delia Di Stasi & Monica Rodolfo

  2. Department of Pathology, Istituto Nazionale per lo Studio e la Cura dei Tumori, via Venezian 1, Milan, 20133, Italy

    Maria Oggionni, Federica Perrone, Chiara Luoni, Simona Suardi, Milo Frattini, Silvana Pilotti & Gabrina Tragni

  3. Unit of Molecular Mechanisms of Tumour Growth and Progression, Istituto Nazionale per lo Studio e la Cura dei Tumori, via Venezian 1, Milan, 20133, Italy

    Gabriella Della Torre & Marco A Pierotti

  4. Unit of Human Tumour Immunobiology, Istituto Nazionale per lo Studio e la Cura dei Tumori, via Venezian 1, Milan, 20133, Italy

    Andrea Anichini

  5. Unit of Immunotherapy of Human Tumours, Istituto Nazionale per lo Studio e la Cura dei Tumori, via Venezian 1, Milan, 20133, Italy

    Giorgio Parmiani

  6. IFOM, FIRC Institute of Molecular Oncology, via Adamello 16, Milan, 20139, Italy

    Marco A Pierotti

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  1. Maria Daniotti
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Correspondence to Monica Rodolfo.

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Daniotti, M., Oggionni, M., Ranzani, T. et al. BRAF alterations are associated with complex mutational profiles in malignant melanoma. Oncogene 23, 5968–5977 (2004). https://doi.org/10.1038/sj.onc.1207780

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