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NRAS and BRAF mutations in melanoma tumours in relation to clinical characteristics: a study based on mutation screening by pyrosequencing

Edlundh-Rose, Esthera; Egyha´zi, Suzanneb; Omholt, Katarinab; Mansson-Brahme, Eva; Platz, Antonb; Hansson, Johanb; Lundeberg, Joakima

doi: 10.1097/01.cmr.0000232300.22032.86

We have previously demonstrated the use of pyrosequencing to investigate NRAS [neuroblastoma RAS viral (v-ras) oncogene homolog] mutations in melanoma biopsies. Here, we expanded the analysis to include BRAF (V-raf murine sarcoma viral oncogene homolog B1), another member of the Ras–Raf–mitogen-activated protein kinase (MAPK) signalling pathway, and analysed a total of 294 melanoma tumours from 219 patients. Mutations in BRAF exons 11 and 15 were identified in 156 (53%) tumours and NRAS exon 2 mutations in 86 (29%) tumours. Overall, mutations in NRAS or BRAF were found in 242 of 294 tumours (82%) and were found to be mutually exclusive in all but two cases (0.7%). Multiple metastases were analysed in 57 of the cases and mutations were identical in all except three, indicating that BRAF and NRAS mutations occur before metastasis. Association with preexisting nevi was significantly higher in BRAF mutated tumours (P=0.014). In addition, tumours with BRAF mutations showed a significantly more frequent moderate to pronounced infiltration of lymphocytes (P=0.013). NRAS mutations were associated with a significantly higher Clark level of invasion (P=0.022) than BRAF mutations. Age at diagnosis was significantly higher in tumours with NRAS mutations than in those with BRAF mutations (P=0.019). NRAS and BRAF mutations, however, did not influence the overall survival from time of diagnosis (P=0.7). In conclusion, the separate genotypes were associated with differences in several key clinical and pathological parameters, indicating differences in the biology of melanoma tumours with different proto-oncogene mutations.

aDepartment of Gene Technology, School of Biotechnology, Royal Institute of Technology (KTH), AlbaNova University Center

bDepartment of Oncology–Pathology, Karolinska Institute, Cancer Centre Karolinska, Karolinska University Hospital Solna, Stockholm, Sweden

Correspondence and requests for reprints to Professor Joakim Lundeberg, PhD, The Royal Institute of Technology, AlbaNova, Roslagstullsbacken 21, Stockholm 11421, Sweden

Tel: +46 8 5537 8327; fax: +46 8 5537 8141; e-mail:

Sponsorship: This investigation was supported by grants from the Swedish Cancer Society, the Research Funds of Radiumhemmet and the Research Funds of Karolinska Institutet, Stockholm Sweden.

Received 21 March 2006 Accepted 8 May 2006

© 2006 Lippincott Williams & Wilkins, Inc.