BRAF and NRAS Mutations Are Frequent in Nodular Melanoma but Are not Associated with Tumor Cell Proliferation or Patient Survival

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Abstract
Several genes and signalling cascades, including the RAS–RAF–MEK–ERK–MAP kinase pathway, have been implicated in the pathogenesis of cutaneous melanoma. In a previous study, a high frequency of BRAF mutations (66%) was found in a limited number of melanoma specimens ( Davies et al, 2002 x Davies et al., 2002 Davies, H., Bignell, G.R., Cox, C. et al. Mutations of the BRAF gene in human cancer. Nature. 2002; 417: 949–954 Crossref | PubMed | Scopus (6138) | Google Scholar See all References Davies et al, 2002 ), and subsequent studies have supported these findings ( Brose et al, 2002 x Brose et al., 2002 Brose, M.S., Volpe, P., Feldman, M. et al. BRAF and RAS mutations in human lung cancer and melanoma. Cancer Res. 2002; 62: 6997–7000 PubMed | Google Scholar See all References Brose et al, 2002 ; Dong et al, 2003 x Dong et al., 2003 Dong, J., Phelps, R.G., Qiao, R., Yao, S., Benard, O., Ronai, Z., and Aaronson, S.A. BRAF oncogenic mutations correlate with progression rather than initiation of human melanoma. Cancer Res. 2003; 63: 3883–3885 PubMed | Google Scholar See all References Dong et al, 2003 ; Kumar et al, 2003a x Kumar et al., 2003a Kumar, R., Angelini, S., Czene, K., Sauroja, I., Hahka-Kemppinen, M., Pyrhonen, S., and Hemminki, K. BRAF mutations in metastatic melanoma: A possible association with clinical outcome. Clin Cancer Res. 2003; 9: 3362–3368 PubMed | Google Scholar See all References Kumar et al, 2003a ; Yazdi et al, 2003 x Yazdi et al., 2003 Yazdi, A.S., Palmedo, G., Flaig, M.J., Kutzner, H., and Sander, C.A. SP-11 different frequencies of a BRAF point mutation in melanocytic skin lesions. Pigment Cell Res. 2003; 16: 580 Crossref | Google Scholar See all References Yazdi et al, 2003 ; Houben et al, 2004 x Houben et al., 2004 Houben, R., Becker, J.C., Kappel, A., Terheyden, P., Brocker, E.B., Goetz, R., and Rapp, U.R. Constitutive activation of the Ras-Raf signaling pathway in metastatic melanoma is associated with poor prognosis. J Carcinog. 2004; 3: 6 Crossref | PubMed | Scopus (222) | Google Scholar See all References Houben et al, 2004 ). A significantly lower frequency of mutations in BRAF was reported in melanomas from sites with no or minimal sun exposure, as well as sites with evidence of chronic sun damage ( Maldonado et al, 2003 x Maldonado et al., 2003 Maldonado, J.L., Fridlyand, J., Patel, H. et al. Determinants of BRAF mutations in primary melanomas. J Natl Cancer Inst. 2003; 95: 1878–1890 Crossref | PubMed | Google Scholar See all References Maldonado et al, 2003 ). In benign nevi, frequent BRAF mutations (71%–82%) have been described, suggesting an early role of this pathway in the development of some melanomas ( Dong et al, 2003 x Dong et al., 2003 Dong, J., Phelps, R.G., Qiao, R., Yao, S., Benard, O., Ronai, Z., and Aaronson, S.A. BRAF oncogenic mutations correlate with progression rather than initiation of human melanoma. Cancer Res. 2003; 63: 3883–3885 PubMed | Google Scholar See all References Dong et al, 2003 ; Govindarajan et al, 2003 x Govindarajan et al., 2003 Govindarajan, B., Bai, X., Cohen, C. et al. Malignant transformation of melanocytes to melanoma by constitutive activation of mitogen-activated protein kinase kinase (MAPKK) signaling. J Biol Chem. 2003; 278: 9790–9795 Crossref | PubMed | Scopus (95) | Google Scholar See all References Govindarajan et al, 2003 ; Pollock et al, 2003 x Pollock et al., 2003 Pollock, P.M., Harper, U.L., Hansen, K.S. et al. High frequency of BRAF mutations in nevi. Nat Genet. 2003; 33: 19–20 Crossref | PubMed | Scopus (1116) | Google Scholar See all References Pollock et al, 2003 ; Yazdi et al, 2003 x Yazdi et al., 2003 Yazdi, A.S., Palmedo, G., Flaig, M.J., Kutzner, H., and Sander, C.A. SP-11 different frequencies of a BRAF point mutation in melanocytic skin lesions. Pigment Cell Res. 2003; 16: 580 Crossref | Google Scholar See all References Yazdi et al, 2003 ; Kumar et al, 2004 x Kumar et al., 2004 Kumar, R., Angelini, S., Snellman, E., and Hemminki, K. BRAF mutations are common somatic events in melanocytic nevi. J Invest Dermatol. 2004; 122: 342–348 Abstract | Full Text | Full Text PDF | PubMed | Scopus (163) | Google Scholar See all References Kumar et al, 2004 ), along with other factors ( Arbiser, 2003 x Arbiser, 2003 Arbiser, J.L. Activation of B-raf in non-malignant nevi predicts a novel tumor suppressor gene in melanoma (MAP kinase phosphatase). J Invest Dermatol. 2003; 121: xiv Abstract | Full Text | Full Text PDF | PubMed | Scopus (9) | Google Scholar See all References Arbiser, 2003 ). Also, mutations in NRAS have been reported in 5%–33% of melanoma cases ( Demunter et al, 2001 x Demunter et al., 2001 Demunter, A., Stas, M., Degreef, H., De Wolf-Peeters, C., and van den Oord, J.J. Analysis of N- and K-ras mutations in the distinctive tumor progression phases of melanoma. J Invest Dermatol. 2001; 117: 1483–1489 Crossref | PubMed | Scopus (134) | Google Scholar See all References Demunter et al, 2001 ; Omholt et al, 2002 x Omholt et al., 2002 Omholt, K., Karsberg, S., Platz, A., Kanter, L., Ringborg, U., and Hansson, J. Screening of N-ras codon 61 mutations in paired primary and metastatic cutaneous melanomas: Mutations occur early and persist throughout tumor progression. Clin Cancer Res. 2002; 8: 3468–3474 PubMed | Google Scholar See all References Omholt et al, 2002 ; Houben et al, 2004 x Houben et al., 2004 Houben, R., Becker, J.C., Kappel, A., Terheyden, P., Brocker, E.B., Goetz, R., and Rapp, U.R. Constitutive activation of the Ras-Raf signaling pathway in metastatic melanoma is associated with poor prognosis. J Carcinog. 2004; 3: 6 Crossref | PubMed | Scopus (222) | Google Scholar See all References Houben et al, 2004 ). Since the relationship between mutations in BRAF or NRAS and tumor cell proliferation has not been examined in human melanoma, we studied these alterations in 51 nodular melanomas and 18 paired metastases, with a focus on tumor cell proliferation by Ki-67 expression, other markers of aggressive tumors, and prognosis. Our findings support that BRAF or NRAS mutations are present in a subgroup of cutaneous melanoma and subsequent metastases, but there was no apparent association with tumor cell proliferation or patient outcome.