BRAF/NRAS Mutation Frequencies Among Primary Tumors and Metastases in Patients With Melanoma

Abstract

Purpose The prevalence of BRAF, NRAS, and p16CDKN2A mutations during melanoma progression remains inconclusive. We investigated the prevalence and distribution of mutations in these genes in different melanoma tissues. Patients and Methods In all, 291 tumor tissues from 132 patients with melanoma were screened. Paired samples of primary melanomas (n = 102) and synchronous or asynchronous metastases from the same patients (n = 165) were included. Tissue samples underwent mutation analysis (automated DNA sequencing). Secondary lesions included lymph nodes (n = 84), and skin (n = 36), visceral (n = 25), and brain (n = 44) sites. Results BRAF/NRAS mutations were identified in 58% of primary melanomas (43% BRAF; 15% NRAS); 62% in lymph nodes, 61% subcutaneous, 56% visceral, and 70% in brain sites. Mutations were observed in 63% of metastases (48% BRAF; 15% NRAS), a nonsignificant increase in mutation frequency after progression from primary melanoma. Of the paired samples, lymph nodes (93% consistency) and visceral metastases (96% consistency) presented a highly similar distribution of BRAF/NRAS mutations versus primary melanomas, with a significantly less consistent pattern in brain (80%) and skin metastases (75%). This suggests that independent subclones are generated in some patients. p16CDKN2A mutations were identified in 7% and 14% of primary melanomas and metastases, with a low consistency (31%) between secondary and primary tumor samples. Conclusion In the era of targeted therapies, assessment of the spectrum and distribution of alterations in molecular targets among patients with melanoma is needed. Our findings about the prevalence of BRAF/NRAS/p16CDKN2A mutations in paired tumor lesions from patients with melanoma may be useful in the management of this disease.

Time and tumor type (primary or metastatic) do not influence the detection of BRAF/NRAS mutations in formalin fixed paraffin embedded samples from melanomas

“…We observed discordances between mutations found in the primary melanoma and the SLN and/or the metastasis in some cases. This evidence has already been reported [16]. As previously observed [15,[17][18][19], in some samples we have detected co-occurrence of BRAF and NRAS mutations.…”

Immunohistochemistry is highly sensitive and specific for the detection of NRASQ61R mutation in melanoma

“…Among RAS mutations, NRASQ61R is the most common in the majority of studies. [11][12][13][14][15] These results have been recently confirmed by a retrospective analysis in a large cohort of patients with advanced melanoma who underwent testing for both BRAF (exon 15) and NRAS (exons 1 and 2) mutations. 5 Finally, it is important to underline that NRASQ61R has been reported to correlate with resistance to BRAF inhibitors in preclinical and clinical data.…”

Signaling Pathways Altered During the Metastatic Progression of Melanoma

“…In 2012, Colombino and colleagues analyzed primary and metastatic melanoma samples and found that overall 43% of primary melanomas have mutated BRAF with no significant frequency increase in metastatic lesions [84]. However, Shinozaki and collaborators in 2004 analyzed the BRAF mutation in tumor specimens and showed that this mutation is more frequent in melanoma metastasis (57%) than in primary melanomas (31%), which suggests that it can be acquired during metastasis.…”