BRAF/NRAS mutation frequencies among primary tumors and metastases in patients with melanoma.

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.