In
melanoma, the
mitogen-activated
protein (MAP)
kinase pathway plays a crucial oncogenic role. Recent studies identified additional genetic alterations, eg, TERT-promoter mutations. Up to 8% of
melanoma patients present with multiple primary
melanomas (
MPMs). The pathogenesis is not fully understood, and data on the genetic diversity of
MPMs are limited. To identify putative diagnostic and therapeutic consequences, we assessed the mutational status of the BRAF and NRAS genes and TERT promoter in patients with
MPMs. The study cohort consisted of 96 patients with 237
malignant melanomas. The BRAF, NRAS, and TERT-promoter genotypes were assessed in all
MPMs and were correlated with patients' clinicopathological characteristics. BRAF mutations were found in 84
melanomas (35.4%), NRAS mutations, in 33 (14.0%); and TERT-promoter mutations, in 112 (47.3%). Mutation patterns were concordant between first and subsequent primary
tumors in 23.9% of patients and were discordant in 61.4% of patients. The genetic alterations were partially different in 14.7% of patients. By Cox regression analysis, only the NRAS mutation had a significant negative prognostic impact on time to progression to stage III (P = 0.016) and on distant
metastasis-free survival (P = 0.032). In the majority of primary
melanomas in patients with
MPMs, BRAF, NRAS, and TERT-promoter genotypes were discordant. Thus, molecular testing for targeted
therapy should be performed on metastatic tissue and not on primary
tumors.