MAPK pathway and TERT promoter gene mutation pattern and its prognostic value in melanoma patients： a retrospective study of 2793 cases

Purpose: Ethnic differences are conspicuous in melanoma. This study is to obtain a comprehensive view of a genomic landscape and a better understanding of the correlations of gene mutation status with clinicopathological characteristics and disease prognosis in Asian population.<br /><br />Experimental Design: 2793 melanoma patient samples were retrospectively collected and analyzed for mutations in C-KIT, BRAF, NRAS, and PDGFRA coding regions and TERT promoter region by Sanger sequencing. Mutations were correlated to clinicopathological features and overall survival.<br /><br />Results: The incidences of somatic mutations within the BRAF, NRAS, C-KIT, TERT-228, TERT-250, and PDGFRA genes were 23.7%, 10.4% 8.0%, 5.9%, 5.5%, and 1.4%, respectively. Hotspot mutations accounted for 95.8% and 87.2% of BRAF and NRAS mutations, respectively; meanwhile, C-KIT and PDGFRA mutations showed more heterogeneity. BRAF, C-KIT, and NRAS mutations were mutually exclusive. BRAF, C-KIT, NRAS, and numbers of gene mutations of MAPK pathway were all independent negative prognostic factors (P=0.007, other P<0.001, respectively). In acral melanoma, BRAF, C-KIT, and NRAS mutations were all independent prognostic factors of worse OS (all P<0.001); while in mucosal melanoma only C-KIT was (P=0.006). Although correlated with BRAF mutations (P=0.001 and P<0.001 for C228T and C250T, respectively), TERT promoter gene mutations were not correlated with OS (P=0.406 and 0.256, respectively).<br /><br />Conclusions: MAPK pathway and TERT promoter gene mutations are differentially represented in Asian population. Mutations in BRAF, C-KIT, and NRAS have prognostic values that vary by melanoma subtypes. Clinical treatment targeting these critical pathways should be directly at these poor prognosis subpopulations for maximum potential impact.

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