Data from <i>MAPK</i> Pathway and <i>TERT</i> Promoter Gene Mutation Pattern and Its Prognostic Value in Melanoma Patients: A Retrospective Study of 2,793 Cases

Abstract

<div>Abstract<p><b>Purpose:</b> 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 clinicopathologic characteristics and disease prognosis in the Asian population.</p><p><b>Experimental Design:</b> A total of 2,793 melanoma patient samples were retrospectively collected and analyzed for mutations in C-KIT, BRAF, NRAS, and PDGFRA coding regions and telomerase reverse transcriptase (TERT) promoter region by Sanger sequencing. Mutations were correlated to clinicopathologic features and overall survival.</p><p><b>Results:</b> 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 the MAPK pathway were all independent negative prognostic factors (<i>P</i> = 0.007, other <i>P</i> < 0.001, respectively). In acral melanoma, BRAF, C-KIT, and NRAS mutations were all independent prognostic factors of worse overall survival (all <i>P</i> < 0.001), whereas in mucosal melanoma, only C-KIT was (<i>P</i> = 0.006). Although correlated with BRAF mutations (<i>P</i> = 0.001 and <i>P</i> < 0.001 for C228T and C250T, respectively), TERT promoter gene mutations were not correlated with overall survival (<i>P</i> = 0.406 and 0.256, respectively).</p><p><b>Conclusions:</b> The MAPK pathway and TERT promoter gene mutations are differentially represented in the 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 aimed directly at these poor-prognosis subpopulations for maximum potential impact. <i>Clin Cancer Res; 23(20); 6120–7. ©2017 AACR</i>.</p></div>