MAPK Pathway and TERT Promoter Gene Mutation Pattern and Its Prognostic Value in Melanoma Patients: A Retrospective Study of 2,793 Cases
MAPK Pathway and TERT Promoter Gene Mutation Pattern and Its Prognostic Value in Melanoma Patients: A Retrospective Study of 2,793 Cases
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MAPK通路和TERT启动子基因突变模式及其在黑色素瘤患者中的预后价值：一项2793例的回顾性研究
DOI：
10.1158/1078-0432.ccr-17-0980
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发表时间：
2017-10-15
影响因子：
11.5
通讯作者：
Si, Lu
中科院分区：
文献类型：
--
作者：
Bai, Xue;Kong, Yan;Si, Lu
目的：黑色素瘤的种族差异很明显。本研究旨在全面了解亚洲人群的基因组图谱，更好地了解基因突变状态与临床病理特征和疾病预后的相关性。实验设计：回顾性收集了 2,793 例黑色素瘤患者样本，并通过桑格测序分析了 C-KIT、BRAF、NRAS 和 PDGFRA 编码区以及端粒酶逆转录酶 (TERT) 启动子区的突变。突变与临床病理特征和总生存率相关。结果：BRAF、NRAS、C-KIT、TERT-228、TERT-250 和 PDGFRA 基因内体细胞突变的发生率分别为 23.7%、10.4%、8.0%、5.9%、5.5% 和 1.4%。热点突变分别占BRAF和NRAS突变的95.8%和87.2%；同时，C-KIT和PDGFRA突变表现出更多的异质性。 BRAF、C-KIT 和 NRAS 突变是相互排斥的。 BRAF、C-KIT、NRAS和MAPK通路基因突变数量均为独立的负性预后因素（分别为P = 0.007，其他P < 0.001）。在肢端黑色素瘤中，BRAF、C-KIT 和 NRAS 突变都是总体生存率较差的独立预后因素（均 P < 0.001），而在粘膜黑色素瘤中，只有 C-KIT 是（P = 0.006）。尽管与 BRAF 突变相关（C228T 和 C250T 分别为 P = 0.001 和 P < 0.001），但 TERT 启动子基因突变与总生存期无关（分别为 P = 0.406 和 0.256）。 结论：MAPK 通路和 TERT 启动子基因突变在亚洲人群中存在差异。 BRAF、C-KIT 和 NRAS 突变的预后价值因黑色素瘤亚型而异。针对这些关键途径的临床治疗应直接针对这些预后不良的亚群，以获得最大的潜在影响。 (C) 2017 年 AACR。
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 clinicopathologic characteristics and disease prognosis in the Asian population.Experimental Design: 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.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 the 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 overall survival (all P < 0.001), whereas 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 overall survival (P = 0.406 and 0.256, respectively).Conclusions: 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. (C) 2017 AACR.