PMID- 29245078 OWN - NLM STAT- MEDLINE DCOM- 20180828 LR - 20180828 IS - 1879-0852 (Electronic) IS - 0959-8049 (Linking) VI - 89 DP - 2018 Jan TI - Analysis of NRAS gain in 657 patients with melanoma and evaluation of its sensitivity to a MEK inhibitor. PG - 90-101 LID - S0959-8049(17)31408-9 [pii] LID - 10.1016/j.ejca.2017.11.011 [doi] AB - BACKGROUND: Neuroblastoma rat-sarcoma (NRAS) mutations have been described in Chinese patients with melanoma. However, the status and the clinical significance of NRAS gain have not been investigated on a large scale. METHODS: A total of 657 melanoma samples were included in the study. NRAS copy number was examined using the QuantiGene Plex DNA assay. The sensitivities of cell lines and patient-derived xenograft (PDX) models containing NRAS gain to a MAP/ERK kinase (MEK) inhibitor (binimetinib) were also evaluated. RESULTS: The overall incidence of NRAS gain was 14.0% (92 of 657). Incidence of NRAS gain in acral, mucosal, chronic sun-induced damage (CSD) and non-CSD melanomas was 12.2%, 15.8%, 9.5% and 19.4%, respectively. NRAS gain was mutually exclusive to NRAS mutations (P = 0.036). The median survival time for melanoma patients with NRAS gain was significantly shorter than that for patients with normal NRAS copy number (P = 0.006). For patients containing NRAS gain, the median survival time for higher copy number (>4 copies) was significantly shorter than those with lower copy number (2-4 copies; P = 0.002). The MEK inhibitor (binimetinib) inhibited the proliferation of melanoma cells and the tumour growth of PDX models with NRAS gain. CONCLUSIONS: NRAS gain is frequent in patients with melanoma and may predict a poor prognosis of melanoma. The melanoma cells and PDX models containing NRAS gain are sensitive to MEK inhibitor (binimetinib), indicating that NRAS gain might be a new therapeutic target for melanoma. CI - Copyright (c) 2017 Elsevier Ltd. All rights reserved. FAU - Yan, Junya AU - Yan J AD - Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing, China. FAU - Wu, Xiaowen AU - Wu X AD - Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing, China. FAU - Yu, Jiayi AU - Yu J AD - Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing, China. FAU - Yu, Huan AU - Yu H AD - Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing, China. FAU - Xu, Tianxiao AU - Xu T AD - Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing, China. FAU - Brown, Kevin M AU - Brown KM AD - Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA. FAU - Bai, Xue AU - Bai X AD - Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing, China. FAU - Dai, Jie AU - Dai J AD - Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing, China. FAU - Ma, Meng AU - Ma M AD - Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing, China. FAU - Tang, Huan AU - Tang H AD - Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing, China. FAU - Si, Lu AU - Si L AD - Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing, China. FAU - Chi, Zhihong AU - Chi Z AD - Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing, China. FAU - Sheng, Xinan AU - Sheng X AD - Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing, China. FAU - Cui, Chuanliang AU - Cui C AD - Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing, China. FAU - Kong, Yan AU - Kong Y AD - Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing, China. Electronic address: k-yan08@163.com. FAU - Guo, Jun AU - Guo J AD - Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing, China. Electronic address: guoj307@126.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20171212 PL - England TA - Eur J Cancer JT - European journal of cancer (Oxford, England : 1990) JID - 9005373 RN - 0 (Membrane Proteins) RN - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases) RN - EC 3.6.1.- (GTP Phosphohydrolases) RN - EC 3.6.1.- (NRAS protein, human) SB - IM MH - Adult MH - Aged MH - Animals MH - Cell Line, Tumor MH - Female MH - GTP Phosphohydrolases/*genetics MH - Gene Dosage MH - Humans MH - Male MH - Melanoma/drug therapy/*genetics/mortality/pathology MH - Membrane Proteins/*genetics MH - Mice MH - Middle Aged MH - Mitogen-Activated Protein Kinase Kinases/*antagonists & inhibitors MH - Mutation OTO - NOTNLM OT - Melanoma OT - NRAS gain OT - Prognosis OT - Targeted therapy EDAT- 2017/12/16 06:00 MHDA- 2018/08/29 06:00 CRDT- 2017/12/16 06:00 PHST- 2017/08/14 00:00 [received] PHST- 2017/10/15 00:00 [revised] PHST- 2017/11/05 00:00 [accepted] PHST- 2017/12/16 06:00 [pubmed] PHST- 2018/08/29 06:00 [medline] PHST- 2017/12/16 06:00 [entrez] AID - S0959-8049(17)31408-9 [pii] AID - 10.1016/j.ejca.2017.11.011 [doi] PST - ppublish SO - Eur J Cancer. 2018 Jan;89:90-101. doi: 10.1016/j.ejca.2017.11.011. Epub 2017 Dec 12.