Analysis of NRAS gain in 657 patients with melanoma and evaluation of its sensitivity to a MEK inhibitor
Analysis of NRAS gain in 657 patients with melanoma and evaluation of its sensitivity to a MEK inhibitor
复制标题
657例黑色素瘤患者NRAS增益分析及其对MEK抑制剂敏感性评估
DOI：
10.1016/j.ejca.2017.11.011
复制
发表时间：
2018
影响因子：
8.4
通讯作者：
Guo Jun
中科院分区：
文献类型：
--
作者：
Yan Junya;Wu Xiaowen;Yu Jiayi;Yu Huan;Xu Tianxiao;Brown Kevin M;Bai Xue;Dai Jie;Ma Meng;Tang Huan;Si Lu;Chi Zhihong;Sheng Xinan;Cui Chuanliang;Kong Yan;Guo Jun
背景神经母细胞瘤大鼠肉瘤（NRAS）基因突变在中国黑色素瘤患者中已有报道。方法收集657例恶性黑色素瘤标本，采用QuantiGene法检测NRAS基因拷贝数。细胞系和患者来源的异种移植（PDX）模型containingNRASgain MAP/ERK激酶（MEK）抑制剂（binimetinib）的敏感性也evaluated.ResultsThe总体发病率ofNRASgain为14.0%（92 657）。肢端黑色素瘤、粘膜黑色素瘤、慢性日光损伤黑色素瘤（CSD）黑色素瘤和非CSD黑色素瘤的NRAS基因突变发生率分别为12.2%、15.8%、9.5%和19.4%，NRAS基因突变与NRAS基因突变之间存在显著性差异（P= 0.036）。NRAS拷贝数增加的黑色素瘤患者的中位生存期明显短于NRAS拷贝数正常的黑色素瘤患者（P= 0.006）。对于NRAS基因阳性的患者，高拷贝数（>4拷贝）的中位生存时间明显短于低拷贝数（2-4拷贝;P= 0.002）的患者。MEK抑制剂（binimetinib）抑制黑色素瘤细胞的增殖和PDX模型的肿瘤生长withNRASgain.ConclusionsNRASgain是常见的黑色素瘤患者，并可能预测黑色素瘤的预后不良。含NRASgain的黑色素瘤细胞和PDX模型对MEK抑制剂（binimetinib）敏感，提示NRASgain可能成为黑色素瘤治疗的新靶点。
BackgroundNeuroblastoma rat-sarcoma (NRAS) mutations have been described in Chinese patients with melanoma. However, the status and the clinical significance ofNRASgain have not been investigated on a large scale.MethodsA total of 657 melanoma samples were included in the study.NRAScopy number was examined using the QuantiGene Plex DNA assay. The sensitivities of cell lines and patient-derived xenograft (PDX) models containingNRASgain to a MAP/ERK kinase (MEK) inhibitor (binimetinib) were also evaluated.ResultsThe overall incidence ofNRASgain was 14.0% (92 of 657). Incidence ofNRASgain in acral, mucosal, chronic sun-induced damage (CSD) and non-CSD melanomas was 12.2%, 15.8%, 9.5% and 19.4%, respectively.NRASgain was mutually exclusive toNRASmutations (P= 0.036). The median survival time for melanoma patients withNRASgain was significantly shorter than that for patients with normalNRAScopy number (P= 0.006). For patients containingNRASgain, 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 withNRASgain.ConclusionsNRASgain is frequent in patients with melanoma and may predict a poor prognosis of melanoma. The melanoma cells and PDX models containingNRASgain are sensitive to MEK inhibitor (binimetinib), indicating thatNRASgain might be a new therapeutic target for melanoma.