High MET Overexpression Does Not Predict the presence of MET exon 14 Splice Mutations in NSCLC: Results From the IFCT PREDICT.amm study
High MET Overexpression Does Not Predict the presence of MET exon 14 Splice Mutations in NSCLC: Results From the IFCT PREDICT.amm study
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DOI：
10.1016/j.jtho.2019.09.196
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发表时间：
2020-01-01
影响因子：
20.4
通讯作者：
Cortot, Alexis B.
中科院分区：
文献类型：
--
作者：
Baldacci, Simon;Figeac, Martin;Cortot, Alexis B.
简介：最近在 NSCLC 中描述了 MET 原癌基因 (MET) 外显子 14 剪接位点 (METex14) 突变，并据报道与 MET 酪氨酸激酶抑制剂的疗效相关。这些改变的高度多样性使得它们在临床实践中很难通过 DNA 测序来检测。由于 METex14 突变会诱导 MET 受体的稳定性增强，因此预计这些突变与 MET 过度表达有关。我们的目的是确定具有高 MET 过表达的 NSCLC 是否可以定义一个具有高 METex14 突变率的患者子集。方法：从法国胸腔组间 PREDICT.amm 队列中，连续 843 例符合一线治疗条件的初治晚期 NSCLC 患者中，使用片段长度分析结合优化靶向，对 108 个由免疫化学评分 3+ 定义的高 MET 过表达 NSCLC 样本进行了 METex14 突变检测。下一代测序。 MET 拷贝数分析也源自测序数据。结果：在两名患者 (2.2%) 中检测到 METex14 突变，他们还分别表现出 TP53 突变和 PIK3CA 突变。在另外 7 名患者 (7.7%) 中观察到 MET 基因拷贝数增加。下一代测序分析显示TP53（52.7%）和PTEN（1.1%）的失活突变，以及KRAS（28.6%）、EGFR（7.7%）、PIK3CA（4.4%）、BRAF（4.4%）、NRAS（2.2%）、GNAS（1.1%）和IDH1（1.1%）的致癌突变。结论： MET 高表达的 NSCLC 中的 METex14 突变与未选择的 NSCLC 中发现的相似。此外，我们观察到其他致癌基因的驱动基因改变频率很高。因此，这些发现不支持使用 MET 免疫组织化学作为 METex14 突变的替代标记。 (C) 2019 年国际肺癌研究协会。由爱思唯尔公司出版。保留所有权利。
Introduction: MET proto-oncogene (MET) exon 14 splice site (METex14) mutations were recently described in NSCLC and has been reported to correlate with efficacy of MET tyrosine kinase inhibitors. High diversity of these alterations makes them hard to detect by DNA sequencing in clinical practice. Because METex14 mutations induce increased stabilization of the MET receptor, it is anticipated that these mutations are associated with MET over-expression. We aim to determine whether NSCLC with high MET overexpression could define a subset of patients with a high rate of METex14 mutations.Methods: From The French Cooperative Thoracic Intergroup PREDICT.amm cohort of 843 consecutive patients with a treatment-naive advanced NSCLC who were eligible for a first-line therapy, 108 NSCLC samples with high MET overexpression defined by an immunochemistry score 3+ were tested for METex14 mutations using fragment length analysis combined with optimized targeted next-generation sequencing. MET copy number analysis was also derived from the sequencing data.Results: METex14 mutations were detected in two patients (2.2%) who also displayed a TP53 mutation and a PIK3CA mutation, respectively. An MET gene copy number increase was observed in seven additional patients (7.7%). Next-generation sequencing analysis revealed inactivating mutations in TP53 (52.7%) and PTEN (1.1%), and oncogenic mutations in KRAS (28.6%), EGFR (7.7%), PIK3CA (4.4%), BRAF (4.4%), NRAS (2.2%), GNAS (1.1%), and IDH1 (1.1%).Conclusions: The rate of METex14 mutations in NSCLC with high MET overexpression was similar to that found in unselected NSCLC. Moreover, we observed a high frequency of driver alterations in other oncogenes. Consequently these findings do not support the use of MET immunohistochemistry as a surrogate marker for METex14 mutations. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.