BACKGROUND MET exon 14 splice site (METex14) mutations were recently described in Non Small Cell Lung Cancer (NSCLC) and reported to correlate with efficacy of MET tyrosine kinase inhibitors. High diversity of these alterations make 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 overexpression. 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 IFCT Predict.amm cohort of 843 consecutive patients with a treatment-naïve advanced NSCLC who were eligible for a first-line therapy, 108 NSCLC samples with high MET overexpression defined by an immunochemistry (IHC) score 3+ were tested for METex14 mutations using fragment length analysis combined with optimized targeted next generation sequencing (NGS). 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. A MET gene copy number increase was observed in 7 additional patients (7.7%). NGS 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%). CONCLUSION 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 IHC as a surrogate marker for METex14 mutations.

中文翻译：

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简要报告：高 MET 过表达并不能预测 NSCLC 中 MET 外显子 14 剪接突变的存在：IFCT Predict.amm 研究的结果

背景 MET 外显子 14 剪接位点 (METex14) 突变最近在非小细胞肺癌 (NSCLC) 中得到描述，并据报道与 MET 酪氨酸激酶抑制剂的功效相关。这些改变的高度多样性使得它们很难在临床实践中通过 DNA 测序检测到。因为 METex14 突变诱导 MET 受体的稳定性增加，预计这些突变与 MET 过表达有关。我们旨在确定具有高 MET 过表达的 NSCLC 是否可以定义具有高 METex14 突变率的患者子集。方法来自 IFCT Predict.amm 队列，该队列包含 843 名符合一线治疗条件的初治晚期 NSCLC 患者，使用片段长度分析结合优化的靶向二代测序 (NGS) 对 108 个具有高 MET 过表达的免疫化学 (IHC) 评分 3+ 的 NSCLC 样本进行了 METex14 突变检测。MET拷贝数分析也来源于测序数据。结果 两名患者 (2.2%) 检测到 METex14 突变，这些患者也分别表现出 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。NGS 分析显示 TP53 (52.7%) 和 PTEN (1.1%) 的失活突变和 KRAS (28.6%)、EGFR (7.7%)、PIK3CA (4.4%)、BRAF (4.4%)、NRAS (2.2%) 的致癌突变, GNAS (1.1%) 和 IDH1 (1.1%)。结论 高 MET 过表达的 NSCLC 中 METex14 突变率与未选择的 NSCLC 中发现的相似。而且，我们观察到其他致癌基因的驱动改变频率很高。因此，这些发现不支持使用 MET IHC 作为 METex14 突变的替代标记。