Mark M. Awad, Geoffrey R. Oxnard, David M. Jackman, Jennifer C. Heng, Suzanne E. Dahlberg, Pasi A. Jänne, and Peter S. Hammerman, Dana-Farber Cancer Institute; Mark M. Awad, Geoffrey R. Oxnard, David M. Jackman, Daniel O. Savukoski, Dimity Hall, Priyanka Shivdasani, Pasi A. Jänne, Peter S. Hammerman, and Lynette M. Sholl, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Suman Verma, ResearchDX, Irvine; and James Christensen, Mirati Therapeutics, San Diego, CA.
J Clin Oncol. 2016 Mar 1;34(7):721-30. doi: 10.1200/JCO.2015.63.4600. Epub 2016 Jan 4.
Non-small-cell lung cancers (NSCLCs) harboring mutations in MET exon 14 and its flanking introns may respond to c-Met inhibitors. We sought to describe the clinical, pathologic, and genomic characteristics of patients with cancer with MET exon 14 mutations.
We interrogated next-generation sequencing results from 6,376 cancers to identify those harboring MET exon 14 mutations. Clinical characteristics of MET exon 14 mutated NSCLCs were compared with those of NSCLCs with activating mutations in KRAS and EGFR. Co-occurring genomic mutations and copy number alterations were identified. c-Met immunohistochemistry and real-time polymerase chain reaction to detect exon 14 skipping were performed where sufficient tissue was available.
MET exon 14 mutations were identified in 28 of 933 nonsquamous NSCLCs (3.0%) and were not seen in other cancer types in this study. Patients with MET exon 14-mutated NSCLC were significantly older (median age, 72.5 years) than patients with EGFR-mutant (median age, 61 years; P < .001) or KRAS-mutant NSCLC (median age, 65 years; P < .001). Among patients with MET exon 14 mutations, 68% were women, and 36% were never-smokers. Stage IV MET exon 14-mutated NSCLCs were significantly more likely to have concurrent MET genomic amplification (mean ratio of MET to chromosome 7, 4.3) and strong c-Met immunohistochemical expression (mean H score, 253) than stage IA to IIIB MET exon 14-mutated NSCLCs (mean ratio of MET to chromosome 7, 1.4; P = .007; mean H score, 155; P = .002) and stage IV MET exon 14-wild-type NSCLCs (mean ratio of MET to chromosome 7, 1.2; P < .001; mean H score, 142; P < .001). A patient whose lung cancer harbored a MET exon 14 mutation with concurrent genomic amplification of the mutated MET allele experienced a major partial response to the c-Met inhibitor crizotinib.
MET exon 14 mutations represent a clinically unique molecular subtype of NSCLC. Prospective clinical trials with c-Met inhibitors will be necessary to validate MET exon 14 mutations as an important therapeutic target in NSCLC.
含有 MET 外显子 14 及其侧翼内含子突变的非小细胞肺癌（NSCLC）可能对 c-Met 抑制剂有反应。我们旨在描述携带 MET 外显子 14 突变的癌症患者的临床、病理和基因组特征。
我们从 6376 例癌症中进行了下一代测序结果的检测，以确定那些含有 MET 外显子 14 突变的癌症。比较了携带 MET 外显子 14 突变的 NSCLC 患者与 KRAS 和 EGFR 中具有激活突变的 NSCLC 患者的临床特征。鉴定了共存的基因组突变和拷贝数改变。在有足够组织的情况下，进行了 MET 免疫组化和实时聚合酶链反应检测外显子 14 跳跃。
在 933 例非鳞状 NSCLC 中发现了 28 例 MET 外显子 14 突变（3.0%），在本研究中的其他癌症类型中未见。MET 外显子 14 突变的 NSCLC 患者明显比 EGFR 突变（中位年龄 61 岁；P<0.001）或 KRAS 突变（中位年龄 65 岁；P<0.001）的 NSCLC 患者年龄更大（中位年龄 72.5 岁）。在携带 MET 外显子 14 突变的患者中，68%为女性，36%为从不吸烟者。IV 期 MET 外显子 14 突变的 NSCLC 患者明显更可能同时存在 MET 基因组扩增（MET 与 7 号染色体的平均比值为 4.3）和强烈的 MET 免疫组化表达（平均 H 评分 253），而 IA 期至 IIIB 期 MET 外显子 14 突变的 NSCLC（MET 与 7 号染色体的平均比值为 1.4；P=0.007；平均 H 评分 155；P=0.002）和 IV 期 MET 外显子 14 野生型 NSCLC（MET 与 7 号染色体的平均比值为 1.2；P<0.001；平均 H 评分 142；P<0.001）。一名患有携带 MET 外显子 14 突变的肺癌患者，其突变的 MET 等位基因同时发生基因组扩增，对 c-Met 抑制剂克唑替尼有明显的部分缓解反应。
MET 外显子 14 突变代表 NSCLC 的一种临床独特的分子亚型。需要进行前瞻性的 c-Met 抑制剂临床试验，以验证 MET 外显子 14 突变作为 NSCLC 的一个重要治疗靶点。
