MET Exon 14 Mutations in Non-Small-Cell Lung Cancer Are Associated With Advanced Age and Stage-Dependent MET Genomic Amplification and c-Met Overexpression
MET Exon 14 Mutations in Non-Small-Cell Lung Cancer Are Associated With Advanced Age and Stage-Dependent MET Genomic Amplification and c-Met Overexpression
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DOI：
10.1200/jco.2015.63.4600
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发表时间：
2016-03-01
影响因子：
45.3
通讯作者：
Sholl, Lynette M.
中科院分区：
文献类型：
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作者：
Awad, Mark M.;Oxnard, Geoffrey R.;Sholl, Lynette M.
目的Met外显子14及其两侧内含子突变的非小细胞肺癌可能对c-Met抑制剂有反应。我们试图描述MET外显子14突变的癌症患者的临床、病理和基因组特征。患者和方法我们询问了6,376例癌症的下一代测序结果，以识别那些携带MET外显子14突变的患者。比较MET外显子14突变的非小细胞肺癌与KRAS和EGFR激活突变的非小细胞肺癌的临床特征。发现了共生的基因组突变和拷贝数改变。结果在933例非鳞状细胞癌中，28例(3.0%)检测到MET外显子14的突变，而在其他类型的非鳞癌中未检测到突变。MET外显子14突变的非小细胞肺癌患者的年龄(中位年龄，72.5岁)显著高于EGFR突变的患者(中位年龄61岁；P<0.01)或KRAS突变的非小细胞肺癌患者(中位年龄，65岁；P<0.01)。在MET外显子14突变的患者中，68%是女性，36%是从不吸烟的人。与IA-IIIB期MET外显子14突变的NSCLC(MET与7号染色体的平均比率1.4；P=.007；平均H分155；P=.002)和IV期MET外显子14的野生型NSCLC(MET与7号染色体的平均比率1.2；P<；.001；平均H分142；P<；.001)相比，IV期MET外显子14突变的NSCLC更有可能同时出现MET基因组扩增(MET与7号染色体的平均比率为4.3)和c-Met免疫组织化学表达(平均H分，253)。1例肺癌患者携带MET外显子14突变，同时伴有突变的MET等位基因的NT基因组扩增，患者对c-Met抑制剂Crizotinib有较大的部分反应。结论MET外显子14突变是临床上独特的NSCLC分子亚型。有必要对c-Met抑制剂进行前瞻性临床试验，以验证Met外显子14突变是否为NSCLC的重要治疗靶点。(C)2016年度美国临床肿瘤学会
PurposeNon-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.Patients and MethodsWe 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.ResultsMET 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 concurre nt genomic amplification of the mutated MET allele experienced a major partial response to the c-Met inhibitor crizotinib.ConclusionMET 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. (C) 2016 by American Society of Clinical Oncology