HER2 Amplification and HER2 Mutation Are Distinct Molecular Targets in Lung Cancers.
HER2 Amplification and HER2 Mutation Are Distinct Molecular Targets in Lung Cancers.
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DOI：
10.1016/j.jtho.2015.10.025
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发表时间：
2016-03
期刊：
影响因子：
--
通讯作者：
Arcila ME
中科院分区：
文献类型：
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作者：
Li BT;Ross DS;Aisner DL;Chaft JE;Hsu M;Kako SL;Kris MG;Varella-Garcia M;Arcila ME
人表皮生长因子受体2（HER 2，ERBB 2）的改变已被确定为肺癌的致癌驱动因子和潜在的治疗靶点。肺癌中HER 2基因扩增、突变和HER 2蛋白过表达的分子相关性尚未明确定义。为了探索这些关联，Memorial Sloan Kettering和科罗拉多大学结合了他们关于肺癌中HER 2改变的数据。对175例既往未接受过靶向治疗的肺腺癌患者的肿瘤标本进行了HER 2扩增、突变和HER 2蛋白过表达的评估。通过荧光原位杂交（FISH）评估扩增，并定义为HER 2/CEP 17比值≥2.0。通过片段分析、质谱基因分型和桑格测序评估突变。通过免疫组织化学（IHC）评估过表达。计算HER 2扩增、突变和HER 2过表达的频率，并检查其重叠。在175例病例中有5例（3%）通过FISH检测到HER 2扩增。148例标本中有4例（3%）检测到HER 2突变，包括3个相同的12 bp插入（p.A775_G776insYVMA）和1个9 bp插入，均位于外显子20。HER 2突变病例均未扩增。在25份可用于检测的标本中，未检测到IHC上的HER 2过表达（2+、3+），且阴性IHC与FISH阴性结果相关。HER 2突变与HER 2扩增无关，提示不同的实体和治疗靶点。“HER 2阳性肺癌”可能不是一个适当的术语，HER 2靶向药物研究的患者队列应根据存在的特定HER 2改变来定义。
Human epidermal growth factor receptor 2 (HER2, ERBB2) alterations have been identified as oncogenic drivers and potential therapeutic targets in lung cancers. The molecular associations of HER2 gene amplification, mutation, and HER2 protein overexpression in lung cancers have not been distinctly defined. To explore these associations, Memorial Sloan Kettering and University of Colorado combined their data on HER2 alterations in lung cancers. Tumor specimens from 175 patients with lung adenocarcinomas with no prior targeted therapy were evaluated for the presence of HER2 amplification, mutation, and HER2 protein overexpression. Amplification was assessed by fluorescence in-situ hybridization (FISH) and defined as HER2/CEP17 ratio ≥2.0. Mutation was assessed by fragment analysis, mass spectrometry genotyping and Sanger sequencing. Overexpression was assessed by immunohistochemistry (IHC). The frequencies of HER2 amplification, mutation and HER2 overexpression were calculated and their overlap examined. HER2 amplification by FISH was detected in 5 of 175 (3%) cases. HER2 mutation was detected in 4 of 148 (3%) specimens, including 3 identical 12bp insertions (p.A775_G776insYVMA) and a 9bp insertion, all in exon 20. None of the HER2 mutant cases were amplified. HER2 overexpression (2+, 3+) on IHC was not detected in the 25 specimens available for testing and negative IHC correlated with negative results on FISH. HER2 mutations are not associated with HER2 amplification suggesting a distinct entity and therapeutic target. “HER2-positive lung cancer” may not be an adequate term and patient cohorts for the study of HER2 targeted agents should be defined by the specific HER2 alteration present.