Department of Pathology, and Thoracic Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Clin Cancer Res. 2012 Sep 15;18(18):4910-8. doi: 10.1158/1078-0432.CCR-12-0912. Epub 2012 Jul 3.
Activating mutations in the tyrosine kinase domain of HER2 (ERBB2) have been described in a subset of lung adenocarcinomas (ADCs) and are mutually exclusive with EGFR and KRAS mutations. The prevalence, clinicopathologic characteristics, prognostic implications, and molecular heterogeneity of HER2-mutated lung ADCs are not well established in U.S. patients.
Lung ADC samples (N = 1,478) were first screened for mutations in EGFR (exons 19 and 21) and KRAS (exon 2), and negative cases were then assessed for HER2 mutations (exons 19-20) using a sizing assay and mass spectrometry. Testing for additional recurrent point mutations in EGFR, KRAS, BRAF, NRAS, PIK3CA, MEK1, and AKT was conducted by mass spectrometry. ALK rearrangements and HER2 amplification were assessed by FISH.
We identified 25 cases with HER2 mutations, representing 6% of EGFR/KRAS/ALK-negative specimens. Small insertions in exon 20 accounted for 96% (24/25) of the cases. Compared with insertions in EGFR exon 20, there was less variability, with 83% (20/24) being a 12 bp insertion causing duplication of amino acids YVMA at codon 775. Morphologically, 92% (23/25) were moderately or poorly differentiated ADC. HER2 mutation was not associated with concurrent HER2 amplification in 11 cases tested for both. HER2 mutations were more frequent among never-smokers (P < 0.0001) but there were no associations with sex, race, or stage.
HER2 mutations identify a distinct subset of lung ADCs. Given the high prevalence of lung cancer worldwide and the availability of standard and investigational therapies targeting HER2, routine clinical genotyping of lung ADC should include HER2.
在一部分肺腺癌（ADC）中已发现 HER2（ERBB2）酪氨酸激酶结构域的激活突变，且与 EGFR 和 KRAS 突变互斥。HER2 突变型肺 ADC 在美籍患者中的流行率、临床病理特征、预后意义和分子异质性尚不清楚。
首先对 1478 例肺 ADC 样本进行 EGFR（外显子 19 和 21）和 KRAS（外显子 2）突变筛查，阴性病例随后使用测序分析和质谱法评估 HER2 突变（外显子 19-20）。通过质谱法对 EGFR、KRAS、BRAF、NRAS、PIK3CA、MEK1 和 AKT 的其他常见点突变进行检测。通过 FISH 检测 ALK 重排和 HER2 扩增。
我们发现了 25 例 HER2 突变病例，占 EGFR/KRAS/ALK 阴性标本的 6%。外显子 20 的小插入占 96%（24/25）的病例。与 EGFR 外显子 20 的插入相比，其变异性更小，83%（20/24）是导致 775 密码子处 YVMA 氨基酸重复的 12bp 插入。形态学上，92%（23/25）为中或低分化 ADC。在 11 例同时检测到两种情况的病例中，HER2 突变与同时的 HER2 扩增无关。HER2 突变在从不吸烟者中更为常见（P <0.0001），但与性别、种族或分期无关。
HER2 突变确定了肺 ADC 的一个独特亚群。鉴于全球肺癌的高患病率和针对 HER2 的标准和研究性治疗方法的可用性，肺 ADC 的常规临床基因分型应包括 HER2。
