Somatic mutations of the HER2 kinase domain in lung adenocarcinomas
Somatic mutations of the HER2 kinase domain in lung adenocarcinomas
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DOI：
10.1158/0008-5472.can-04-4235
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发表时间：
2005-03-01
期刊：
影响因子：
11.2
通讯作者：
Gazdar, AF
中科院分区：
文献类型：
--
作者：
Shigematsu, H;Takahashi, T;Gazdar, AF
肺癌中表皮生长因子受体基因（EGFR）突变可预测EGFR激酶抑制剂的敏感性。HER 2（也称为NEU、EGFR 2或ERBB 2）是EGFR受体酪氨酸激酶家族的成员，在某些人类癌症的发病机制中起重要作用，最近在肺癌中报告了突变。我们对671例原发性非小细胞肺癌中HER 2的酪氨酸激酶结构域进行了测序。细胞肺癌（NSCLC）、80个NSCLC细胞系和55个SCLC和其他神经内分泌肺癌以及85个其他上皮癌（乳腺癌、膀胱癌、前列腺癌和结直肠癌），并将突变状态与临床病理学特征和EGFR或KRAS突变的存在进行比较。1.6%（11/671）的NSCLC中存在HER 2突变，其他类型的癌症中不存在。只有一个腺癌细胞系（NCI-H1781）有突变。所有HER 2突变均为外显子20中的框内插入，并且靶向与EGFR插入相同的相应区域。HER 2突变在从不吸烟者（3.2%，8/248; P = 0.02）和腺癌组织学（2.8%，11/394; P = 0.003）中显著更常见。在394例腺癌病例中，与其他种族（0.7%）相比，HER 2突变优先靶向东方种族（3.9%），女性（3.6%）与男性（1.9%）相比，从不吸烟者（4.1%）与吸烟者（1.4%）相比。EGFR、HER 2和KRAS基因的突变从未同时出现在单个肿瘤和细胞系中。EGFR和HER 2基因突变的显著相似性涉及肿瘤类型和亚型、突变类型、基因位置和靶向的特定患者亚群，这是前所未有的，表明病因相似。EGFR、HER 2和KRAS突变是相互排斥的，表明吸烟者和从不吸烟者肺癌的不同途径。
Mutations in the epidermal growth factor receptor gene (EGFR) in lung cancers predict for sensitivity to EGFR kinase inhibitors. HER2 (also known as NEU, EGFR2, or ERBB2) is a member of the EGFR family of receptor tyrosine kinases and plays important roles in the pathogenesis of certain human cancers, and mutations have recently been reported in lung cancers. We sequenced the tyrosine kinase domain of HER2 in 671 primary non-small. cell lung cancers (NSCLC), 80 NSCLC cell lines, and 55 SCLCs and other neuroendocrine lung tumors as well as 85 other epithelial cancers (breast, bladder, prostate, and colorectal cancers) and compared the mutational status with clinicopathologic features and the presence of EGFR or KRAS mutations. HER2 mutations were present in 1.6% (11 of 671) of NSCLC and were absent in other types of cancers. Only one adenocarcinoma cell line (NCI-H1781) had a mutation. All HER2 mutations were in-frame insertions in exon 20 and target the identical corresponding region as did EGFR insertions. HER2 mutations were significantly more frequent in never smokers (3.2%, 8 of 248; P = 0.02) and adenocarcinoma histology (2.8%, 11 of 394; P = 0.003). In 394 adenocarcinoma cases, HER2 mutations preferentially targeted Oriental ethnicity (3.9%) compared with other ethnicities (0.7%), female gender (3.6%) compared with male gender (1.9%) and never smokers (4.1%) compared with smokers (1.4%). Mutations in EGFR, HER2, and KRAS genes were never present together in individual tumors and cell lines. The remarkable similarities of mutations in EGFR and HER2 genes involving tumor type and subtype, mutation type, gene location, and specific patient subpopulations targeted are unprecedented and suggest similar etiologic factors. EGFR, HER2, and KRAS mutations are mutually exclusive, suggesting different pathways to lung cancer in smokers and never smokers.