Prevalence, clinicopathologic associations, and molecular spectrum of ERBB2 (HER2) tyrosine kinase mutations in lung adenocarcinomas.
Prevalence, clinicopathologic associations, and molecular spectrum of ERBB2 (HER2) tyrosine kinase mutations in lung adenocarcinomas.
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DOI：
10.1158/1078-0432.ccr-12-0912
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发表时间：
2012-09-15
期刊：
影响因子：
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通讯作者：
Ladanyi M
中科院分区：
文献类型：
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作者：
Arcila ME;Chaft JE;Nafa K;Roy-Chowdhuri S;Lau C;Zaidinski M;Paik PK;Zakowski MF;Kris MG;Ladanyi M
已在肺腺癌（ADC）的一个子集中描述了HER 2酪氨酸激酶结构域（ERBB 2）的激活突变，并且与EGFR和KRAS突变相互排斥。在美国患者中，尚未明确HER 2突变肺ADC的患病率、临床病理学特征、预后意义和分子异质性。首先对肺ADC样本（n=1478）进行EGFR（外显子19和21）和KRAS（外显子2）突变筛查，然后使用大小测定和质谱法评估阴性病例的HER 2突变（外显子19-20）。通过质谱法检测EGFR、KRAS、BRAF、NRAS、PIK 3CA、MEK 1和AKT中的其他复发性点突变。通过FISH评估ALK重排和HER 2扩增。我们确定了25例HER 2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）。与EGFR外显子20中的插入相比，变异性较小，83%（20/24）为12 bp插入，导致密码子775处氨基酸YVMA重复。形态学上，92%（23/25）为中、低分化ADC。在11例同时检测HER 2突变和HER 2扩增的病例中，两者均不相关。HER 2突变在从不吸烟者中更常见（p<0.0001），但与性别，种族或阶段无关。HER 2突变识别了肺ADC的不同子集。鉴于全球肺癌的高患病率以及针对HER 2的标准和研究性疗法的可用性，肺ADC的常规临床基因分型应包括HER 2。
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 US patients. Lung ADC samples (n=1478) 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 performed 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 to insertions in EGFR exon 20, there was less variability, with 83% (20/24) being a 12bp 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.