EGFR exon 20 insertion mutations in lung adenocarcinomas: prevalence, molecular heterogeneity, and clinicopathologic characteristics.
EGFR exon 20 insertion mutations in lung adenocarcinomas: prevalence, molecular heterogeneity, and clinicopathologic characteristics.
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DOI：
10.1158/1535-7163.mct-12-0620
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发表时间：
2013-02
影响因子：
5.7
通讯作者：
Ladanyi M
中科院分区：
文献类型：
--
作者：
Arcila ME;Nafa K;Chaft JE;Rekhtman N;Lau C;Reva BA;Zakowski MF;Kris MG;Ladanyi M
与肺腺癌中的其他原发性EGFR突变相反，EGFR外显子20中的插入通常与EGFR酪氨酸激酶抑制剂耐药相关。它们的分子谱、临床病理特征和患病率尚未完全确定。通过对1500例肺腺癌进行算法筛选，确定携带EGFR 20号外显子插入的肿瘤。首先检测病例的EGFR（外显子19和21）和KRAS（外显子2）常见突变，如果阴性，则进一步分析EGFR外显子20插入。通过质谱法对所有样本进行EGFR、KRAS、BRAF、NRAS、PIK3CA、MEK 1和AKT中其他驱动突变的扩展基因分型;对一个子集进行ALK重排评价。我们确定了33例EGFR 20号外显子插入病例（2.2%，95% CI 1.6 - 3.1%），所有病例均与检测的其他基因突变（PIK3CA除外）互斥。在从不吸烟者中更常见（p <0.0001）。与年龄、性别、种族或分期无关。形态学上，肿瘤与常见EGFR突变的肿瘤相似，但组织学上常见实体瘤。插入在位置和大小上高度可变，范围从3至12bp，导致13种不同的插入，通过分子建模，预测其对厄洛替尼结合具有潜在的不同影响。EGFR 20号外显子插入检测可识别一个独特的肺腺癌亚组，占所有EGFR突变病例的至少9%，是继19号外显子缺失和L858 R之后第三种最常见的EGFR突变类型。插入在结构上是异质的，对EGFR抑制剂的反应具有潜在影响。
In contrast to other primary EGFR mutations in lung adenocarcinomas, insertions in exon 20 of EGFR have been generally associated with resistance to EGFR tyrosine kinase inhibitors. Their molecular spectrum, clinicopathologic characteristics and prevalence are not well established. Tumors harboring EGFR exon 20 insertions were identified through an algorithmic screen of 1500 lung adenocarcinomas. Cases were first tested for common mutations in EGFR (exons 19 and 21) and KRAS (exon 2) and, if negative, further analyzed for EGFR exon 20 insertions. All samples underwent extended genotyping for other driver mutations in EGFR, KRAS, BRAF, NRAS, PIK3CA, MEK1 and AKT by mass spectrometry; a subset was evaluated for ALK rearrangements. We identified 33 EGFR exon 20 insertion cases (2.2%, 95% CI 1.6 to 3.1%), all mutually exclusive with mutations in the other genes tested (except PIK3CA). They were more common among never-smokers (p<0.0001). There was no association with age, sex, race, or stage. Morphologically, tumors were similar to those with common EGFR mutations, but with frequent solid histology. Insertions were highly variable in position and size, ranging from 3 to 12bp, resulting in 13 different insertions which, by molecular modeling, are predicted to have potentially different effects on erlotinib binding. EGFR exon 20 insertion testing identifies a distinct subset of lung adenocarcinomas, accounting for at least 9% of all EGFR mutated cases, representing the third most common type of EGFR mutation after exon 19 deletions and L858R. Insertions are structurally heterogeneous with potential implications for response to EGFR inhibitors.