Patterns of EGFR, HER2, TP53, and KRAS mutations of p14arf expression in non-small cell lung cancers in relation to smoking history
Patterns of EGFR, HER2, TP53, and KRAS mutations of p14arf expression in non-small cell lung cancers in relation to smoking history
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DOI：
10.1158/0008-5472.can-06-4229
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发表时间：
2007-06-15
期刊：
影响因子：
11.2
通讯作者：
Hainaut, Pierre
中科院分区：
文献类型：
--
作者：
Mounawar, Mounia;Mukeria, Anush;Hainaut, Pierre
在从不吸烟的非小细胞肺癌(NSCLC)中，表皮生长因子受体EGFR的酪氨酸激酶域的突变很常见，而HER2突变很少见。我们分析了116例NSCLC中的EGFR和HER2突变以及CDKN2A基因的两个产物(p14(Arf)和p16(INK4a))的表达与吸烟史的关系。在116例肿瘤中有20例(17%)检测到EGFR突变，而5例(4.3%)肿瘤含有HER2突变。没有一种肿瘤同时含有这两种突变。在带有EGFR或HER2突变的肿瘤中，72%是腺癌，68%来自从不吸烟的人，32%来自曾经吸烟的人。EGFR突变与KRAS突变互斥，而HER2突变与KRAS突变互斥。在从不吸烟者中，16例有EGFR突变的肿瘤中有11例也有tp53突变，而在17例无EGFR突变的肿瘤中有2例有tp53突变(P=0.0008)。不吸烟者p14(Arf)表达下调的频率(62.5%)高于吸烟者(35%；P=0.008)，但p16(Ink4a)表达下调的频率高于吸烟者。所有具有EGFR或HER2突变的肿瘤和野生型TP53均显示p14(Arf)表达下调。这些观察表明，在带有EGFR或HER2突变的肿瘤中，p14(Arf)/p53连接的功能失活是必需的，这与这些蛋白质是保护细胞免受不及时或过度有丝分裂信号的故障保护机制的一部分的概念一致。
Mutations in the tyrosine kinase domain of the epidermal growth factor receptor EGFR are common in non-small cell lung cancer (NSCLC) of never smokers, whereas HER2 mutations are rare. We have analyzed EGFR and HER2 mutations and the expression of the two products of the CDKN2A gene (p14(arf) and p16(INK4a)) in 116 NSCLC that have been previously analyzed for TP53 and KRAS mutations in relation to smoking history of patients. EGFR mutations were detected in 20 of 116 (17%) tumors, whereas five (4.3%) tumors contained HER2 mutations. No tumor contained both mutations. Of tumors with EGFR or HER2 mutation, 72% were adenocarcinomas, 68% were from never smokers, and 32% were from former smokers. EGFR but not HER2 mutations were mutually exclusive with KRAS mutation. Among never smokers, 11 of 16 tumors with EGFR mutation also had TP53 mutation' in contrast with two of 17 tumors without EGFR mutation inW, (P = 0.0008). Expression of p14(arf), but not p16(ink4a), was more frequently down-regulated in never smokers (62.5%) than ever smokers (35%; P = 0.008). All tumors with EGFR or HER2 mutations and wild-type TP53 showed down-regulation of p14(arf) expression. These observations suggest that functional inactivation of the p14(arf)/p53 connection is required in tumors with EGFR or HER2 mutations, consistent with the notion that these proteins are part of a fail-safe mechanism protecting cells against untimely or excessive mitotic signals.