Mounawar Mounia, Mukeria Anush, Le Calvez Florence, Hung Rayjean J, Renard Helene, Cortot Alexis, Bollart Claire, Zaridze David, Brennan Paul, Boffetta Paolo, Brambilla Elisabeth, Hainaut Pierre
IARC, Lyon, France.
Cancer Res. 2007 Jun 15;67(12):5667-72. doi: 10.1158/0008-5472.CAN-06-4229.
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 (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.
表皮生长因子受体（EGFR）酪氨酸激酶结构域的突变在从不吸烟者的非小细胞肺癌（NSCLC）中很常见，而HER2突变则很少见。我们分析了116例NSCLC中EGFR和HER2突变以及细胞周期蛋白依赖性激酶抑制剂2A基因（CDKN2A）的两种产物（p14（arf）和p16（INK4a））的表达情况，这些病例之前已针对患者的吸烟史分析过TP53和KRAS突变。在116个肿瘤中有20个（17%）检测到EGFR突变，而5个（4.3%）肿瘤含有HER2突变。没有肿瘤同时包含这两种突变。在有EGFR或HER2突变的肿瘤中，72%为腺癌，68%来自从不吸烟者，32%来自既往吸烟者。EGFR而非HER2突变与KRAS突变相互排斥。在从不吸烟者中，16个有EGFR突变的肿瘤中有11个也有TP53突变，相比之下，17个无EGFR突变的肿瘤中有2个有TP53突变（P = 0.0008）。与曾经吸烟者（35%）相比，从不吸烟者中p14（arf）而非p16（ink4a）的表达下调更为频繁（62.5%；P = 0.008）。所有有EGFR或HER2突变且TP53野生型的肿瘤均显示p14（arf）表达下调。这些观察结果表明，在有EGFR或HER2突变的肿瘤中，p14（arf）/p53连接的功能失活是必需的，这与这些蛋白是保护细胞免受不合时宜或过度有丝分裂信号影响的故障安全机制的一部分这一观点一致。
