Increased ALK gene copy number and amplification are frequent in non-small cell lung cancer.
Increased ALK gene copy number and amplification are frequent in non-small cell lung cancer.
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DOI：
10.1097/jto.0b013e3181fb7cd6
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发表时间：
2011-01
期刊：
影响因子：
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通讯作者：
Arriola E
中科院分区：
文献类型：
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作者：
Salido M;Pijuan L;Martínez-Avilés L;Galván AB;Cañadas I;Rovira A;Zanui M;Martínez A;Longarón R;Sole F;Serrano S;Bellosillo B;Wynes MW;Albanell J;Hirsch FR;Arriola E
间变性淋巴瘤激酶（ALK）基因的易位涉及非小细胞肺癌（NSCLC）亚组的肿瘤发生，并可识别对ALK抑制剂敏感的患者。ALK拷贝数变化和扩增在肿瘤（如神经母细胞瘤）中起致癌作用，但在NSCLC中的特征性较差。我们的目的是研究ALK拷贝数变化的患病率及其与ALK蛋白表达、表皮生长因子受体（EGFR）状态和NSCLC患者临床病理学数据的相关性。通过荧光原位杂交（FISH）评价ALK状态。研究了具有ALK易位的标本的棘皮动物微管相关蛋白样4（EML 4）、KIF 5 B和TFG状态。通过免疫组织化学评估ALK表达。检测腺癌中EGFR基因和蛋白的表达情况。进行生存分析。对107例NSCLC病例进行了评价。有两例EML 4-ALK易位病例和一例非典型ALK易位病例。两例EML 4-ALK易位病例均有ALK蛋白表达，而在其余病例中，ALK未检测到。11例病例（10%）显示ALK扩增和68例（63%）拷贝数增加。ALK扩增和EGFR FISH阳性之间存在相关性（p < 0.0001），但与预后无关。总之，EML 4-ALK易位是NSCLC中的罕见事件。该研究揭示了肺腺癌中ALK扩增的显著频率及其与EGFR FISH阳性的相关性。基于这些发现，ALK扩增在NSCLC患者中对ALK抑制剂单用或与EGFR抑制剂联合治疗的反应中的潜在作用值得进一步研究。
Translocation of the anaplastic lymphoma kinase (ALK) gene is involved in the tumorigenesis of a subset of non-small cell lung carcinomas (NSCLCs) and identifies patients sensitive to ALK inhibitors. ALK copy number changes and amplification, which plays an oncogenic role in tumors such as neuroblastoma, are poorly characterized in NSCLC. We aimed to study the prevalence of ALK copy number changes and their correlation to ALK protein expression, epidermal growth factor receptor (EGFR) status, and clinicopathological data in patients with NSCLC. ALK status was evaluated by fluorescence in situ hybridization (FISH). Specimens with ALK translocation were studied for echinoderm microtubule-associated protein-like 4 (EML4), KIF5B, and TFG status. ALK expression was assessed by immunohistochemistry. EGFR gene and protein status were evaluated in adenocarcinomas. Survival analysis was performed. One hundred seven NSCLC cases were evaluated. There were two cases of EML4-ALK translocation and one with an atypical translocation of ALK. Both cases of EML4-ALK translocation had ALK protein expression, whereas in the rest, ALK was undetected. Eleven cases (10%) exhibited ALK amplification and 68 (63%) copy number gains. There was an association between ALK amplification and EGFR FISH positivity (p < 0.0001) but not with prognosis. In conclusion, EML4-ALK translocation is a rare event in NSCLC. The study reveals a significant frequency of ALK amplification and its association with EGFR FISH positivity in lung adenocarcinomas. Based on these findings, a potential role of ALK amplification in the response to ALK inhibitors alone or combined with EGFR inhibitors in NSCLC merits further studies.