EML4-ALK fusion is linked to histological characteristics in a subset of lung cancers
EML4-ALK fusion is linked to histological characteristics in a subset of lung cancers
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DOI：
10.1097/jto.0b013e31815e8b60
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发表时间：
2008-01-01
影响因子：
20.4
通讯作者：
Ishikawa, Yuichi
中科院分区：
文献类型：
--
作者：
Inamura, Kentaro;Takeuchi, Kengo;Ishikawa, Yuichi
简介：最近，我们在非小细胞肺癌（NSCLC）中发现了棘皮动物微管相关蛋白样4（EML 4）和间变性淋巴瘤激酶（ALK）之间的一种新型融合产物。具有EML 4-ALK融合的肿瘤构成了可能对ALK抑制剂高度敏感的NSCLC亚型。在此，我们提出的EML 4-ALK融合在肺癌的第一个大规模的研究结果。方法：使用EML 4-ALK融合mRNA的逆转录-聚合酶链反应，我们调查了149肺腺癌，48鳞状细胞癌，3大细胞神经内分泌癌，和21小细胞癌。结果：149例腺癌中有5例（3.4%）表达EML 4-ALK融合mRNA，而其他类型腺癌中无表达（0/72）。在所有融合阳性的病例中，免疫组化均能在胞浆中检测到ALK融合蛋白。5例融合病例的特征为2例EML 4-ALK变体1融合和3例变体2融合。组织学上，两例变异1均为混合型腺癌，表现为乳头状和细支气管肺泡成分。有趣的是，所有3例变异体2病例均为腺泡腺癌，这种联系具有统计学显著性（p = 0.00018）。5例融合阳性病例均未显示EGFR或KRAS的任何突变，表明存在相互排斥的关系（p = 0.014）。有没有与吸烟habits.Conclusions：在目前的第一次调查EML 4-ALK融合在肺癌的大型研究（5/221），我们发现了一个有趣的组织型基因型的关系。此外，我们可以通过免疫组织化学检测融合蛋白，指出可能的临床应用。
Introduction: Very recently, we have found a novel fusion product between the echinoderm microtubule-associated protein-like4 (EML4) and the anaplastic lymphoma kinase (ALK) in non-small cell lung cancers (NSCLCs). Tumors featuring EML4-ALK fusion constitute one subtype of NSCLC that might be highly sensitive to ALK inhibitors. Herein, we present results of a first large scale study of EML4-ALK fusion in lung cancers.Methods: Using reverse transcription-polymerase chain reaction for EML4-ALK fusion mRNA, we investigated 149 lung adenocarcinomas, 48 squamous cell carcinomas, 3 large-cell neuroendocrine carcinomas, and 21 small-cell carcinomas. For EML4-ALK-positive cancers, we further investigated the presence of ALK fusion proteins by immunohistochemistry.Results: Five of 149 adenocarcinomas (3.4%) showed EML4-ALK fusion mRNA, this being totally lacking in carcinomas of other types (0/72). In all the fusion-positive cases, ALK fusion protein could be detected in the cytoplasm immunohistochemically. The five fusion cases featured two EML4-ALK variant 1 fusions and three variant 2 fusions. Histologically, both variant 1 cases were mixed type adenocarcinomas, showing papillary with bronchioloalveolar components. Interestingly, all three variant 2 cases were acinar adenocarcinomas, the link being statistically significant (p = 0.00018). None of the five fusion-positive cases demonstrated any mutations of EGFR or KRAS, pointing to a mutually exclusive relationship (p = 0.014). There was no association with smoking habits.Conclusions: In the present first investigation of EML4-ALK fusion in a large study of lung cancers (5/221), we found an interesting histotype-genotype relationship. Furthermore, we could detect the fusion protein by immunohistochemistry, pointing to possible clinical applications.