EML4-ALK Rearrangement in Non-Small Cell Lung Cancer and Non-Tumor Lung Tissues
EML4-ALK Rearrangement in Non-Small Cell Lung Cancer and Non-Tumor Lung Tissues
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DOI：
10.2353/ajpath.2009.080755
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发表时间：
2009-02-01
影响因子：
6
通讯作者：
Falini, Brunangelo
中科院分区：
文献类型：
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作者：
Martelli, Maria Paola;Sozzi, Gabriella;Falini, Brunangelo
最近在非小细胞肺癌（NSCLC）的一个亚群中发现了一种融合基因，即enchinoderm微管相关蛋白样4-间变性淋巴瘤激酶（EML4-ALK），具有转化活性，但其发病、诊断和治疗作用尚不清楚。采用反转录PCR技术对意大利和西班牙120例冷冻非小细胞肺癌标本中EML4-ALK转录本的频率和类型进行了研究；选取远离肿瘤的非肿瘤性肺组织作为对照。在携带融合转录物的病例中，我们使用荧光原位杂交、Western blotting和免疫沉淀检测EML4-ALK基因和蛋白水平。我们还分析了662例NSCLC标本石蜡样品中的ALK蛋白水平，其中包括分子研究中调查的120例。EML4-ALK转录本（变体I和3）在120例非小细胞肺癌样本中的9例中检测到，但并非针对非小细胞肺癌，因为它们也存在于远离肿瘤的非癌性肺组织中。值得注意的是，在这些患者的匹配肿瘤样本中没有检测到转录本。对表达EML4-ALK转录本的病例进行荧光原位杂交分析显示，只有少数细胞携带EML4-ALK基因。通过免疫组织化学、免疫印迹和免疫沉淀检测，这些病例均未发现表达EML4-ALK蛋白。EML4-ALK转录本不能作为非小细胞肺癌的特异性诊断工具。因此，我们的研究结果表明，EML4-ALK作为治疗靶点的因果作用和价值仍有待确定。（美国病理杂志2009,174:661-670;DOI: 10.2353/ajpath.2009.080755）
A fusion gene, enchinoderm microtubule associated protein like 4 - anaplastic lymphoma kinase (EML4-ALK), with transforming activity has recently been identified in a subset of non-small cell lung cancer (NSCLC), but its pathogenetic, diagnostic, and therapeutic roles remain unclear. Both frequency and type of EML4-ALK transcripts were investigated by reverse transcription PCR in 120 frozen NSCLC specimens from Italy and Spain; non-neoplastic lung tissues taken far from the tumor were used as controls. in cases carrying the fusion transcript, we determined EML4-ALK gene and protein levels using fluorescence in situ hybridization, Western blotting, and immunoprecipitation. We also analyzed ALK protein levels in paraffin samples from 662 NSCLC specimens, including the 120 cases investigated in the molecular studies. EML4-ALK transcripts (variants I and 3) were detected in 9 of 120 NSCLC samples but were not specific for NSCLC since they were also found in non-cancerous lung tissues taken far from the tumor. Notably, no transcripts were detected in matching tumor samples from these patients. Fluorescence in situ hybridization analysis of cases expressing EML4-ALK transcripts showed that only a minority of cells harbored the EML4-ALK gene. None of these cases was found to express the EML4-ALK protein as examined by immunohistochemistry, Western blotting, and immunoprecipitation. The EML4-ALK transcript cannot be regarded as a specific diagnostic tool for NSCLC. Our results show therefore that the causal role and value of EML4-ALK as a therapeutic target remain to be defined. (Am J Pathol 2009, 174:661-670; DOI: 10.2353/ajpath.2009.080755)