Guo Yongjun, Ma Jie, Lyu Xiaodong, Liu Hai, Wei Bing, Zhao Jiuzhou, Fu Shuang, Ding Lu, Zhang Jihong
Hematology Laboratory of Hematology Malignancy Treatment Center, Shengjing Hospital of China Medical University, No, 39 Huaxiang Road, Tiexi District, Shenyang, Liaoning 100022, China.
BMC Cancer. 2014 Nov 18;14:834. doi: 10.1186/1471-2407-14-834.
The translocations of the anaplastic lymphoma kinase (ALK) gene with the echinoderm microtubule-associated protein-like 4 (EML4) gene on chromosome 2p have been identified in non-small-cell lung cancers (NSCLCs) as oncogenic driver mutations. It has been suggested that EML4-ALK fusion is associated with the resistance in NSCLCs to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), such as gefitinib and erlotinib. In contrast, ALK tyrosine kinase inhibitor (ALK TKI) crizotinib has shown superior effects in combating NSCLCs with EML4-ALK. Thus, characterization of EML4-ALK fusion genes and clinical features of resulting carcinomas would be a great benefit to disease diagnosis and designing customized treatment plans. Studies have suggested that EML4-ALK translocation occurs more frequently in never-smokers with NSCLC, especially in female patients. However, it is not clear whether this is the case in male patients, too. In this study, we have determined the frequency of EML4-ALK translocation in male never-smokers with NSCLC in a cohort of Chinese patients. The clinical features associated with EML4-ALK translocation were also investigated.
A cohort of 95 Chinese male never-smokers with NSCLC was enrolled in this study. EML4-ALK fusion genes were detected using one-step real time RT-PCR and DNA sequencing. We further determined the expression levels of ALK mRNA by RT-PCR and ALK protein by immunohistochemistry in these specimens. The clinical features of EML4-ALK-positive carcinomas were also determined.
We have identified EML4-ALK fusion genes in 8 out of 95 carcinoma cases, accounting for 8.42% in Chinese male never-smokers with NSCLC. It is significantly higher than that in all Chinese male patients (3.44%) regardless smoking habit. It is also significantly higher than that in all Chinese smokers (8/356 or 2.25%) or in smokers worldwide (2.9%) by comparing to published data. Interestingly, EML4-ALK fusion genes are more frequently found in younger patients and associated with less-differentiated carcinomas.
The frequency of EML4-ALK translocation is strongly associated with smoking habits in Chinese male patients with higher frequency in male never-smokers. EML4-ALK translocation is associated with early-onset and less-differentiated carcinomas.
在非小细胞肺癌（NSCLC）中，间变性淋巴瘤激酶（ALK）基因与2号染色体上的棘皮动物微管相关蛋白样4（EML4）基因易位已被确定为致癌驱动突变。有人提出，EML4-ALK融合与NSCLC对表皮生长因子受体酪氨酸激酶抑制剂（EGFR TKIs），如吉非替尼和厄洛替尼的耐药性有关。相比之下，ALK酪氨酸激酶抑制剂（ALK TKI）克唑替尼在对抗伴有EML4-ALK的NSCLC方面显示出更好的效果。因此，对EML4-ALK融合基因的特征及由此产生的癌的临床特征进行研究，将对疾病诊断和制定个性化治疗方案大有裨益。研究表明，EML4-ALK易位在NSCLC的从不吸烟者中更常见，尤其是女性患者。然而，男性患者是否也是如此尚不清楚。在本研究中，我们确定了中国一组男性NSCLC从不吸烟者中EML4-ALK易位的频率。还对与EML4-ALK易位相关的临床特征进行了研究。
本研究纳入了95名中国男性NSCLC从不吸烟者。使用一步实时RT-PCR和DNA测序检测EML4-ALK融合基因。我们进一步通过RT-PCR测定这些标本中ALK mRNA的表达水平，并通过免疫组织化学测定ALK蛋白的表达水平。还确定了EML4-ALK阳性癌的临床特征。
我们在95例癌病例中的8例中鉴定出EML4-ALK融合基因，在中国男性NSCLC从不吸烟者中占8.42%。这显著高于所有中国男性患者（3.44%），无论其吸烟习惯如何。与已发表的数据相比，这也显著高于所有中国吸烟者（8/356或2.25%）或全球吸烟者（2.9%）。有趣的是，EML4-ALK融合基因在年轻患者中更常见，且与低分化癌相关。
在中国男性患者中，EML4-ALK易位的频率与吸烟习惯密切相关，在从不吸烟者中频率更高。EML4-ALK易位与早发和低分化癌相关。
