Exon Array Profiling Detects EML4-ALK Fusion in Breast, Colorectal, and Non-Small Cell Lung Cancers
Exon Array Profiling Detects EML4-ALK Fusion in Breast, Colorectal, and Non-Small Cell Lung Cancers
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DOI：
10.1158/1541-7786.mcr-08-0522
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发表时间：
2009-09-01
影响因子：
5.2
通讯作者：
Modrusan, Zora
中科院分区：
文献类型：
--
作者：
Lin, Eva;Li, Li;Modrusan, Zora
棘皮动物微管相关蛋白样4-间变性淋巴瘤激酶（EML 4-ALK）融合基因已被鉴定为非小细胞肺癌（NSCLC）亚组中的癌基因。我们使用外显子阵列上的癌症基因组分析来开发一种用于基因重排的全局搜索的新计算方法。这种方法导致除了NSCLC之外，还在乳腺癌和结直肠癌中检测到EML 4-ALK融合。对大量患者肿瘤样本的筛查显示，2.4%的乳腺癌（5/209）、2.4%的结直肠癌（2/83）和11.3%的NSCLC（12/106）存在EML 4-ALK融合。除了先前已知的EML 4-ALK变体1（E13; A20）和2（E20; A20）外，在结直肠癌中发现了一种新的变体E21; A20。通过鉴定代表乳腺、结肠和NSCLC的肿瘤样本中的基因组融合点，验证是否存在EML-ALK重排。荧光原位杂交试验也证实了EML 4-ALK易位，这表明其在原发性肿瘤和肿瘤衍生细胞系中具有实质性异质性。为了阐明EML 4-ALK的功能意义，我们检查了通过小干扰RNA沉默EML 4和ALK后携带融合的细胞系的生长。在一些但不是所有细胞系中观察到显著的生长抑制，表明它们对ALK介导的细胞存活信号传导的可变依赖性。总的来说，这些发现显示了EML 4-ALK融合在多种实体瘤中的复发，并进一步证实了其在肿瘤发生中的作用。(Mol Cancer Res 2009;7（9）：1466-76）
The echinoderm, microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion gene has been identified as an oncogene in a subset of non-small cell lung cancers (NSCLC). We used profiling of cancer genomes on an exon array to develop a novel computational method for the global search of gene rearrangements. This approach led to the detection of EML4-ALK fusion in breast and colorectal carcinomas in addition to NSCLC. Screening of a large collection of patient tumor samples showed the presence of EML4-ALK fusion in 2.4% of breast (5 of 209),2.4% of colorectal (2 of 83), and in 11.3% of NSCLC (12 of 106). Besides previously known EML4-ALK variants 1 (E13; A20) and 2 (E20; A20), a novel variant E21; A20 was found in colorectal carcinoma. The presence of an EML-ALK rearrangement was verified by identifying genomic fusion points in tumor samples representative of breast, colon, and NSCLC. EML4-ALK translocation was also confirmed by fluorescence in situ hybridization assay, which revealed its substantial heterogeneity in both primary tumors and tumor-derived cell lines. To elucidate the functional significance of EML4-ALK, we examined the growth of cell lines harboring the fusion following EML4 and ALK silencing by small interfering RNA. Significant growth inhibition was observed in some but not all cell lines, suggesting their variable dependence on ALK-mediated cell survival signaling. Collectively, these findings show the recurrence of EML4-ALK fusion in multiple solid tumors and further substantiate its role in tumorigenesis. (Mol Cancer Res 2009;7(9):1466-76)