EML4-ALK fusion transcripts, but no NPM-, TPM3-, CLTC-, ATIC-, or TFG-ALK fusion transcripts, in non-small cell lung carcinomas

Shinmura, Kazuya; Kageyama, Shinji; Hong, Tao; Bunai, Tomoyasu; Suzuki, Mitsuaki; Kamo, Takaharu; Takamochi, Kazuya; Suzuki, Kazuya; Tanahashi, Masayuki; Niwa, Hiroshi; Sugimura, Haruhiko

doi:10.1016/j.lungcan.2007.12.013

Cited by 153 publications

(116 citation statements)

References 29 publications

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“…Similar to other studies (14,16,18,31), the presence of EML4-ALK fusion was detected only in adenocarcinomas. All of our EML4-ALKpositive NSCLC samples were wild-type for EGFR and KRAS (data not shown), confirming that the presence of fusion and EGFR/KRAS mutations are mutually exclusive (12,14,16,18). In summary, the presence of EML4-ALK fusion in multiple carcinomas, including breast, colorectal, and NSCLC, shows that its occurrence is broader than previously thought and, furthermore, not specific to NSCLC.…”

Section: Discussionsupporting

confidence: 89%

“…The breakpoints in HF-15512 were located 4,726 bp downstream of EML4 exon 13 and 1,021 bp upstream of ALK exon 20, whereas the ones in HF-15560 were located 3,116 bp downstream of EML4 exon 13 and 523 bp upstream of ALK exon 20. These fusion points were distinct and different from those reported previously (12,16,18,19). The genomic structure of the EML4-ALK fusion was characterized in breast tumor samples harboring variant E13; A20 and E20; A20 (Fig.…”

Section: Genomic Confirmation Of Eml4-alk Translocationcontrasting

confidence: 58%

“…Although the presence of EML4-ALK fusion in NSCLC has been well documented (12,(14)(15)(16)(17)(18), our study is the first one to report its occurrence in breast and colorectal carcinomas. Based on RT-PCR screening of patient samples, we detected the presence of EML4-ALK fusion in 2.4% of breast, 2.4% colorectal, and in 11.3% of NSCLC.…”

Section: Discussionmentioning

confidence: 70%

“…The EML4-ALK fusion was shown to result from a small inversion within chromosome 2p and was detected in 7% of NSCLC patient population. The presence of EML-ALK fusion in NSCLC was confirmed in a number of subsequent studies (14)(15)(16)(17)(18); however, it has not yet been detected in other carcinomas, including breast and colorectal (19,20). A number of EML4-ALK fusion variants have been identified up to date (12,18,(20)(21)(22)(23); all of them involve an almost identical portion of ALK (exons [20][21][22][23][24][25][26][27][28][29] The constitutive kinase activity of ALK is essential for proliferation of ALCL cells and its inactivation represents a feasible therapeutic approach for the treatment of ALCL (24).…”

Section: Introductionmentioning

confidence: 71%

“…Sequencing analysis of PCR products showed that HF-18138 sample contained a previously known E20; A20 variant, whereas HF-18092 harbored a novel E21; A20 variant where EML4 exons 1 to 21 were fused to ALK exon 20. Although the E21; A20 variant was predicted as a possible in-frame fusion of EML and ALK (20), it has not yet been found in NSCLC (16,18). Comparing with the breast and colorectal carcinomas, a higher frequency of EML4-ALK fusion transcript was found in NSCLC (12 of 106, 11.3%; Fig.…”

Section: Rt-pcr Detection Of Eml4-alk Fusionmentioning

confidence: 99%

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Exon Array Profiling Detects EML4-ALK Fusion in Breast, Colorectal, and Non–Small Cell Lung Cancers

Lin¹,

Li²,

Guan³

et al. 2009

Molecular Cancer Research

275

190

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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)

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