The EML4‐ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild‐type EGFR and KRAS

Wong, Daisy Wing Sze; Leung, Elaine Lai Han; So, Kimpton; Tam, Issan Yee San; Sihoe, Alan D. L.; Cheng, Lik Cheung; Ho, Kwok Keung; Au, Joseph Siu Kie; Chung, Lap Ping; Wong, Maria Pik

doi:10.1002/cncr.24181

Cited by 659 publications

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“…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). The intact ALK kinase domain within EML4-ALK possesses marked transforming as well as oncogenic activity in vitro and in vivo, respectively (12,21,25).…”

Section: Introductionmentioning

confidence: 69%

“…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

276

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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Section: Introductionmentioning

confidence: 69%

Section: Rt-pcr Detection Of Eml4-alk Fusionmentioning

confidence: 99%

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

276

190

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“…The histology of these tumors is typically characterized by mucin production and either a solid growth pattern containing signet ring cells in western patients or an acinar growth pattern in Asian patients. [159][160][161][162] Compared with patients with wildtype ALK and EGFR, patients with the EML4-ALK fusion gene tend to be younger (median, 52 vs 64 years), of Asian ethnicity, diagnosed at an advanced clinical stage at presentation, male dominant (58 vs 32%), and more likely to be never-smokers (74 vs 26%), but with a comparable response rate to chemotherapy and overall survival. 8,148,159,160 The EML4-ALK fusion gene was detected in 19 of 141 (13%) tumor samples by FISH.…”

Section: Eml4-alk Rearrangement: Driver Mutation Of Lung Cancermentioning

confidence: 99%

Molecular pathology of lung cancer: key to personalized medicine

et al. 2012

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The majority of lung adenocarcinoma patients with epidermal growth factor receptor-(EGFR) mutated or EML4-ALK rearrangement-positive tumors are sensitive to tyrosine kinase inhibitors. Both primary and acquired resistance in a significant number of those patients to these therapies remains a major clinical problem. The specific molecular mechanisms associated with tyrosine kinase inhibitor resistance are not fully understood. Clinicopathological observations suggest that molecular alterations involving so-called 'driver mutations' could be used as markers that aid in the selection of patients most likely to benefit from targeted therapies. In this review, we summarize recent developments involving the specific molecular mechanisms and markers that have been associated with primary and acquired resistance to EGFR-targeted therapy in lung adenocarcinomas. Understanding these mechanisms may provide new treatment avenues and improve current treatment algorithms.

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“…Some features previously reported to be associated with ALK rearrangements include young age of onset, reduced smoking history, advanced stage at presentation, adenocarcinoma histology, and mutual exclusivity with activating mutations in EGFR and KRAS. 4,[7][8][9][10][11][12][13][14][15][16] In spite of the common findings among the above studies, the results of detailed pathologic analyses have varied. Previously, our microscopic analysis of 20 ALK þ lung adenocarcinomas revealed a strong association with a solid-predominant architecture and the presence of signet ring cells with intracytoplasmic mucin vacuoles and peripherally displaced and flattened nuclei.…”

mentioning

confidence: 99%

Histologic and cytomorphologic features of ALK-rearranged lung adenocarcinomas

et al. 2012

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Chromosomal rearrangements leading to constitutive activation of anaplastic lymphoma receptor tyrosine kinase (ALK) define a category of lung adenocarcinomas that may be amenable to targeted therapy with the ALK inhibitor crizotinib. Defining distinctive features of ALK-rearranged (ALK þ ) lung adenocarcinomas may help identify cases that merit molecular testing. However, data describing the morphologic features of ALK þ lung adenocarcinomas are conflicting and are primarily based on analysis of resected primary lung tumors. It is unclear whether the findings from prior studies are applicable to metastatic lung tumors or to small biopsy/ cytology specimens. To address these issues, we examined resection, excision, small biopsy, and cytology cell block specimens from 104 ALK þ and 215 ALKÀ lung adenocarcinomas from primary and metastatic sites. All cases were evaluated for ALK rearrangements by fluorescence in situ hybridization. The predominant histologic subtypes and distinctive cytomorphologic features were assessed in each case. Primary ALK þ lung adenocarcinomas showed a significant association with solid, micropapillary, and papillary-predominant histologic patterns and tumor cells with a signet ring or hepatoid cytomorphology. Among metastatic lung tumors and small biopsy/cytology specimens, the only distinguishing morphologic feature of ALK þ tumors was the presence of signet ring cells. Based on these results, we developed a morphology-based scoring system for predicting ALK rearrangements in lung adenocarcinomas. The scoring system predicted ALK rearrangements in a new cohort of 78 lung adenocarcinomas (29 ALK þ and 49 ALKÀ) with a sensitivity of 88% and a specificity of 45%. In conclusion, ALK þ lung adenocarcinomas have distinctive morphologic features, with signet ring cells showing a significant association with ALK rearrangements irrespective of tumor site (primary vs metastatic) or specimen type. However, morphologic screening alone will not detect a minority of ALK þ lung adenocarcinomas, and the routine use of ancillary studies may be warranted to identify all patients who may benefit from crizotinib treatment.

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The EML4‐ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild‐type EGFR and KRAS

Abstract: BACKGROUND:The echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion gene resulting from the chromosome inversion inv(2)(p21;p23) recently was identified in non-

Cited by 659 publications

References 31 publications

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

Molecular pathology of lung cancer: key to personalized medicine

Histologic and cytomorphologic features of ALK-rearranged lung adenocarcinomas

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