Identification of the transforming EML4–ALK fusion gene in non-small-cell lung cancer

Soda, Manabu; Choi, Young Lim; Enomoto, Masaya; Takada, Shuji; Yamashita, Yuichi; Ishikawa, Shunpei; Fujiwara, Shin-ichiro; Watanabe, Hideki; Kurashina, Kentaro; Hatanaka, Hisashi; Bando, Masashi; Ohno, Shoji; Ishikawa, Yuichi; Aburatani, Hiroyuki; Niki, Toshiro; Sohara, Yasunori; Sugiyama, Yukihiko; Mano, Hiroyuki

doi:10.1038/nature05945

Cited by 4,780 publications

(4,020 citation statements)

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“…[15][16][17][18] More recently, the ALK gene has been shown to be involved in small subsets of epithelial malignancies, including carcinomas of pulmonary, esophageal, mammary gland, and gastrointestinal origin. [19][20][21][22] To the best of our knowledge, this is the first report of a recurrent ALK locus rearrangement in a primary kidney tumor. Although 2p23 chromosomal abnormalities have not been previously emphasized as recurrent in renal cell carcinoma, a review of the literature and search of the Mitelman database (http://www.ncbi.nlm.nih.gov/cancerchromosomes) yielded four additional primary renal carcinomas and one renal carcinoma cell line exhibiting karyotypic aberrations at or near the ALK gene 5,[33][34][35][36] (Table 4).…”

Section: Discussionmentioning

confidence: 72%

“…[19][20][21][22] The predicted structure and function of VCL-ALK oncoprotein follows the archetypical pattern defined by the combined properties of the N-terminal partner (ubiquitous expression and homopolymerization) and the C-terminal kinase domain (constitutive activation). On the basis of the current data, we propose that ALK fusion genes represent an oncogenic driver in a subset of renal cell carcinomas, and that recognition of these cases may be useful in ascertaining a patient's eligibility for emerging tyrosine kinase-targeted therapies, the clinical efficacy of which has been recently reported in a trial of ALK-positive non-small cell lung carcinoma.…”

Section: Discussionmentioning

confidence: 99%

“…11 Subsequently, ALK rearrangements were found in several phenotypically different hematologic neoplasms [12][13][14] and in histogenetically unrelated inflammatory myofibroblastic tumor. [15][16][17][18] Recently, ALK rearrangements and EML4-ALK and KIF5B-ALK fusions were discovered in a subset of non-small cell lung carcinomas; 19,20 proteomics reports suggested a possible TPM4-ALK fusion in esophageal carcinoma; 21,22 and an exon array profiling study demonstrated the EML4-ALK fusion in 2.5% of breast and colon cancers. 23 ALK is also activated in B5 to 35% of neuroblastomas and neuroblastoma cell lines by a different mechanism involving point mutations and/or gene locus amplifications.…”

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Renal cell carcinoma with novel VCL–ALK fusion: new representative of ALK-associated tumor spectrum

et al. 2011

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Renal cell carcinoma represents a model for contemporary classification of solid tumors; however, unusual and unclassifiable cases exist and are not rare in children and young adults. The anaplastic lymphoma kinase (ALK) gene has recently been implicated in subsets of pulmonary, esophageal, breast, and colon cancers. These findings strengthen the importance of molecular classification of carcinomas across different organ sites, especially considering the evolving targeted anticancer therapies with ALK inhibitors. In the current study of six pediatric renal cell carcinomas, two cases exhibited structural karyotypic abnormalities involving the ALK locus on chromosomal band 2p23. Fluorescence in situ hybridization (FISH) studies were positive for an ALK rearrangement in one case, and subsequent 5 0 rapid amplification of cDNA ends analysis of this tumor revealed that the 3 0 portion of the ALK transcript encoding for the kinase domain was fused in frame to the 5 Keywords: ALK; FISH; fusion gene; renal cell carcinoma; translocation; VCL Renal cell carcinoma has an incidence of 209 000 cases per year and is responsible for 102 000 deaths worldwide annually. 1,2 Approximately 80% of all renal carcinoma cases are currently classified as clear cell, papillary, or chromophobe subtypes with discrete molecular abnormalities characteristic for each group. 2-7 Rare subtypes have also been defined by the 2004 World Health Organization classification and include collecting duct, multilocular cystic, mucinous tubular and spindle cell, medullary, and Xp11.2 translocation-and neuroblastoma-associated carcinomas; each of these subtypes constitutes B1% of all primary kidney epithelial tumors and the three latter subtypes are diagnosed predominantly in children. 8,9 Additional

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Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

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Renal cell carcinoma with novel VCL–ALK fusion: new representative of ALK-associated tumor spectrum

et al. 2011

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“…Furthermore, ALK‐rearranged NSCLC patients who have not treated with ALK therapy, exhibited a high incidence of CNS metastasis from approximately 45%‐70%, implying that BM is the most common pattern in ALK + NSCLC with therapy failure 71, 72. The production of anaplastic lymphoma kinase with the echinoderm microtubule‐associated protein‐like 4 (EML4‐ALK) fusion tyrosine kinase is the most common changes 73. The promoter of EML4 is located upstream of the intracellular tyrosine kinase of ALK, resulting in activation of the fusion gene and expressing the EML4‐ALK fusion protein.…”

Section: The Mechanism Of Brain Metastasismentioning

confidence: 99%

Emerging findings into molecular mechanism of brain metastasis

Chen

2018

Cancer Medicine

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Brain metastasis is an important cause of morbidity and mortality in cancer patients. Hence, the need to develop improved therapies to prevent and treat metastasis to the brain is becoming urgent. Recent studies in this area are bringing about some advanced progress on brain metastasis. It was concluded that the occurrence and poor prognosis of brain metastasis have been mostly attributed to the exclusion of anticancer drugs from the brain by the blood‐brain barrier. And several highly potent new generation targeted drugs with enhanced CNS distribution have been developed constantly. However, the noted “seed and soil” hypothesis also suggests that the outcome of metastasis depends on the relationship between unique tumor cells and the specific organ microenvironment. Moreover, increasing studies in multiple tumor types demonstrated that brain metastasis has great molecular differences between primary tumors and extracranial metastasis to a large extent. Here, the authors summarized the most common malignancies that could lead to brain metastasis—lung cancer, breast cancer and melanoma and their related mutated factors. Only by comprehending a deeper understanding of the molecular mechanisms, more effective brain‐specific therapies will be developed for brain metastasis.

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“…Soda et al were the first to demonstrate that EML4-ALK fusion was a distinct oncogenic event in a subset of NSCLC [2]. The fusion proteins lead to constitutive activity of the ALK tyrosine kinase.…”

Section: Introductionmentioning

confidence: 99%

The Current Landscape of Anaplastic Lymphoma Kinase (ALK) in Non-Small Cell Lung Cancer: Emerging Treatment Paradigms and Future Directions

Qin

Gadgeel

2017

Targ Oncol

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Tumorigenic rearrangements in anaplastic lymphoma kinase (ALK) account for 3–7% of all non-small cell lung cancers (NSCLC). Treatment with targeted tyrosine kinase inhibitors (TKIs) has shown impressive clinical responses. Crizotinib was the first agent approved for front-line therapy of ALK-rearranged NSCLC after it demonstrated superiority to chemotherapy in response rate, duration of response, and progression-free survival. However, eventually all patients progress on crizotinib therapy, with the central nervous system (CNS) being the most common site, which served as the impetus for the development of more potent next-generation ALK inhibitors. Currently, ceritinib, alectinib, and brigatinib are all approved for second-line therapy after progression on or intolerance to crizotinib. Investigations into whether the initiation of a second-generation ALK inhibitor as first-line therapy is the superior treatment paradigm has resulted in the approval of ceritinib as initial therapy. Alectinib has also shown impressive results as front-line therapy, as recently reported in two large randomized studies that compared it to crizotinib. There is a significant need to better understand the drivers of and mechanisms underlying resistance to ALK inhibitors. While specific mutations have been identified, there is currently only limited evidence that the identification of specific mutations should impact selection of the next ALK inhibitor. The best treatment option for patients who become TKI refractory is also unclear, though there is some evidence to suggests that these patients are not responsive to checkpoint inhibitors and may respond better to chemotherapy. Combination therapy with other classes of agents may help to overcome resistance mechanisms and should be investigated further.

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Identification of the transforming EML4–ALK fusion gene in non-small-cell lung cancer

Cited by 4,780 publications

References 25 publications

Renal cell carcinoma with novel VCL–ALK fusion: new representative of ALK-associated tumor spectrum

Renal cell carcinoma with novel VCL–ALK fusion: new representative of ALK-associated tumor spectrum

Emerging findings into molecular mechanism of brain metastasis

The Current Landscape of Anaplastic Lymphoma Kinase (ALK) in Non-Small Cell Lung Cancer: Emerging Treatment Paradigms and Future Directions

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