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      Aberrant expression of ALK and EZH2 in Merkel cell carcinoma

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          Abstract

          Background

          Distinct characteristic features categorize Merkel cell carcinoma (MCC) into two subgroups according to the Merkel cell polyomavirus infection. Many mutational studies on MCC have been carried out in recent years without identifying a prominent driver mutation. However, there is paucity reporting the expression of cancer genes at the RNA level in MCC tumors. In this study, we studied the RNA expression profiles of 26 MCC tumors, with a goal to identify prospective molecular targets that could improve the treatment strategies of MCC.

          Methods

          RNA expression of 50 cancer-related genes in 26 MCC tumors was analyzed by targeted amplicon based next-generation sequencing using the Ion Torrent technology and the expression compared with that of normal, non-cancerous skin samples. Sequencing data were processed using Torrent Suite™ Software. Expression profiles of MCV-negative and MCV-positive tumors were compared. Fluorescence in situ hybridization was performed to study ALK rearrangements and immunohistochemistry to study ALK expression in tumor tissue.

          Results

          ALK, CDKN2A, EZH2 and ERBB4 were overexpressed, and EGFR, ERBB2, PDGFRA and FGFR1 were underexpressed in MCC tumors compared to normal skin. In the MCV-negative tumors, MET, NOTCH1, FGFR3, and SMO were overexpressed and JAK3 and NPM1 were under-expressed compared to the MCV-positive tumors.

          Conclusions

          High expression of ALK, CDKN2A and EZH2 was recorded in MCC tumors. No ALK fusion was seen by FISH analysis. Overexpression of EZH2 suggests its potential as a drug target in MCC.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s12885-017-3233-5) contains supplementary material, which is available to authorized users.

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          Most cited references24

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          Targeting EZH2 in cancer.

          Recent genomic studies have resulted in an emerging understanding of the role of chromatin regulators in the development of cancer. EZH2, a histone methyl transferase subunit of a Polycomb repressor complex, is recurrently mutated in several forms of cancer and is highly expressed in numerous others. Notably, both gain-of-function and loss-of-function mutations occur in cancers but are associated with distinct cancer types. Here we review the spectrum of EZH2-associated mutations, discuss the mechanisms underlying EZH2 function, and synthesize a unifying perspective that the promotion of cancer arises from disruption of the role of EZH2 as a master regulator of transcription. We further discuss EZH2 inhibitors that are now showing early signs of promise in clinical trials and also additional strategies to combat roles of EZH2 in cancer.
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            Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma.

            The 2;5 chromosomal translocation occurs in most anaplastic large-cell non-Hodgkin's lymphomas arising from activated T lymphocytes. This rearrangement was shown to fuse the NPM nucleolar phosphoprotein gene on chromosome 5q35 to a previously unidentified protein tyrosine kinase gene, ALK, on chromosome 2p23. In the predicted hybrid protein, the amino terminus of nucleophosmin (NPM) is linked to the catalytic domain of anaplastic lymphoma kinase (ALK). Expressed in the small intestine, testis, and brain but not in normal lymphoid cells, ALK shows greatest sequence similarity to the insulin receptor subfamily of kinases. Unscheduled expression of the truncated ALK may contribute to malignant transformation in these lymphomas.
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              p16(Ink4a) overexpression in cancer: a tumor suppressor gene associated with senescence and high-grade tumors.

              p16(Ink4a) is a protein involved in regulation of the cell cycle. Currently, p16(Ink4a) is considered a tumor suppressor protein because of its physiological role and downregulated expression in a large number of tumors. Intriguingly, overexpression of p16(Ink4a) has also been described in several tumors. This review attempts to elucidate when and why p16(Ink4a) overexpression occurs, and to suggest possible implications of p16(Ink4a) in the diagnosis, prognosis and treatment of cancer.
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                Author and article information

                Contributors
                tuukka.veija@helsinki.fi
                virve.koljonen@gmail.fi
                tom.bohling@helsinki.fi
                mia.kero@hus.fi
                sakari.knuutila@helsinki.fi
                virinder.sarhadi@helsinki.fi
                Journal
                BMC Cancer
                BMC Cancer
                BMC Cancer
                BioMed Central (London )
                1471-2407
                31 March 2017
                31 March 2017
                2017
                : 17
                : 236
                Affiliations
                [1 ]GRID grid.7737.4, Department of Pathology, Faculty of Medicine, , University of Helsinki, ; Haartmaninkatu 3, P.O. Box 21, FI-00014 Helsinki, Finland
                [2 ]GRID grid.15485.3d, Department of Pathology, University of Helsinki and HUSLAB, , Helsinki University Hospital, ; Haartmaninkatu 3, P.O. Box 21, FI-00014 Helsinki, Finland
                [3 ]GRID grid.7737.4, Department of Plastic Surgery, , University of Helsinki and Helsinki University Hospital, ; Topeliuksenkatu 5, P.O. Box 266, FI-00029 Helsinki, Finland
                Article
                3233
                10.1186/s12885-017-3233-5
                5374569
                28359267
                6a76e13a-d897-4164-b58b-b507c4e48722
                © The Author(s). 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 16 September 2016
                : 24 March 2017
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2017

                Oncology & Radiotherapy
                merkel cell carcinoma,next-generation sequencing,rna,alk,ezh2
                Oncology & Radiotherapy
                merkel cell carcinoma, next-generation sequencing, rna, alk, ezh2

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