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      m 6A RNA modification and its writer/reader VIRMA/YTHDF3 in testicular germ cell tumors: a role in seminoma phenotype maintenance

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          Abstract

          Background

          Covalent RNA modifications, such as N-6-methyladenosine (m 6A), have been associated with various biological processes, but their role in cancer remains largely unexplored. m 6A dynamics depends on specific enzymes whose deregulation may also impact in tumorigenesis. Herein, we assessed the differential abundance of m 6A, its writer VIRMA and its reader YTHDF3, in testicular germ cell tumors (TGCTs), looking for clinicopathological correlates.

          Methods

          In silico analysis of TCGA data disclosed altered expression of VIRMA (52%) and YTHDF3 (48%), prompting subsequent validation. Formalin-fixed paraffin-embedded tissues from 122 TGCTs (2005–2016) were selected. RNA extraction, cDNA synthesis and real-time qPCR (Taqman assays) for VIRMA and YTHDF3 were performed, as well as immunohistochemistry for VIRMA, YTHDF3 and m 6A, for staining intensity assessment. Associations between categorical variables were assessed using Chi square and Fisher’s exact test. Distribution of continuous variables between groups was compared using the nonparametric Mann–Whitney and Kruskal–Wallis tests. Biomarker performance was assessed through receiver operating characteristics (ROC) curve construction and a cut-off was established by Youden’s index method. Statistical significance was set at p < 0.05.

          Results

          In our cohort, VIRMA and YTHDF3 mRNA expression levels differed among TGCT subtypes, with Seminomas (SEs) depicting higher levels than Non-Seminomatous tumors (NSTs) (p < 0.01 for both). A positive correlation was found between VIRMA and YTHDF3 expression levels. VIRMA discriminated SEs from NSTs with AUC = 0.85 (Sensitivity 77.3%, Specificity 81.1%, PPV 71.6%, NPV 85.3%, Accuracy 79.7%). Immunohistochemistry paralleled transcript findings, as patients with strong m 6A immunostaining intensity depicted significantly higher VIRMA mRNA expression levels and stronger VIRMA immunoexpression intensity (p < 0.001 and p < 0.01, respectively).

          Conclusion

          Abundance of m 6A and expression of VIRMA/ YTHDF3 were different among TGCT subtypes, with higher levels in SEs, suggesting a contribution to SE phenotype maintenance. VIRMA and YTHDF3 might cooperate in m 6A establishment in TGCTs, and their transcript levels accurately discriminate between SEs and NSTs, constituting novel candidate biomarkers for patient management.

          Electronic supplementary material

          The online version of this article (10.1186/s12967-019-1837-z) contains supplementary material, which is available to authorized users.

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          Most cited references 65

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                Author and article information

                Contributors
                jpedro.lobo@ipoporto.min-saude.pt
                alscosta94@gmail.com
                marianacantantecf@gmail.com
                ritaguimaraes.apct@gmail.com
                lopesanapaula.s@gmail.com
                luis.antunes@ipoporto.min-saude.pt
                isaac.braga@gmail.com
                urojorge@gmail.com
                mattia.pelizzola@iit.it
                +351 225084000 , henrique@ipoporto.min-saude.pt , rmhenrique@icbas.up.pt
                +351 225084000 , carmenjeronimo@ipoporto.min-saude.pt , cljeronimo@icbas.up.pt
                Journal
                J Transl Med
                J Transl Med
                Journal of Translational Medicine
                BioMed Central (London )
                1479-5876
                12 March 2019
                12 March 2019
                2019
                : 17
                Affiliations
                [1 ]GRID grid.435544.7, Cancer Biology and Epigenetics Group (CBEG), , IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto) & Porto Comprehensive Cancer Center (P.CCC), ; R. Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal
                [2 ]Department of Pathology, Portuguese Oncology Institute of Porto (IPOP), R. Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal
                [3 ]ISNI 0000 0001 1503 7226, GRID grid.5808.5, Department of Pathology and Molecular Immunology, , Institute of Biomedical Sciences Abel Salazar, University of Porto (ICBAS-UP), ; Rua Jorge Viterbo Ferreira 228, 4050-513 Porto, Portugal
                [4 ]Department of Epidemiology, Portuguese Oncology Institute of Porto (IPOP), R. Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal
                [5 ]Department of Urology, Portuguese Oncology Institute of Porto (IPOP), R. Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal
                [6 ]Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), 20139 Milan, Italy
                Article
                1837
                10.1186/s12967-019-1837-z
                6416960
                30866959
                © The Author(s) 2019

                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.

                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001871, Fundação para a Ciência e a Tecnologia;
                Award ID: SFRH/BD/132751/2017
                Award ID: POCI-01-0145-FEDER-29043
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2019

                Medicine

                ythdf3, virma, testicular germ-cell tumors, rna, m6a, epitranscriptomics

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