Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukaemia
Histone methyltransferases (HMTs) are important epigenetic regulators of gene transcription and are disrupted at the genomic level in a spectrum of human tumours including haematological malignancies. Using high-resolution single nucleotide polymorphism (SNP) arrays, we identified recurrent deletion...
| Autores: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2016 |
| País: | España |
| Institución: | Consejo Superior de Investigaciones Científicas (CSIC) |
| Repositorio: | DIGITAL.CSIC. Repositorio Institucional del CSIC |
| OAI Identifier: | oai:digital.csic.es:10261/168538 |
| Acceso en línea: | http://hdl.handle.net/10261/168538 |
| Access Level: | acceso abierto |
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Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukaemiaParker, HelenRose-Zerilli, M. J. J.Larráyoz, María JoséClifford, R.Edelmann, J.Blakemore, S.Gibson, J.Wang, J.Ljungström, V.Wojdacz, T. K.Chaplin, T.Roghanian, A.Davis, ZadieParker, AntónTausch, E.Ntoufa, S.Ramos, S.Robbe, P.Alsolami, R.Steele, A. J.Packham, G.Rodríguez-Vicente, Ana EugeniaBrown, L.McNicholl, F.Forconi, F.Pettitt, A.Hillmen, P.Dyer, M.Cragg, M. S.Chelala, C.Oakes, C. C.Rosenquist, RichardStamatopoulos, KostasStilgenbauer, S.Knight, S.Schuh, A.Oscier, David G.Strefford, Jonathan C.Histone methyltransferases (HMTs) are important epigenetic regulators of gene transcription and are disrupted at the genomic level in a spectrum of human tumours including haematological malignancies. Using high-resolution single nucleotide polymorphism (SNP) arrays, we identified recurrent deletions of the SETD2 locus in 3% (8/261) of chronic lymphocytic leukaemia (CLL) patients. Further validation in two independent cohorts showed that SETD2 deletions were associated with loss of TP53, genomic complexity and chromothripsis. With next-generation sequencing we detected mutations of SETD2 in an additional 3.8% of patients (23/602). In most cases, SETD2 deletions or mutations were often observed as a clonal event and always as a mono-allelic lesion, leading to reduced mRNA expression in SETD2-disrupted cases. Patients with SETD2 abnormalities and wild-type TP53 and ATM from five clinical trials employing chemotherapy or chemo-immunotherapy had reduced progression-free and overall survival compared with cases wild type for all three genes. Consistent with its postulated role as a tumour suppressor, our data highlight SETD2 aberration as a recurrent, early loss-of-function event in CLL pathobiology linked to aggressive disease.This work was funded by Bloodwise (11052, 12036), the Kay Kendall Leukaemia Fund (873), Cancer Research UK (C34999/A18087, ECMC C24563/A15581), Wessex Medical Research and the Bournemouth Leukaemia Fund. SS is supported by the Else Kröner-FreseniusStiftung (2012_A146) and Deutsche Forschungsgemeinschaft (SFB 1074 projects B1, B2). The LRF CLL4 trial was funded by a core grant from Leukaemia and Lymphoma Research. DG and DC acknowledge the support by The Royal Marsden Hospital and The Institute of Cancer Research National Institute of Health Research Biomedical Research Center. RR is supported by the Swedish Cancer Society, the Swedish Research Council, Science for Life Laboratory, Uppsala University, Uppsala University Hospital, and the Lion’s Cancer Research Foundation, Uppsala.Peer ReviewedNature Publishing GroupLeukaemia & Lymphoma Research (UK)Royal Marsden NHS Foundation TrustThe Institute of Cancer Research (UK)Swedish Research CouncilSwedish Cancer SocietyPolysackaridforskning i Uppsala ABGerman Research FoundationLeukaemia FoundationWessex Medical ResearchKay Kendall Leukaemia FundCancer Research UKConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2018201820162018info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/168538reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttps://doi.org/10.1038/leu.2016.134Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/1685382026-05-22T06:33:51Z |
| dc.title.none.fl_str_mv |
Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukaemia |
| title |
Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukaemia |
| spellingShingle |
Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukaemia Parker, Helen |
| title_short |
Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukaemia |
| title_full |
Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukaemia |
| title_fullStr |
Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukaemia |
| title_full_unstemmed |
Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukaemia |
| title_sort |
Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukaemia |
| dc.creator.none.fl_str_mv |
Parker, Helen Rose-Zerilli, M. J. J. Larráyoz, María José Clifford, R. Edelmann, J. Blakemore, S. Gibson, J. Wang, J. Ljungström, V. Wojdacz, T. K. Chaplin, T. Roghanian, A. Davis, Zadie Parker, Antón Tausch, E. Ntoufa, S. Ramos, S. Robbe, P. Alsolami, R. Steele, A. J. Packham, G. Rodríguez-Vicente, Ana Eugenia Brown, L. McNicholl, F. Forconi, F. Pettitt, A. Hillmen, P. Dyer, M. Cragg, M. S. Chelala, C. Oakes, C. C. Rosenquist, Richard Stamatopoulos, Kostas Stilgenbauer, S. Knight, S. Schuh, A. Oscier, David G. Strefford, Jonathan C. |
| author |
Parker, Helen |
| author_facet |
Parker, Helen Rose-Zerilli, M. J. J. Larráyoz, María José Clifford, R. Edelmann, J. Blakemore, S. Gibson, J. Wang, J. Ljungström, V. Wojdacz, T. K. Chaplin, T. Roghanian, A. Davis, Zadie Parker, Antón Tausch, E. Ntoufa, S. Ramos, S. Robbe, P. Alsolami, R. Steele, A. J. Packham, G. Rodríguez-Vicente, Ana Eugenia Brown, L. McNicholl, F. Forconi, F. Pettitt, A. Hillmen, P. Dyer, M. Cragg, M. S. Chelala, C. Oakes, C. C. Rosenquist, Richard Stamatopoulos, Kostas Stilgenbauer, S. Knight, S. Schuh, A. Oscier, David G. Strefford, Jonathan C. |
| author_role |
author |
| author2 |
Rose-Zerilli, M. J. J. Larráyoz, María José Clifford, R. Edelmann, J. Blakemore, S. Gibson, J. Wang, J. Ljungström, V. Wojdacz, T. K. Chaplin, T. Roghanian, A. Davis, Zadie Parker, Antón Tausch, E. Ntoufa, S. Ramos, S. Robbe, P. Alsolami, R. Steele, A. J. Packham, G. Rodríguez-Vicente, Ana Eugenia Brown, L. McNicholl, F. Forconi, F. Pettitt, A. Hillmen, P. Dyer, M. Cragg, M. S. Chelala, C. Oakes, C. C. Rosenquist, Richard Stamatopoulos, Kostas Stilgenbauer, S. Knight, S. Schuh, A. Oscier, David G. Strefford, Jonathan C. |
| author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Leukaemia & Lymphoma Research (UK) Royal Marsden NHS Foundation Trust The Institute of Cancer Research (UK) Swedish Research Council Swedish Cancer Society Polysackaridforskning i Uppsala AB German Research Foundation Leukaemia Foundation Wessex Medical Research Kay Kendall Leukaemia Fund Cancer Research UK Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72] |
| description |
Histone methyltransferases (HMTs) are important epigenetic regulators of gene transcription and are disrupted at the genomic level in a spectrum of human tumours including haematological malignancies. Using high-resolution single nucleotide polymorphism (SNP) arrays, we identified recurrent deletions of the SETD2 locus in 3% (8/261) of chronic lymphocytic leukaemia (CLL) patients. Further validation in two independent cohorts showed that SETD2 deletions were associated with loss of TP53, genomic complexity and chromothripsis. With next-generation sequencing we detected mutations of SETD2 in an additional 3.8% of patients (23/602). In most cases, SETD2 deletions or mutations were often observed as a clonal event and always as a mono-allelic lesion, leading to reduced mRNA expression in SETD2-disrupted cases. Patients with SETD2 abnormalities and wild-type TP53 and ATM from five clinical trials employing chemotherapy or chemo-immunotherapy had reduced progression-free and overall survival compared with cases wild type for all three genes. Consistent with its postulated role as a tumour suppressor, our data highlight SETD2 aberration as a recurrent, early loss-of-function event in CLL pathobiology linked to aggressive disease. |
| publishDate |
2016 |
| dc.date.none.fl_str_mv |
2016 2018 2018 2018 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article http://purl.org/coar/resource_type/c_6501 Publisher's version info:eu-repo/semantics/publishedVersion |
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article |
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publishedVersion |
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http://hdl.handle.net/10261/168538 |
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http://hdl.handle.net/10261/168538 |
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Inglés |
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Inglés |
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https://doi.org/10.1038/leu.2016.134 Sí |
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info:eu-repo/semantics/openAccess |
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openAccess |
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Nature Publishing Group |
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Nature Publishing Group |
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