Genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to myeloproliferative neoplasms

Nature Communications - Tập 6 Số 1
William Tapper1, Amy V. Jones1, Róbert Královics2, Ashot S. Harutyunyan2, Katerina Zoi3, William Leung4, Anna L. Godfrey5, Paola Guglielmelli6, Alison Callaway4, Daniel Ward4, Paula Aranaz4, Helen White4, Katherine Waghorn4, Feng Lin4, Andrew Chase4, E. Joanna Baxter5, Cathy MacLean5, Jyoti Nangalia5, Edwin Chen5, Paul Evans7, Michael Short7, Andrew Jack7, Louise Wallis8, David Oscier8, Andrew Duncombe9, Anna Schuh10, Adam J. Mead11, Mike Griffiths12, Joanne Ewing13, Rosemary E. Gale14, Susanne Schnittger15, Torsten Haferlach15, Frank Stegelmann16, Konstanze Döhner16, Harald Grallert17, Konstantin Strauch17, Toshiko Tanaka18, Stefania Bandinelli19, Andreas Giannopoulos3, Lisa Pieri6, Carmela Mannarelli6, Heinz Gisslinger20, Giovanni Barosi21, Mario Cazzola22, Andreas Reiter23, Claire Harrison24, Peter J. Campbell25, Anthony R. Green26, Alessandro M. Vannucchi6, Nicholas C.P. Cross4
1Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK
2CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria
3Haematology Research Laboratory, Biomedical Research Foundation, Academy of Athens, Athens, 11527, Greece
4Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury SP2 8BJ, UK
5Department of Haematology, Addenbrooke’s Hospital, Cambridge, CB2 0XY, UK
6Department of Experimental and Clinical Medicine, Laboratorio Congiunto MMPC, University of Florence, Florence, 50134, Italy
7Haematological Malignancy Diagnostic Service, St James's Institute of Oncology, Bexley Wing, St James's University Hospital, Leeds, LS9 7TF, UK
8Department of Haematology, Royal Bournemouth Hospital, Bournemouth, BH7 7DW, UK
9Department of Haematology, University Hospital Southampton, Southampton SO16 6YD, UK,
10Oxford Biomedical Research Centre, Molecular Diagnostic Laboratory, Oxford University Hospitals NHS Trust, Oxford, OX3 7LE, UK
11Haematopoietic Stem Cell Biology Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK
12School of Cancer Sciences, University of Birmingham, Birmingham B15 2TT, UK
13Birmingham Heartlands Hospital, Birmingham B9 5SS, UK
14Department of Haematology, UCL Cancer Institute, London, WC1 E6BT, UK
15MLL Munich Leukaemia Laboratory, Munich, 81377, Germany
16Department of Internal Medicine III, University Hospital of Ulm, Ulm, 89081, Germany
17Institute of Epidemiology II, Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, 85764, Germany
18Longitudinal Study Section, Translational Gerontology Branch, National Institute on Aging, Baltimore, 21224-6825, Maryland, USA
19Geriatric Unit, Azienda Sanitaria Firenze (ASF), Florence, 50122, Italy
20Department of Internal Medicine I, Division of Hematology and Blood Coagulation, Medical University of Vienna, Vienna, 1090, Austria
21Center for the Study of Myelofibrosis, IRCCS Policlinico San Matteo Foundation, Pavia, 27100, Italy
22Department of Molecular Medicine, University of Pavia, Pavia, Italy
23III. Medizinische Klinik, Universitätsmedizin Mannheim, Mannheim, 68167, Germany
24Department of Haematology, Guy's and St Thomas' NHS Foundation Trust, Guy's Hospital, London, SE1 9RT, UK
25Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
26Department of Haematology, University of Cambridge, Cambridge CB2 0XY, UK

Tóm tắt

AbstractClonal proliferation in myeloproliferative neoplasms (MPN) is driven by somatic mutations inJAK2,CALRorMPL, but the contribution of inherited factors is poorly characterized. Using a three-stage genome-wide association study of 3,437 MPN cases and 10,083 controls, we identify two SNPs with genome-wide significance inJAK2V617F-negative MPN: rs12339666 (JAK2;meta-analysisP=1.27 × 10−10) and rs2201862 (MECOM; meta-analysisP=1.96 × 10−9). Two additional SNPs, rs2736100 (TERT) and rs9376092 (HBS1L/MYB), achieve genome-wide significance when includingJAK2V617F-positive cases. rs9376092 has a stronger effect inJAK2V617F-negative cases withCALRand/orMPLmutations (Breslow–DayP=4.5 × 10−7), whereas inJAK2V617F-positive cases rs9376092 associates with essential thrombocythemia (ET) rather than polycythemia vera (allelicχ2P=7.3 × 10−7). ReducedMYBexpression, previously linked to development of an ET-like disease in model systems, associates with rs9376092 in normal myeloid cells. These findings demonstrate that multiple germline variants predispose to MPN and link constitutional differences inMYBexpression to disease phenotype.

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