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

William Tapper, Amy V. Jones, Robert Kralovics, Ashot S. Harutyunyan, Katerina Zoi, William Leung, Anna L. Godfrey, Paola Guglielmelli, Alison Callaway, Daniel Ward, Paula Aranaz, Helen E. White, Katherine Waghorn, Feng Lin, Andrew Chase, E. Joanna Baxter, Cathy Maclean, Jyoti Nangalia, Edwin Chen, Paul Evans, Michael Short, Andrew Jack, Louise Wallis, David Oscier, Andrew S. Duncombe, Anna Schuh, Adam J. Mead, Michael Griffiths, Joanne Ewing, Rosemary E. Gale, Susanne Schnittger, Torsten Haferlach, Frank Stegelmann, Konstanze Döhner, Harald Grallert, Konstantin Strauch, Toshiko Tanaka, Stefania Bandinelli, Andreas Giannopoulos, Lisa Pieri, Carmela Mannarelli, Heinz Gisslinger, Giovanni Barosi, Mario Cazzola, Andreas Reiter, Claire Harrison, Peter Campbell, Anthony R. Green, Alessandro Vannucchi and Nicholas C.P. Cross ()
Additional contact information
William Tapper: Faculty of Medicine, University of Southampton
Amy V. Jones: Faculty of Medicine, University of Southampton
Robert Kralovics: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Ashot S. Harutyunyan: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Katerina Zoi: Haematology Research Laboratory, Biomedical Research Foundation, Academy of Athens, Athens
William Leung: Faculty of Medicine, University of Southampton
Anna L. Godfrey: Addenbrooke’s Hospital
Paola Guglielmelli: Laboratorio Congiunto MMPC, University of Florence
Alison Callaway: Wessex Regional Genetics Laboratory, Salisbury District Hospital
Daniel Ward: Wessex Regional Genetics Laboratory, Salisbury District Hospital
Paula Aranaz: Wessex Regional Genetics Laboratory, Salisbury District Hospital
Helen E. White: Faculty of Medicine, University of Southampton
Katherine Waghorn: Faculty of Medicine, University of Southampton
Feng Lin: Faculty of Medicine, University of Southampton
Andrew Chase: Faculty of Medicine, University of Southampton
E. Joanna Baxter: Addenbrooke’s Hospital
Cathy Maclean: Addenbrooke’s Hospital
Jyoti Nangalia: Addenbrooke’s Hospital
Edwin Chen: Addenbrooke’s Hospital
Paul Evans: Haematological Malignancy Diagnostic Service, St James's Institute of Oncology, Bexley Wing, St James's University Hospital
Michael Short: Haematological Malignancy Diagnostic Service, St James's Institute of Oncology, Bexley Wing, St James's University Hospital
Andrew Jack: Haematological Malignancy Diagnostic Service, St James's Institute of Oncology, Bexley Wing, St James's University Hospital
Louise Wallis: Royal Bournemouth Hospital
David Oscier: Royal Bournemouth Hospital
Andrew S. Duncombe: University Hospital Southampton
Anna Schuh: Oxford Biomedical Research Centre, Molecular Diagnostic Laboratory, Oxford University Hospitals NHS Trust
Adam J. Mead: Haematopoietic Stem Cell Biology Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford
Michael Griffiths: School of Cancer Sciences, University of Birmingham,
Joanne Ewing: Birmingham Heartlands Hospital
Rosemary E. Gale: UCL Cancer Institute
Susanne Schnittger: MLL Munich Leukaemia Laboratory
Torsten Haferlach: MLL Munich Leukaemia Laboratory
Frank Stegelmann: University Hospital of Ulm
Konstanze Döhner: University Hospital of Ulm
Harald Grallert: Institute of Epidemiology II, Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health
Konstantin Strauch: Institute of Epidemiology II, Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health
Toshiko Tanaka: Longitudinal Study Section, Translational Gerontology Branch, National Institute on Aging
Stefania Bandinelli: Geriatric Unit, Azienda Sanitaria Firenze (ASF)
Andreas Giannopoulos: Haematology Research Laboratory, Biomedical Research Foundation, Academy of Athens, Athens
Lisa Pieri: Laboratorio Congiunto MMPC, University of Florence
Carmela Mannarelli: Laboratorio Congiunto MMPC, University of Florence
Heinz Gisslinger: Medical University of Vienna
Giovanni Barosi: Center for the Study of Myelofibrosis, IRCCS Policlinico San Matteo Foundation
Mario Cazzola: University of Pavia
Andreas Reiter: III. Medizinische Klinik, Universitätsmedizin Mannheim
Claire Harrison: Guy's and St Thomas' NHS Foundation Trust, Guy's Hospital
Peter Campbell: Cancer Genome Project, Wellcome Trust Sanger Institute
Anthony R. Green: Addenbrooke’s Hospital
Alessandro Vannucchi: Laboratorio Congiunto MMPC, University of Florence
Nicholas C.P. Cross: Faculty of Medicine, University of Southampton

Nature Communications, 2015, vol. 6, issue 1, 1-11

Abstract: Abstract Clonal proliferation in myeloproliferative neoplasms (MPN) is driven by somatic mutations in JAK2, CALR or MPL, 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 in JAK2V617F-negative MPN: rs12339666 (JAK2; meta-analysis P=1.27 × 10−10) and rs2201862 (MECOM; meta-analysis P=1.96 × 10−9). Two additional SNPs, rs2736100 (TERT) and rs9376092 (HBS1L/MYB), achieve genome-wide significance when including JAK2V617F-positive cases. rs9376092 has a stronger effect in JAK2V617F-negative cases with CALR and/or MPL mutations (Breslow–Day P=4.5 × 10−7), whereas in JAK2V617F-positive cases rs9376092 associates with essential thrombocythemia (ET) rather than polycythemia vera (allelic χ2 P=7.3 × 10−7). Reduced MYB expression, 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 in MYB expression to disease phenotype.

Date: 2015
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DOI: 10.1038/ncomms7691

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