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Nat Commun. 2015 Apr 7;6:6691. doi: 10.1038/ncomms7691.

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

Author information

1
1] Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK [2] Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury SP2 8BJ, UK.
2
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria.
3
Haematology Research Laboratory, Biomedical Research Foundation, Academy of Athens, Athens 11527, Greece.
4
1] Department of Haematology, Addenbrooke's Hospital, Cambridge CB2 0XY, UK [2] Department of Haematology, University of Cambridge, Cambridge CB2 0XY, UK.
5
Laboratorio Congiunto MMPC, Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy.
6
Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury SP2 8BJ, UK.
7
Haematological Malignancy Diagnostic Service, St James's Institute of Oncology, Bexley Wing, St James's University Hospital, Leeds LS9 7TF, UK.
8
Department of Haematology, Royal Bournemouth Hospital, Bournemouth BH7 7DW, UK.
9
Department of Haematology, University Hospital Southampton, Southampton SO16 6YD, UK.
10
Oxford Biomedical Research Centre, Molecular Diagnostic Laboratory, Oxford University Hospitals NHS Trust, Oxford OX3 7LE, UK.
11
Haematopoietic Stem Cell Biology Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
12
1] School of Cancer Sciences, University of Birmingham,, Birmingham B15 2TT, UK [2] West Midlands Regional Genetics Laboratory, Birmingham Women's NHS Foundation Trust, Birmingham B15 2TG, UK.
13
Birmingham Heartlands Hospital, Birmingham B9 5SS, UK.
14
Department of Haematology, UCL Cancer Institute, London WC1 E6BT, UK.
15
MLL Munich Leukaemia Laboratory, Munich 81377, Germany.
16
Department of Internal Medicine III, University Hospital of Ulm, Ulm 89081, Germany.
17
1] Institute of Epidemiology II, Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg 85764, Germany [2] German Center for Diabetes Research, Neuherberg 85764, Germany.
18
1] Institute of Epidemiology II, Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg 85764, Germany [2] Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, 80539 Munich, Germany.
19
Longitudinal Study Section, Translational Gerontology Branch, National Institute on Aging, Baltimore, Maryland 21224-6825, USA.
20
Geriatric Unit, Azienda Sanitaria Firenze (ASF), Florence 50122, Italy.
21
Medical University of Vienna, Department of Internal Medicine I, Division of Hematology and Blood Coagulation, Vienna 1090, Austria.
22
Center for the Study of Myelofibrosis, IRCCS Policlinico San Matteo Foundation, Pavia 27100, Italy.
23
1] Department of Molecular Medicine, University of Pavia, Pavia, Italy [2] Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia 27100, Italy.
24
III. Medizinische Klinik, Universitätsmedizin Mannheim, Mannheim 68167, Germany.
25
Department of Haematology, Guy's and St Thomas' NHS Foundation Trust, Guy's Hospital, London SE1 9RT, UK.
26
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.

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 JAK2(V617F)-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 JAK2(V617F)-positive cases. rs9376092 has a stronger effect in JAK2(V617F)-negative cases with CALR and/or MPL mutations (Breslow-Day P=4.5 × 10(-7)), whereas in JAK2(V617F)-positive cases rs9376092 associates with essential thrombocythemia (ET) rather than polycythemia vera (allelic χ(2) 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.

PMID:
25849990
PMCID:
PMC4396373
DOI:
10.1038/ncomms7691
[Indexed for MEDLINE]
Free PMC Article

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