title: Genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to myeloproliferative neoplasms.
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.
authors: 1] Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK [2] Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury SP2 8BJ, UK.
authors: William
authors: W
authors: Tapper
authors: 1] Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK [2] Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury SP2 8BJ, UK.
authors: Amy V
authors: AV
authors: Jones
authors: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria.
authors: Robert
authors: R
authors: Kralovics
authors: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria.
authors: Ashot S
authors: AS
authors: Harutyunyan
authors: Haematology Research Laboratory, Biomedical Research Foundation, Academy of Athens, Athens 11527, Greece.
authors: Katerina
authors: K
authors: Zoi
authors: 1] Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK [2] Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury SP2 8BJ, UK.
authors: William
authors: W
authors: Leung
authors: 1] Department of Haematology, Addenbrooke's Hospital, Cambridge CB2 0XY, UK [2] Department of Haematology, University of Cambridge, Cambridge CB2 0XY, UK.
authors: Anna L
authors: AL
authors: Godfrey
authors: Laboratorio Congiunto MMPC, Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy.
authors: Paola
authors: P
authors: Guglielmelli
authors: Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury SP2 8BJ, UK.
authors: Alison
authors: A
authors: Callaway
authors: Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury SP2 8BJ, UK.
authors: Daniel
authors: D
authors: Ward
authors: Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury SP2 8BJ, UK.
authors: Paula
authors: P
authors: Aranaz
authors: 1] Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK [2] Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury SP2 8BJ, UK.
authors: Helen E
authors: HE
authors: White
authors: 1] Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK [2] Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury SP2 8BJ, UK.
authors: Katherine
authors: K
authors: Waghorn
authors: 1] Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK [2] Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury SP2 8BJ, UK.
authors: Feng
authors: F
authors: Lin
authors: 1] Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK [2] Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury SP2 8BJ, UK.
authors: Andrew
authors: A
authors: Chase
authors: 1] Department of Haematology, Addenbrooke's Hospital, Cambridge CB2 0XY, UK [2] Department of Haematology, University of Cambridge, Cambridge CB2 0XY, UK.
authors: E Joanna
authors: EJ
authors: Baxter
authors: 1] Department of Haematology, Addenbrooke's Hospital, Cambridge CB2 0XY, UK [2] Department of Haematology, University of Cambridge, Cambridge CB2 0XY, UK.
authors: Cathy
authors: C
authors: Maclean
authors: 1] Department of Haematology, Addenbrooke's Hospital, Cambridge CB2 0XY, UK [2] Department of Haematology, University of Cambridge, Cambridge CB2 0XY, UK.
authors: Jyoti
authors: J
authors: Nangalia
authors: 1] Department of Haematology, Addenbrooke's Hospital, Cambridge CB2 0XY, UK [2] Department of Haematology, University of Cambridge, Cambridge CB2 0XY, UK.
authors: Edwin
authors: E
authors: Chen
authors: Haematological Malignancy Diagnostic Service, St James's Institute of Oncology, Bexley Wing, St James's University Hospital, Leeds LS9 7TF, UK.
authors: Paul
authors: P
authors: Evans
authors: Haematological Malignancy Diagnostic Service, St James's Institute of Oncology, Bexley Wing, St James's University Hospital, Leeds LS9 7TF, UK.
authors: Michael
authors: M
authors: Short
authors: Haematological Malignancy Diagnostic Service, St James's Institute of Oncology, Bexley Wing, St James's University Hospital, Leeds LS9 7TF, UK.
authors: Andrew
authors: A
authors: Jack
authors: Department of Haematology, Royal Bournemouth Hospital, Bournemouth BH7 7DW, UK.
authors: Louise
authors: L
authors: Wallis
authors: Department of Haematology, Royal Bournemouth Hospital, Bournemouth BH7 7DW, UK.
authors: David
authors: D
authors: Oscier
authors: Department of Haematology, University Hospital Southampton, Southampton SO16 6YD, UK.
authors: Andrew S
authors: AS
authors: Duncombe
authors: Oxford Biomedical Research Centre, Molecular Diagnostic Laboratory, Oxford University Hospitals NHS Trust, Oxford OX3 7LE, UK.
authors: Anna
authors: A
authors: Schuh
authors: Haematopoietic Stem Cell Biology Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
authors: Adam J
authors: AJ
authors: Mead
authors: 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.
authors: Michael
authors: M
authors: Griffiths
authors: Birmingham Heartlands Hospital, Birmingham B9 5SS, UK.
authors: Joanne
authors: J
authors: Ewing
authors: Department of Haematology, UCL Cancer Institute, London WC1 E6BT, UK.
authors: Rosemary E
authors: RE
authors: Gale
authors: MLL Munich Leukaemia Laboratory, Munich 81377, Germany.
authors: Susanne
authors: S
authors: Schnittger
authors: MLL Munich Leukaemia Laboratory, Munich 81377, Germany.
authors: Torsten
authors: T
authors: Haferlach
authors: Department of Internal Medicine III, University Hospital of Ulm, Ulm 89081, Germany.
authors: Frank
authors: F
authors: Stegelmann
authors: Department of Internal Medicine III, University Hospital of Ulm, Ulm 89081, Germany.
authors: Konstanze
authors: K
authors: Döhner
authors: 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.
authors: Harald
authors: H
authors: Grallert
authors: 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.
authors: Konstantin
authors: K
authors: Strauch
authors: Longitudinal Study Section, Translational Gerontology Branch, National Institute on Aging, Baltimore, Maryland 21224-6825, USA.
authors: Toshiko
authors: T
authors: Tanaka
authors: Geriatric Unit, Azienda Sanitaria Firenze (ASF), Florence 50122, Italy.
authors: Stefania
authors: S
authors: Bandinelli
authors: Haematology Research Laboratory, Biomedical Research Foundation, Academy of Athens, Athens 11527, Greece.
authors: Andreas
authors: A
authors: Giannopoulos
authors: Laboratorio Congiunto MMPC, Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy.
authors: Lisa
authors: L
authors: Pieri
authors: Laboratorio Congiunto MMPC, Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy.
authors: Carmela
authors: C
authors: Mannarelli
authors: Medical University of Vienna, Department of Internal Medicine I, Division of Hematology and Blood Coagulation, Vienna 1090, Austria.
authors: Heinz
authors: H
authors: Gisslinger
authors: Center for the Study of Myelofibrosis, IRCCS Policlinico San Matteo Foundation, Pavia 27100, Italy.
authors: Giovanni
authors: G
authors: Barosi
authors: 1] Department of Molecular Medicine, University of Pavia, Pavia, Italy [2] Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia 27100, Italy.
authors: Mario
authors: M
authors: Cazzola
authors: III. Medizinische Klinik, Universitätsmedizin Mannheim, Mannheim 68167, Germany.
authors: Andreas
authors: A
authors: Reiter
authors: Department of Haematology, Guy's and St Thomas' NHS Foundation Trust, Guy's Hospital, London SE1 9RT, UK.
authors: Claire
authors: C
authors: Harrison
authors: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
authors: Peter
authors: P
authors: Campbell
authors: 1] Department of Haematology, Addenbrooke's Hospital, Cambridge CB2 0XY, UK [2] Department of Haematology, University of Cambridge, Cambridge CB2 0XY, UK.
authors: Anthony R
authors: AR
authors: Green
authors: Laboratorio Congiunto MMPC, Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy.
authors: Alessandro
authors: A
authors: Vannucchi
authors: 1] Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK [2] Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury SP2 8BJ, UK.
authors: Nicholas C P
authors: NC
authors: Cross
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D037282:Calreticulin / Q000235:genetics; D016022:Case-Control Studies; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics; D005787:Gene Frequency; D020570:Genes, myb / Q000235:genetics; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics; D000074008:MDS1 and EVI1 Complex Locus Protein; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000235:genetics; D010445:Peptide Elongation Factors / Q000235:genetics; D011087:Polycythemia Vera / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011519:Proto-Oncogenes / Q000235:genetics; D053628:Receptors, Thrombopoietin / Q000235:genetics; D019098:Telomerase / Q000235:genetics; D013920:Thrombocythemia, Essential / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics
chemical_list: C576483:CALR protein, human; D037282:Calreticulin; D004268:DNA-Binding Proteins; D018840:HSP70 Heat-Shock Proteins; D000074008:MDS1 and EVI1 Complex Locus Protein; C063575:MECOM protein, human; D010445:Peptide Elongation Factors; D053628:Receptors, Thrombopoietin; D014157:Transcription Factors; C082218:MPL protein, human; C507924:JAK2 protein, human; D053614:Janus Kinase 2; C509186:TERT protein, human; D019098:Telomerase; D019204:GTP-Binding Proteins; C000628258:HBS1L protein, human