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

Genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to myeloproliferative neoplasms
Genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to myeloproliferative neoplasms
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 ?(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
Tapper, William
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Jones, Amy V.
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Kralovics, Robert
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Zoi, Katerina
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Leung, William
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Godfrey, Anna L.
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Haferlach, Torsten
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Stegelmann, Frank
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Giannopoulos, Andreas
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Pieri, Lisa
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Mannarelli, Carmela
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Gisslinger, Heinz
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Barosi, Giovanni
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Cazzola, Mario
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Reiter, Andreas
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Harrison, Claire
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Campbell, Peter
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Green, Anthony R.
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Vannucchi, Alessandro
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Cross, Nicholas C.P.
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Tapper, William
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Jones, Amy V.
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Kralovics, Robert
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Zoi, Katerina
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Leung, William
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Aranaz, Paula
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White, Helen E.
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Waghorn, Katherine
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Lin, Feng
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Chase, Andrew
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Maclean, Cathy
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Nangalia, Jyoti
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Chen, Edwin
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Short, Michael
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Jack, Andrew
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Wallis, Louise
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Oscier, David
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Duncombe, Andrew S.
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Schuh, Anna
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Haferlach, Torsten
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Stegelmann, Frank
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Pieri, Lisa
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Barosi, Giovanni
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Cazzola, Mario
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Reiter, Andreas
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Harrison, Claire
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Campbell, Peter
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Green, Anthony R.
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Vannucchi, Alessandro
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Cross, Nicholas C.P.
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Tapper, William, Jones, Amy V., Kralovics, Robert, Harutyunyan, Ashot S., Zoi, Katerina, Leung, William, Godfrey, Anna L., Guglielmelli, Paola, Callaway, Alison, Ward, Daniel, Aranaz, Paula, White, Helen E., Waghorn, Katherine, Lin, Feng, Chase, Andrew, Joanna Baxter, E., Maclean, Cathy, Nangalia, Jyoti, Chen, Edwin, Evans, Paul, Short, Michael, Jack, Andrew, Wallis, Louise, Oscier, David, Duncombe, Andrew S., Schuh, Anna, Mead, Adam J., Griffiths, Michael, Ewing, Joanne, Gale, Rosemary E., Schnittger, Susanne, Haferlach, Torsten, Stegelmann, Frank, Döhner, Konstanze, Grallert, Harald, Strauch, Konstantin, Tanaka, Toshiko, Bandinelli, Stefania, Giannopoulos, Andreas, Pieri, Lisa, Mannarelli, Carmela, Gisslinger, Heinz, Barosi, Giovanni, Cazzola, Mario, Reiter, Andreas, Harrison, Claire, Campbell, Peter, Green, Anthony R., Vannucchi, Alessandro and Cross, Nicholas C.P. (2015) Genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to myeloproliferative neoplasms. Nature Communications, 6, [6691]. (doi:10.1038/ncomms7691).

Record type: Article

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 ?(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

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Accepted/In Press date: 20 February 2015
e-pub ahead of print date: 7 April 2015
Organisations: Cancer Sciences, Human Development & Health

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Local EPrints ID: 376406
URI: http://eprints.soton.ac.uk/id/eprint/376406
PURE UUID: 565d09e4-8b6f-4eb1-99cc-d9175e0f8377
ORCID for William Tapper: ORCID iD orcid.org/0000-0002-5896-1889
ORCID for Andrew Chase: ORCID iD orcid.org/0000-0001-6617-9953
ORCID for Nicholas C.P. Cross: ORCID iD orcid.org/0000-0001-5481-2555

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Date deposited: 27 Apr 2015 12:07
Last modified: 15 Mar 2024 03:11

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Contributors

Author: William Tapper ORCID iD
Author: Amy V. Jones
Author: Robert Kralovics
Author: Ashot S. Harutyunyan
Author: Katerina Zoi
Author: William Leung
Author: Anna L. Godfrey
Author: Paola Guglielmelli
Author: Alison Callaway
Author: Daniel Ward
Author: Paula Aranaz
Author: Helen E. White
Author: Katherine Waghorn
Author: Feng Lin
Author: Andrew Chase ORCID iD
Author: E. Joanna Baxter
Author: Cathy Maclean
Author: Jyoti Nangalia
Author: Edwin Chen
Author: Paul Evans
Author: Michael Short
Author: Andrew Jack
Author: Louise Wallis
Author: David Oscier
Author: Andrew S. Duncombe
Author: Anna Schuh
Author: Adam J. Mead
Author: Michael Griffiths
Author: Joanne Ewing
Author: Rosemary E. Gale
Author: Susanne Schnittger
Author: Torsten Haferlach
Author: Frank Stegelmann
Author: Konstanze Döhner
Author: Harald Grallert
Author: Konstantin Strauch
Author: Toshiko Tanaka
Author: Stefania Bandinelli
Author: Andreas Giannopoulos
Author: Lisa Pieri
Author: Carmela Mannarelli
Author: Heinz Gisslinger
Author: Giovanni Barosi
Author: Mario Cazzola
Author: Andreas Reiter
Author: Claire Harrison
Author: Peter Campbell
Author: Anthony R. Green
Author: Alessandro Vannucchi

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