Common variation at 1q23.3, 2p23.3, 2q33.3, and 2p21 influences risk of acute myeloid leukemia

Diyanath Ranasinghe; Wei-Yu Lin; Sarah E Fordham; Abrar A Alharbi; Nicola J Sunter; Claire Elstob; Mohammed H Nahari; Yaobo Xu; Catherine Park; Eric Hungate; Anne Quante; Konstantin Strauch; Christian Gieger; Andrew D Skol; Thahira Rahman; Lara Sucheston-Campbell; Theresa Hahn; Alyssa Ione Clay-Gilmour; Gail L Jones; Helen J Marr; Graham H Jackson; Tobias Menne; Matthew Collin; Adam Ivey; Robert K Hills; Alan K Burnett; Nigel H Russell; Jude Fitzgibbon; Richard A Larson; Michelle M Le Beau; Wendy Stock; Olaf Heidenreich; Amir Enshaei; Dumni Gunasinghe; Zoë L Hawking; Holly S Heslop; Devi Nandana; Bingjing Di; Anna Plokhuta; Imogen T Brown; David J Allsup; Richard S Houlston; Andrew Collins; Paul Milne; Jean Norden; Anne M Dickinson; Beverley Clare Lendrem; Ann K Daly; Louise Palm; Kim Piechocki; Sally Jeffries; Martin Bornhäuser; Christoph Röllig; Heidi Altmann; Leo Ruhnke; Desiree Kunadt; Lisa Wagenführ; Heather J Cordell; Rebecca Darlay; Mette K Andersen; Maria Chiara Fontana; Giovanni Martinelli; Giovanni Marconi; Miguel Ángel Sanz; José Cervera; Ines Gomez-Segui; Thomas Cluzeau; Chimene Moreilhon; Sophie Raynaud; Heinz Sill; Maria Teresa Voso; Hervé Dombret; Meyling H Cheok; Claude Preudhomme; Rosemary E Gale; David C Linch; Julia Weisinger; Andras Masszi; Daniel Nowak; Wolf Karsten Hofmann; Amanda Frances Gilkes; Kimmo Porkka; Jelena D Milosevic Feenstra; Robert Kralovics; Junke Wang; Manja Meggendorfer; Torsten Haferlach; Szilvia Krizsán; Csaba Bödör; Brian L Parkin; Sami N Malek; Friedrich Stölzel; Kenan Onel; James M Allan

doi:10.1182/blood.2025031266

Common variation at 1q23.3, 2p23.3, 2q33.3, and 2p21 influences risk of acute myeloid leukemia

Diyanath Ranasinghe, Wei-Yu Lin, Sarah E Fordham, Abrar A Alharbi, Nicola J Sunter, Claire Elstob, Mohammed H Nahari, Yaobo Xu, Catherine Park, Eric Hungate, Anne Quante, Konstantin Strauch, Christian Gieger, Andrew D Skol, Thahira Rahman, Lara Sucheston-Campbell, Theresa Hahn, Alyssa Ione Clay-Gilmour, Gail L Jones, Helen J MarrGraham H Jackson, Tobias Menne, Matthew Collin, Adam Ivey, Robert K Hills, Alan K Burnett, Nigel H Russell, Jude Fitzgibbon, Richard A Larson, Michelle M Le Beau, Wendy Stock, Olaf Heidenreich, Amir Enshaei, Dumni Gunasinghe, Zoë L Hawking, Holly S Heslop, Devi Nandana, Bingjing Di, Anna Plokhuta, Imogen T Brown, David J Allsup, Richard S Houlston, Andrew Collins, Paul Milne, Jean Norden, Anne M Dickinson, Beverley Clare Lendrem, Ann K Daly, Louise Palm, Kim Piechocki, Sally Jeffries, Martin Bornhäuser, Christoph Röllig, Heidi Altmann, Leo Ruhnke, Desiree Kunadt, Lisa Wagenführ, Heather J Cordell, Rebecca Darlay, Mette K Andersen, Maria Chiara Fontana, Giovanni Martinelli, Giovanni Marconi, Miguel Ángel Sanz, José Cervera, Ines Gomez-Segui, Thomas Cluzeau, Chimene Moreilhon, Sophie Raynaud, Heinz Sill, Maria Teresa Voso, Hervé Dombret, Meyling H Cheok, Claude Preudhomme, Rosemary E Gale, David C Linch, Julia Weisinger, Andras Masszi, Daniel Nowak, Wolf Karsten Hofmann, Amanda Frances Gilkes, Kimmo Porkka, Jelena D Milosevic Feenstra, Robert Kralovics, Junke Wang, Manja Meggendorfer, Torsten Haferlach, Szilvia Krizsán, Csaba Bödör, Brian L Parkin, Sami N Malek, Friedrich Stölzel, Kenan Onel, James M Allan

Afdeling for Genetik DIA

Abstract

Acute myeloid leukemia (AML) is a complex hematological malignancy with multiple disease sub-groups defined by somatic mutations and heterogeneous outcomes. Although genome-wide association studies (GWAS) have identified a small number of common genetic variants influencing AML risk, the heritable component of this disease outside of familial susceptibility remains largely undefined. Here we perform a meta-analysis of four published GWAS plus two new GWAS, totalling 4710 AML cases and 12938 controls. We identify a new genome-wide significant risk locus for pan-AML at 2p23.3 (rs4665765; P=1.35x10-8; EFR3B, POMC, DNMT3A, DNAJC27) which also significantly associates with patient survival (P=6.09x10-3). Our analysis also identifies three new genome-wide significant risk loci for disease sub-groups, including AML with deletions of chromosome 5 and/or 7 at 1q23.3 (rs12078864; P=7.0x10-10; DUSP23) and cytogenetically complex AML at 2q33.3 (rs12988876; P=3.28x10-8; PARD3B) and 2p21 (rs79918355; P=1.60x10-9; EPCAM). We also investigated loci previously associated with risk of clonal hematopoiesis (CH) or clonal hematopoiesis of indeterminate potential (CHIP) and identified several variants associated with risk of AML. Our results further inform on AML etiology and demonstrate the existence of disease sub-group specific risk loci.

Originalsprog	Engelsk
Tidsskrift	Blood
ISSN	0006-4971
DOI	https://doi.org/10.1182/blood.2025031266
Status	E-pub ahead of print - 29 jan. 2026

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10.1182/blood.2025031266Licens: CC BY-NC-ND

Citationsformater

Ranasinghe, D., Lin, W.-Y., Fordham, S. E., Alharbi, A. A., Sunter, N. J., Elstob, C., Nahari, M. H., Xu, Y., Park, C., Hungate, E., Quante, A., Strauch, K., Gieger, C., Skol, A. D., Rahman, T., Sucheston-Campbell, L., Hahn, T., Clay-Gilmour, A. I., Jones, G. L., ... Allan, J. M. (2026). Common variation at 1q23.3, 2p23.3, 2q33.3, and 2p21 influences risk of acute myeloid leukemia. Blood. Advance online publication. https://doi.org/10.1182/blood.2025031266

Ranasinghe, D, Lin, W-Y, Fordham, SE, Alharbi, AA, Sunter, NJ, Elstob, C, Nahari, MH, Xu, Y, Park, C, Hungate, E, Quante, A, Strauch, K, Gieger, C, Skol, AD, Rahman, T, Sucheston-Campbell, L, Hahn, T, Clay-Gilmour, AI, Jones, GL, Marr, HJ, Jackson, GH, Menne, T, Collin, M, Ivey, A, Hills, RK, Burnett, AK, Russell, NH, Fitzgibbon, J, Larson, RA, Le Beau, MM, Stock, W, Heidenreich, O, Enshaei, A, Gunasinghe, D, Hawking, ZL, Heslop, HS, Nandana, D, Di, B, Plokhuta, A, Brown, IT, Allsup, DJ, Houlston, RS, Collins, A, Milne, P, Norden, J, Dickinson, AM, Lendrem, BC, Daly, AK, Palm, L, Piechocki, K, Jeffries, S, Bornhäuser, M, Röllig, C, Altmann, H, Ruhnke, L, Kunadt, D, Wagenführ, L, Cordell, HJ, Darlay, R, Andersen, MK, Fontana, MC, Martinelli, G, Marconi, G, Sanz, MÁ, Cervera, J, Gomez-Segui, I, Cluzeau, T, Moreilhon, C, Raynaud, S, Sill, H, Voso, MT, Dombret, H, Cheok, MH, Preudhomme, C, Gale, RE, Linch, DC, Weisinger, J, Masszi, A, Nowak, D, Hofmann, WK, Gilkes, AF, Porkka, K, Milosevic Feenstra, JD, Kralovics, R, Wang, J, Meggendorfer, M, Haferlach, T, Krizsán, S, Bödör, C, Parkin, BL, Malek, SN, Stölzel, F, Onel, K & Allan, JM 2026, 'Common variation at 1q23.3, 2p23.3, 2q33.3, and 2p21 influences risk of acute myeloid leukemia', Blood. https://doi.org/10.1182/blood.2025031266

@article{203853bf7de84528ab7d499c28f937b8,

title = "Common variation at 1q23.3, 2p23.3, 2q33.3, and 2p21 influences risk of acute myeloid leukemia",

abstract = "Acute myeloid leukemia (AML) is a complex hematological malignancy with multiple disease sub-groups defined by somatic mutations and heterogeneous outcomes. Although genome-wide association studies (GWAS) have identified a small number of common genetic variants influencing AML risk, the heritable component of this disease outside of familial susceptibility remains largely undefined. Here we perform a meta-analysis of four published GWAS plus two new GWAS, totalling 4710 AML cases and 12938 controls. We identify a new genome-wide significant risk locus for pan-AML at 2p23.3 (rs4665765; P=1.35x10-8; EFR3B, POMC, DNMT3A, DNAJC27) which also significantly associates with patient survival (P=6.09x10-3). Our analysis also identifies three new genome-wide significant risk loci for disease sub-groups, including AML with deletions of chromosome 5 and/or 7 at 1q23.3 (rs12078864; P=7.0x10-10; DUSP23) and cytogenetically complex AML at 2q33.3 (rs12988876; P=3.28x10-8; PARD3B) and 2p21 (rs79918355; P=1.60x10-9; EPCAM). We also investigated loci previously associated with risk of clonal hematopoiesis (CH) or clonal hematopoiesis of indeterminate potential (CHIP) and identified several variants associated with risk of AML. Our results further inform on AML etiology and demonstrate the existence of disease sub-group specific risk loci.",

author = "Diyanath Ranasinghe and Wei-Yu Lin and Fordham, {Sarah E} and Alharbi, {Abrar A} and Sunter, {Nicola J} and Claire Elstob and Nahari, {Mohammed H} and Yaobo Xu and Catherine Park and Eric Hungate and Anne Quante and Konstantin Strauch and Christian Gieger and Skol, {Andrew D} and Thahira Rahman and Lara Sucheston-Campbell and Theresa Hahn and Clay-Gilmour, {Alyssa Ione} and Jones, {Gail L} and Marr, {Helen J} and Jackson, {Graham H} and Tobias Menne and Matthew Collin and Adam Ivey and Hills, {Robert K} and Burnett, {Alan K} and Russell, {Nigel H} and Jude Fitzgibbon and Larson, {Richard A} and {Le Beau}, {Michelle M} and Wendy Stock and Olaf Heidenreich and Amir Enshaei and Dumni Gunasinghe and Hawking, {Zo{\"e} L} and Heslop, {Holly S} and Devi Nandana and Bingjing Di and Anna Plokhuta and Brown, {Imogen T} and Allsup, {David J} and Houlston, {Richard S} and Andrew Collins and Paul Milne and Jean Norden and Dickinson, {Anne M} and Lendrem, {Beverley Clare} and Daly, {Ann K} and Louise Palm and Kim Piechocki and Sally Jeffries and Martin Bornh{\"a}user and Christoph R{\"o}llig and Heidi Altmann and Leo Ruhnke and Desiree Kunadt and Lisa Wagenf{\"u}hr and Cordell, {Heather J} and Rebecca Darlay and Andersen, {Mette K} and Fontana, {Maria Chiara} and Giovanni Martinelli and Giovanni Marconi and Sanz, {Miguel {\'A}ngel} and Jos{\'e} Cervera and Ines Gomez-Segui and Thomas Cluzeau and Chimene Moreilhon and Sophie Raynaud and Heinz Sill and Voso, {Maria Teresa} and Herv{\'e} Dombret and Cheok, {Meyling H} and Claude Preudhomme and Gale, {Rosemary E} and Linch, {David C} and Julia Weisinger and Andras Masszi and Daniel Nowak and Hofmann, {Wolf Karsten} and Gilkes, {Amanda Frances} and Kimmo Porkka and {Milosevic Feenstra}, {Jelena D} and Robert Kralovics and Junke Wang and Manja Meggendorfer and Torsten Haferlach and Szilvia Krizs{\'a}n and Csaba B{\"o}d{\"o}r and Parkin, {Brian L} and Malek, {Sami N} and Friedrich St{\"o}lzel and Kenan Onel and Allan, {James M}",

note = "Copyright {\textcopyright} 2026 American Society of Hematology.",

year = "2026",

month = jan,

day = "29",

doi = "10.1182/blood.2025031266",

language = "English",

journal = "Blood",

issn = "0006-4971",

publisher = "Elsevier BV",

}

TY - JOUR

T1 - Common variation at 1q23.3, 2p23.3, 2q33.3, and 2p21 influences risk of acute myeloid leukemia

AU - Ranasinghe, Diyanath

AU - Lin, Wei-Yu

AU - Fordham, Sarah E

AU - Alharbi, Abrar A

AU - Sunter, Nicola J

AU - Elstob, Claire

AU - Nahari, Mohammed H

AU - Xu, Yaobo

AU - Park, Catherine

AU - Hungate, Eric

AU - Quante, Anne

AU - Strauch, Konstantin

AU - Gieger, Christian

AU - Skol, Andrew D

AU - Rahman, Thahira

AU - Sucheston-Campbell, Lara

AU - Hahn, Theresa

AU - Clay-Gilmour, Alyssa Ione

AU - Jones, Gail L

AU - Marr, Helen J

AU - Jackson, Graham H

AU - Menne, Tobias

AU - Collin, Matthew

AU - Ivey, Adam

AU - Hills, Robert K

AU - Burnett, Alan K

AU - Russell, Nigel H

AU - Fitzgibbon, Jude

AU - Larson, Richard A

AU - Le Beau, Michelle M

AU - Stock, Wendy

AU - Heidenreich, Olaf

AU - Enshaei, Amir

AU - Gunasinghe, Dumni

AU - Hawking, Zoë L

AU - Heslop, Holly S

AU - Nandana, Devi

AU - Di, Bingjing

AU - Plokhuta, Anna

AU - Brown, Imogen T

AU - Allsup, David J

AU - Houlston, Richard S

AU - Collins, Andrew

AU - Milne, Paul

AU - Norden, Jean

AU - Dickinson, Anne M

AU - Lendrem, Beverley Clare

AU - Daly, Ann K

AU - Palm, Louise

AU - Piechocki, Kim

AU - Jeffries, Sally

AU - Bornhäuser, Martin

AU - Röllig, Christoph

AU - Altmann, Heidi

AU - Ruhnke, Leo

AU - Kunadt, Desiree

AU - Wagenführ, Lisa

AU - Cordell, Heather J

AU - Darlay, Rebecca

AU - Andersen, Mette K

AU - Fontana, Maria Chiara

AU - Martinelli, Giovanni

AU - Marconi, Giovanni

AU - Sanz, Miguel Ángel

AU - Cervera, José

AU - Gomez-Segui, Ines

AU - Cluzeau, Thomas

AU - Moreilhon, Chimene

AU - Raynaud, Sophie

AU - Sill, Heinz

AU - Voso, Maria Teresa

AU - Dombret, Hervé

AU - Cheok, Meyling H

AU - Preudhomme, Claude

AU - Gale, Rosemary E

AU - Linch, David C

AU - Weisinger, Julia

AU - Masszi, Andras

AU - Nowak, Daniel

AU - Hofmann, Wolf Karsten

AU - Gilkes, Amanda Frances

AU - Porkka, Kimmo

AU - Milosevic Feenstra, Jelena D

AU - Kralovics, Robert

AU - Wang, Junke

AU - Meggendorfer, Manja

AU - Haferlach, Torsten

AU - Krizsán, Szilvia

AU - Bödör, Csaba

AU - Parkin, Brian L

AU - Malek, Sami N

AU - Stölzel, Friedrich

AU - Onel, Kenan

AU - Allan, James M

PY - 2026/1/29

Y1 - 2026/1/29

N2 - Acute myeloid leukemia (AML) is a complex hematological malignancy with multiple disease sub-groups defined by somatic mutations and heterogeneous outcomes. Although genome-wide association studies (GWAS) have identified a small number of common genetic variants influencing AML risk, the heritable component of this disease outside of familial susceptibility remains largely undefined. Here we perform a meta-analysis of four published GWAS plus two new GWAS, totalling 4710 AML cases and 12938 controls. We identify a new genome-wide significant risk locus for pan-AML at 2p23.3 (rs4665765; P=1.35x10-8; EFR3B, POMC, DNMT3A, DNAJC27) which also significantly associates with patient survival (P=6.09x10-3). Our analysis also identifies three new genome-wide significant risk loci for disease sub-groups, including AML with deletions of chromosome 5 and/or 7 at 1q23.3 (rs12078864; P=7.0x10-10; DUSP23) and cytogenetically complex AML at 2q33.3 (rs12988876; P=3.28x10-8; PARD3B) and 2p21 (rs79918355; P=1.60x10-9; EPCAM). We also investigated loci previously associated with risk of clonal hematopoiesis (CH) or clonal hematopoiesis of indeterminate potential (CHIP) and identified several variants associated with risk of AML. Our results further inform on AML etiology and demonstrate the existence of disease sub-group specific risk loci.

AB - Acute myeloid leukemia (AML) is a complex hematological malignancy with multiple disease sub-groups defined by somatic mutations and heterogeneous outcomes. Although genome-wide association studies (GWAS) have identified a small number of common genetic variants influencing AML risk, the heritable component of this disease outside of familial susceptibility remains largely undefined. Here we perform a meta-analysis of four published GWAS plus two new GWAS, totalling 4710 AML cases and 12938 controls. We identify a new genome-wide significant risk locus for pan-AML at 2p23.3 (rs4665765; P=1.35x10-8; EFR3B, POMC, DNMT3A, DNAJC27) which also significantly associates with patient survival (P=6.09x10-3). Our analysis also identifies three new genome-wide significant risk loci for disease sub-groups, including AML with deletions of chromosome 5 and/or 7 at 1q23.3 (rs12078864; P=7.0x10-10; DUSP23) and cytogenetically complex AML at 2q33.3 (rs12988876; P=3.28x10-8; PARD3B) and 2p21 (rs79918355; P=1.60x10-9; EPCAM). We also investigated loci previously associated with risk of clonal hematopoiesis (CH) or clonal hematopoiesis of indeterminate potential (CHIP) and identified several variants associated with risk of AML. Our results further inform on AML etiology and demonstrate the existence of disease sub-group specific risk loci.

U2 - 10.1182/blood.2025031266

DO - 10.1182/blood.2025031266

M3 - Journal article

C2 - 41610418

SN - 0006-4971

JO - Blood

JF - Blood

ER -

Common variation at 1q23.3, 2p23.3, 2q33.3, and 2p21 influences risk of acute myeloid leukemia

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