The complex genetic landscape of familial MDS and AML reveals pathogenic germline variants

被引：84

作者：

Rio-Machin, Ana ^{[1
]}

Vulliamy, Tom ^{[2
]}

Hug, Nele ^{[3
]}

Walne, Amanda ^{[2
]}

Tawana, Kiran ^{[4
]}

Cardoso, Shirleny ^{[2
]}

Ellison, Alicia ^{[2
]}

Pontikos, Nikolas ^{[2
]}

Wang, Jun ^{[5
]}

Tummala, Hemanth ^{[2
]}

Al Seraihi, Ahad Fahad H. ^{[1
]}

Alnajar, Jenna ^{[2
]}

Bewicke-Copley, Findlay ^{[1
]}

Armes, Hannah ^{[1
]}

Barnett, Michael ^{[6
]}

Bloor, Adrian ^{[7
]}

Bodor, Csaba ^{[8
]}

Bowen, David ^{[9
]}

Fenaux, Pierre ^{[10
]}

Green, Andrew ^{[11
]}

Hallahan, Andrew ^{[12
,13
]}

Hjorth-Hansen, Henrik ^{[14
,15
]}

Hossain, Upal ^{[16
]}

Killick, Sally ^{[17
]}

Lawson, Sarah ^{[18
]}

Layton, Mark ^{[19
]}

Male, Alison M. ^{[20
]}

Marsh, Judith ^{[21
]}

Mehta, Priyanka ^{[22
]}

Mous, Rogier ^{[23
]}

Nomdedeu, Josep F. ^{[24
]}

Owen, Carolyn ^{[25
]}

Pavlu, Jiri ^{[19
]}

Payne, Elspeth M. ^{[26
]}

Protheroe, Rachel E. ^{[22
]}

Preudhomme, Claude ^{[27
,28
]}

Pujol-Moix, Nuria ^{[24
]}

Renneville, Aline ^{[29
]}

Russell, Nigel ^{[30
]}

Saggar, Anand ^{[31
]}

Sciuccati, Gabriela ^{[32
]}

Taussig, David ^{[33
]}

Toze, Cynthia L. ^{[6
]}

Uyttebroeck, Anne ^{[34
]}

Vandenberghe, Peter ^{[34
]}

Schlegelberger, Brigitte ^{[35
]}

Ripperger, Tim ^{[35
]}

Steinemann, Doris ^{[35
]}

Wu, John ^{[36
]}

Mason, Joanne ^{[37
]}

机构：

[1] Queen Mary Univ London, Ctr Haematooncol, Barts Canc Inst, London, England

[2] Queen Mary Univ London, Ctr Genom & Child Hlth, Blizard Inst, London, England

[3] Univ Edinburgh, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland

[4] Addenbrookes Hosp, Dept Haematol, Cambridge, England

[5] Queen Mary Univ London, Ctr Mol Oncol, Barts Canc Inst, London, England

[6] Univ British Columbia, Fac Med, Dept Med, Leukemia BMT Program British Columbia,Div Hematol, Vancouver, BC, Canada

[7] Christie Hosp, Dept Haematol, Manchester, Lancs, England

[8] Semmelweis Univ, Dept Pathol & Expt Canc Res 1, MTA SE Lendulet Mol Oncohematol Res Grp, Budapest, Hungary

[9] St James Univ Hosp, Dept Haematol, Leeds, W Yorkshire, England

[10] Hop St Louis Univ Paris, Serv Hematol Seniors, Paris, France

[11] Our Ladys Childrens Hosp, Natl Ctr Med Genet, Dublin, Ireland

[12] Queensland Childrens Hosp, Childrens Hlth Queensland Hosp, South Brisbane, Qld, Australia

[13] Queensland Childrens Hosp, Hlth Serv, South Brisbane, Qld, Australia

[14] Norwegian Univ Sci & Technol NTNU, St Olays Hosp, Dept Hematol, Trondheim, Norway

[15] Norwegian Univ Sci & Technol NTNU, Inst Canc Res & Mol Med IKM, Trondheim, Norway

[16] Barts NHS Trust, Dept Haematol, Whipps Cross Hosp, London, England

[17] Royal Bournemouth Hosp NHS Fdn Trust, Dept Haematol, Bournemouth, Dorset, England

[18] Birmingham Childrens Hosp, Dept Haematol, Birmingham, W Midlands, England

[19] Imperial Coll London, Hammersmith Hosp, Ctr Haematol, London, England

[20] Great Ormond St Hosp Sick Children, Clin Genet Unit, London, England

[21] Kings Coll Hosp London, Haematol Inst, Dept Haematol Med, London, England

[22] Univ Hosp Bristol NHS Fdn Trust, Bristol Haematol Unit, Bristol, Avon, England

[23] Univ Med Ctr Utrecht, UMC Utrecht Canc Ctr, Huispostnummer, Utrecht, Netherlands

[24] Univ Autonoma Barcelona, Lab Hematol, Hosp Santa Creu & St Pau, Barcelona, Spain

[25] Foothills Med Ctr, Div Hematol & Hematol Malignancies, Calgary, AB, Canada

[26] UCL, UCL Canc Inst, Dept Haematol, London, England

[27] Ctr Hosp Reg Univ Lille, Biol & Pathol Ctr, Lab Hematol, Lille, France

[28] Univ Lille, Jean Pierre Aubert Res Ctr, INSERM, Lille, France

[29] Broad Inst Harvard & MIT, Cambridge, MA USA

[30] Nottingham Univ Hosp NHS Trust, Ctr Clin Haematol, Nottingham, England

[31] St George Hosp, Clin Genet, Med Sch, London, England

[32] Hosp Pediat Prof Dr Juan P Garrahan, Serv Hematol & Oncol, Buenos Aires, DF, Argentina

[33] Royal Marsden Hosp, Haemato Oncol Dept, Sutton, Surrey, England

[34] Univ Hosp Leuven, Dept Hematol, Leuven, Belgium

[35] Hannover Med Sch, Inst Humangenet, Hannover, Germany

[36] British Columbia Childrens Hosp, Vancouver, BC, Canada

[37] Birmingham Womens NHS Fdn Trust, West Midlands Reg Genet Lab, Birmingham, W Midlands, England

[38] Hamad Bin Khalifa Med City HBKM, Dept Lab Med & Pathol, Qatar Rehabil Inst, Doha, Qatar

[39] Barts NHS Trust, St Bartholomews Hosp, Dept Haematol, London, England

[40] UCL, Genet Inst, London, England

[41] Barts Hlth NHS Trust, London, England

来源：

NATURE COMMUNICATIONS | 2020年 / 11卷 / 01期

基金：

英国医学研究理事会;

关键词：

ACUTE MYELOID-LEUKEMIA; SAMD9L MUTATIONS CAUSE; PLATELET DISORDER; MYELODYSPLASTIC SYNDROME; DYSKERATOSIS-CONGENITA; MECHANISTIC INSIGHTS; RUNX1; MUTATIONS; SELF-RENEWAL; CEBPA; LINE;

D O I：

10.1038/s41467-020-14829-5

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The inclusion of familial myeloid malignancies as a separate disease entity in the revised WHO classification has renewed efforts to improve the recognition and management of this group of at risk individuals. Here we report a cohort of 86 acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) families with 49 harboring germline variants in 16 previously defined loci (57%). Whole exome sequencing in a further 37 uncharacterized families (43%) allowed us to rationalize 65 new candidate loci, including genes mutated in rare hematological syndromes (ADA, GP6, IL17RA, PRF1 and SEC23B), reported in prior MDS/AML or inherited bone marrow failure series (DNAH9, NAPRT1 and SH2B3) or variants at novel loci (DHX34) that appear specific to inherited forms of myeloid malignancies. Altogether, our series of MDS/AML families offer novel insights into the etiology of myeloid malignancies and provide a framework to prioritize variants for inclusion into routine diagnostics and patient management.

引用

页数：12

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