Clinical and biological implications of driver mutations in myelodysplastic syndromes

被引:1465
|
作者
Papaemmanuil, Elli [1 ]
Gerstung, Moritz [1 ]
Malcovati, Luca [2 ]
Tauro, Sudhir [3 ]
Gundem, Gunes [1 ]
Van Loo, Peter [1 ,4 ,5 ]
Yoon, Chris J. [1 ]
Ellis, Peter [1 ]
Wedge, David C. [1 ]
Pellagatti, Andrea [6 ]
Shlien, Adam [1 ]
Groves, Michael John [3 ]
Forbes, Simon A. [1 ]
Raine, Keiran [1 ]
Hinton, Jon [1 ]
Mudie, Laura J. [1 ]
McLaren, Stuart [1 ]
Hardy, Claire [1 ]
Latimer, Calli [1 ]
Della Porta, Matteo G. [2 ]
O'Meara, Sarah [1 ]
Ambaglio, Ilaria [2 ]
Galli, Anna [2 ]
Butler, Adam P. [1 ]
Walldin, Gunilla [7 ]
Teague, Jon W. [1 ]
Quek, Lynn [8 ]
Sternberg, Alex [8 ,9 ]
Gambacorti-Passerini, Carlo [10 ]
Cross, Nicholas C. P. [11 ]
Green, Anthony R. [12 ,13 ]
Boultwood, Jacqueline [6 ]
Vyas, Paresh [7 ]
Hellstrom-Lindberg, Eva [7 ]
Bowen, David [14 ]
Cazzola, Mario [2 ]
Stratton, Michael R. [1 ]
Campbell, Peter J. [1 ,12 ,13 ]
机构
[1] Wellcome Trust Sanger Inst, Canc Genome Project, Hinxton CB10 1SA, England
[2] Univ Pavia, Policlin San Matteo, Fdn Ist Ricovero & Cura Carattere Sci, I-27100 Pavia, Italy
[3] Univ Dundee, Div Med Sci, Dundee, Scotland
[4] Vlaams Inst Biotechnol, Ctr Biol Dis, Louvain, Belgium
[5] Katholieke Univ Leuven, Dept Human Genet, Louvain, Belgium
[6] Univ Oxford, Nuffield Dept Clin Lab Sci, Oxford, England
[7] Karolinska Inst, Dept Haematol, Stockholm, Sweden
[8] Univ Oxford, Weatherall Inst Mol Med, Oxford, England
[9] Great Western Hosp, Dept Haematol, Swindon, Wilts, England
[10] Univ Milano Bicocca, Dept Haematol, Milan, Italy
[11] Univ Southampton, Fac Med, Southampton SO9 5NH, Hants, England
[12] Univ Cambridge, Dept Haematol, Cambridge, England
[13] Addenbrookes Hosp, Dept Haematol, Cambridge CB2 2QQ, England
[14] St James Hosp, St James Inst Oncol, Leeds LS9 7TF, W Yorkshire, England
基金
英国惠康基金; 英国医学研究理事会;
关键词
ACUTE MYELOID-LEUKEMIA; CHRONIC MYELOMONOCYTIC LEUKEMIA; WORLD-HEALTH-ORGANIZATION; ASXL1; MUTATIONS; GENE ASXL1; CANCER; EVOLUTION; TET2; CLASSIFICATION; LANDSCAPE;
D O I
10.1182/blood-2013-08-518886
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Myelodysplastic syndromes (MDS) are a heterogeneous group of chronic hematological malignancies characterized by dysplasia, ineffective hematopoiesis and a variable risk of progression to acute myeloid leukemia. Sequencing of MDS genomes has identified mutations in genes implicated in RNA splicing, DNA modification, chromatin regulation, and cell signaling. We sequenced 111 genes across 738 patients with MDS or closely related neoplasms (including chronic myelomonocytic leukemia and MDS-myeloproliferative neoplasms) to explore the role of acquired mutations in MDS biology and clinical phenotype. Seventy-eight percent of patients had 1 or more oncogenic mutations. We identify complex patterns of pairwise association between genes, indicative of epistatic interactions involving components of the spliceosome machinery and epigenetic modifiers. Coupled with inferences on subclonal mutations, these data suggest a hypothesis of genetic "predestination," in which early driver mutations, typically affecting genes involved in RNA splicing, dictate future trajectories of disease evolution with distinct clinical phenotypes. Driver mutations had equivalent prognostic significance, whether clonal or subclonal, and leukemia-free survival deteriorated steadily as numbers of drivermutations increased. Thus, analysis of oncogenic mutations in large, well-characterized cohorts of patients illustrates the interconnections between the cancer genome and disease biology, with considerable potential for clinical application.
引用
收藏
页码:3616 / 3627
页数:12
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