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Clinical and biological implications of driver mutations in myelodysplastic syndromes

Clinical and biological implications of driver mutations in myelodysplastic syndromes
Clinical and biological implications of driver mutations in myelodysplastic syndromes
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 CMML and MDS-MPN) to explore the role of acquired mutations in MDS biology and clinical phenotype. 78% patients had one 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 driver mutations 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.
0006-4971
3616-3627
Papaemmanuil, Elli
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Gerstung, Moritz
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Malcovati, Luca
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Tauro, Sudhir
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Gundem, Gunes
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Van Loo, Peter
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Yoon, Chris J.
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Ellis, Peter
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Wedge, David C.
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Pellagatti, Andrea
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Shlien, Adam
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Groves, Michael John
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Forbes, Simon A,
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Raine, Keiran
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Hinton, Jon
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Mudie, Laura J.
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McLaren, Stuart
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Hardy, Claire
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Latimer, Calli
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Della Porta, Matteo
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O'Meara, Sarah
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Ambaglio, Llaria
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Galli, Anna
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Butler, Adam P.
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Waldin, Gunilla
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Teague, Jon W.
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Quek, Lynn
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Sternberg, Alex
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Gambacorti-Passerini, Carlo
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Cross, Nicholas C.P.
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Green, Anthony R.
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Vyas, Paresh
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Hellstrom-Lindberg, Eva
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Bowen, David
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Cazzola, Mario
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Stratton, Michael
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Campbell, Peter J.
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Papaemmanuil, Elli
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Gerstung, Moritz
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Malcovati, Luca
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Tauro, Sudhir
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Gundem, Gunes
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Van Loo, Peter
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Yoon, Chris J.
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Ellis, Peter
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Wedge, David C.
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Pellagatti, Andrea
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Groves, Michael John
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Forbes, Simon A,
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Raine, Keiran
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Hinton, Jon
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Mudie, Laura J.
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McLaren, Stuart
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Hardy, Claire
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Latimer, Calli
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Della Porta, Matteo
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O'Meara, Sarah
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Ambaglio, Llaria
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Galli, Anna
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Butler, Adam P.
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Waldin, Gunilla
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Teague, Jon W.
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Quek, Lynn
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Sternberg, Alex
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Gambacorti-Passerini, Carlo
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Cross, Nicholas C.P.
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Green, Anthony R.
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Boultwood, Jacqueline
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Vyas, Paresh
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Hellstrom-Lindberg, Eva
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Bowen, David
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Cazzola, Mario
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Stratton, Michael
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Campbell, Peter J.
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Papaemmanuil, Elli, Gerstung, Moritz, Malcovati, Luca, Tauro, Sudhir, Gundem, Gunes, Van Loo, Peter, Yoon, Chris J., Ellis, Peter, Wedge, David C., Pellagatti, Andrea, Shlien, Adam, Groves, Michael John, Forbes, Simon A,, Raine, Keiran, Hinton, Jon, Mudie, Laura J., McLaren, Stuart, Hardy, Claire, Latimer, Calli, Della Porta, Matteo, O'Meara, Sarah, Ambaglio, Llaria, Galli, Anna, Butler, Adam P., Waldin, Gunilla, Teague, Jon W., Quek, Lynn, Sternberg, Alex, Gambacorti-Passerini, Carlo, Cross, Nicholas C.P., Green, Anthony R., Boultwood, Jacqueline, Vyas, Paresh, Hellstrom-Lindberg, Eva, Bowen, David, Cazzola, Mario, Stratton, Michael and Campbell, Peter J. (2013) Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood, 122 (22), 3616-3627. (doi:10.1182/blood-2013-08-518886). (PMID:24030381)

Record type: Article

Abstract

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 CMML and MDS-MPN) to explore the role of acquired mutations in MDS biology and clinical phenotype. 78% patients had one 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 driver mutations 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.

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More information

e-pub ahead of print date: 12 September 2013
Published date: 21 November 2013
Organisations: Human Development & Health

Identifiers

Local EPrints ID: 357072
URI: http://eprints.soton.ac.uk/id/eprint/357072
ISSN: 0006-4971
PURE UUID: 6af4b3be-5ffc-44ec-a602-01562ccda4a0
ORCID for Nicholas C.P. Cross: ORCID iD orcid.org/0000-0001-5481-2555

Catalogue record

Date deposited: 26 Sep 2013 11:13
Last modified: 23 Jul 2022 01:49

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Contributors

Author: Elli Papaemmanuil
Author: Moritz Gerstung
Author: Luca Malcovati
Author: Sudhir Tauro
Author: Gunes Gundem
Author: Peter Van Loo
Author: Chris J. Yoon
Author: Peter Ellis
Author: David C. Wedge
Author: Andrea Pellagatti
Author: Adam Shlien
Author: Michael John Groves
Author: Simon A, Forbes
Author: Keiran Raine
Author: Jon Hinton
Author: Laura J. Mudie
Author: Stuart McLaren
Author: Claire Hardy
Author: Calli Latimer
Author: Matteo Della Porta
Author: Sarah O'Meara
Author: Llaria Ambaglio
Author: Anna Galli
Author: Adam P. Butler
Author: Gunilla Waldin
Author: Jon W. Teague
Author: Lynn Quek
Author: Alex Sternberg
Author: Carlo Gambacorti-Passerini
Author: Anthony R. Green
Author: Jacqueline Boultwood
Author: Paresh Vyas
Author: Eva Hellstrom-Lindberg
Author: David Bowen
Author: Mario Cazzola
Author: Michael Stratton
Author: Peter J. Campbell

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