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Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukemia

Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukemia
Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukemia
Histone methyltransferases (HMTs) are important epigenetic regulators of gene transcription and are disrupted at the genomic level in a spectrum of human tumors including haematological malignancies. Using high-resolution SNP-arrays, we identified recurrent deletions of the SETD2 locus in 3% (8/261) of chronic lymphocytic leukemia (CLL) patients. Further validation in two independent cohorts showed that SETD2 deletions were associated with loss of TP53, genomic complexity and chromothripsis. With next generation sequencing we detected mutations of SETD2 in an additional 3.8% of patients (23/602). In most cases, SETD2-deletions or mutations were often observed as a 56 clonal event and always as a mono-allelic lesion, leading to reduced mRNA expression in SETD2-disrupted cases. Patients with SETD2 abnormalities and wild-type TP53 and ATM from five clinical trials employing chemotherapy or chemo-immunotherapy, had reduced progression-free and overall survival compared to cases wild-type for all three genes. Consistent with its postulated role as a tumor suppressor, our data highlights SETD2 aberration as a recurrent, early loss-of-function event in CLL pathobiology linked to aggressive disease.
0887-6924
2179–2186
Parker, Helen
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Rose-Zerilli, Matthew J.J.
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Larrayoz, Marta
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Clifford, Ruth
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Edelmann, Jennifer
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Blakemore, Stuart
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Gibson, Jane
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Wang, Jun
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Ljungstrom, Viktor
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Wojdacz, Tomasz K.
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Chaplin, Tracy
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Roghanian, Ali
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Davis, Zadie
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Parker, Anton
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Tausch, Eugen
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Ntoufa, Stavroula
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Ramos, Sara
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Robbe, Pauline
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Alsolami, Reem
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Steele, Andrew J.
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Packham, Graham
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Rodriquez-Vicente, Ana E.
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Brown, Lee
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McNicholl, Feargal
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Forconi, Francesco
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Pettitt, Andrew
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Hillmen, Peter
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Dyer, Martin
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Cragg, Mark S.
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Chelala, Claude
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Oakes, Christopher C.
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Rosenquist, Richard
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Stamatopoulos, Kostas
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Stilgenbauer, Stephan
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Knight, Samantha
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Schuh, Anna
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Oscier, David G.
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Strefford, Jonathan C.
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Parker, Helen
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Rose-Zerilli, Matthew J.J.
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Larrayoz, Marta
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Clifford, Ruth
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Edelmann, Jennifer
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Blakemore, Stuart
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Gibson, Jane
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Wang, Jun
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Ljungstrom, Viktor
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Wojdacz, Tomasz K.
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Chaplin, Tracy
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Roghanian, Ali
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Davis, Zadie
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Parker, Anton
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Tausch, Eugen
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Ramos, Sara
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Steele, Andrew J.
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Packham, Graham
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Rodriquez-Vicente, Ana E.
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Brown, Lee
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McNicholl, Feargal
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Forconi, Francesco
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Pettitt, Andrew
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Hillmen, Peter
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Dyer, Martin
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Cragg, Mark S.
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Chelala, Claude
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Oakes, Christopher C.
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Rosenquist, Richard
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Stamatopoulos, Kostas
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Stilgenbauer, Stephan
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Knight, Samantha
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Schuh, Anna
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Oscier, David G.
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Strefford, Jonathan C.
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Parker, Helen, Rose-Zerilli, Matthew J.J., Larrayoz, Marta, Clifford, Ruth, Edelmann, Jennifer, Blakemore, Stuart, Gibson, Jane, Wang, Jun, Ljungstrom, Viktor, Wojdacz, Tomasz K., Chaplin, Tracy, Roghanian, Ali, Davis, Zadie, Parker, Anton, Tausch, Eugen, Ntoufa, Stavroula, Ramos, Sara, Robbe, Pauline, Alsolami, Reem, Steele, Andrew J., Packham, Graham, Rodriquez-Vicente, Ana E., Brown, Lee, McNicholl, Feargal, Forconi, Francesco, Pettitt, Andrew, Hillmen, Peter, Dyer, Martin, Cragg, Mark S., Chelala, Claude, Oakes, Christopher C., Rosenquist, Richard, Stamatopoulos, Kostas, Stilgenbauer, Stephan, Knight, Samantha, Schuh, Anna, Oscier, David G. and Strefford, Jonathan C. (2016) Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukemia. Leukemia, 30, 2179–2186. (doi:10.1038/leu.2016.134).

Record type: Article

Abstract

Histone methyltransferases (HMTs) are important epigenetic regulators of gene transcription and are disrupted at the genomic level in a spectrum of human tumors including haematological malignancies. Using high-resolution SNP-arrays, we identified recurrent deletions of the SETD2 locus in 3% (8/261) of chronic lymphocytic leukemia (CLL) patients. Further validation in two independent cohorts showed that SETD2 deletions were associated with loss of TP53, genomic complexity and chromothripsis. With next generation sequencing we detected mutations of SETD2 in an additional 3.8% of patients (23/602). In most cases, SETD2-deletions or mutations were often observed as a 56 clonal event and always as a mono-allelic lesion, leading to reduced mRNA expression in SETD2-disrupted cases. Patients with SETD2 abnormalities and wild-type TP53 and ATM from five clinical trials employing chemotherapy or chemo-immunotherapy, had reduced progression-free and overall survival compared to cases wild-type for all three genes. Consistent with its postulated role as a tumor suppressor, our data highlights SETD2 aberration as a recurrent, early loss-of-function event in CLL pathobiology linked to aggressive disease.

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Accepted/In Press date: 4 May 2016
e-pub ahead of print date: 20 May 2016
Published date: 10 June 2016
Organisations: Cancer Sciences

Identifiers

Local EPrints ID: 394139
URI: https://eprints.soton.ac.uk/id/eprint/394139
ISSN: 0887-6924
PURE UUID: 4852857e-d791-49d8-bae7-a78fd575ecc1
ORCID for Helen Parker: ORCID iD orcid.org/0000-0001-8308-9781
ORCID for Matthew J.J. Rose-Zerilli: ORCID iD orcid.org/0000-0002-1064-5350
ORCID for Jane Gibson: ORCID iD orcid.org/0000-0002-0973-8285
ORCID for Andrew J. Steele: ORCID iD orcid.org/0000-0003-0667-1596
ORCID for Graham Packham: ORCID iD orcid.org/0000-0002-9232-5691
ORCID for Mark S. Cragg: ORCID iD orcid.org/0000-0003-2077-089X
ORCID for Jonathan C. Strefford: ORCID iD orcid.org/0000-0002-0972-2881

Catalogue record

Date deposited: 12 May 2016 09:12
Last modified: 10 Dec 2019 01:52

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Contributors

Author: Helen Parker ORCID iD
Author: Marta Larrayoz
Author: Ruth Clifford
Author: Jennifer Edelmann
Author: Stuart Blakemore
Author: Jane Gibson ORCID iD
Author: Jun Wang
Author: Viktor Ljungstrom
Author: Tomasz K. Wojdacz
Author: Tracy Chaplin
Author: Ali Roghanian
Author: Zadie Davis
Author: Anton Parker
Author: Eugen Tausch
Author: Stavroula Ntoufa
Author: Sara Ramos
Author: Pauline Robbe
Author: Reem Alsolami
Author: Graham Packham ORCID iD
Author: Ana E. Rodriquez-Vicente
Author: Lee Brown
Author: Feargal McNicholl
Author: Andrew Pettitt
Author: Peter Hillmen
Author: Martin Dyer
Author: Mark S. Cragg ORCID iD
Author: Claude Chelala
Author: Christopher C. Oakes
Author: Richard Rosenquist
Author: Kostas Stamatopoulos
Author: Stephan Stilgenbauer
Author: Samantha Knight
Author: Anna Schuh
Author: David G. Oscier

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