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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, H.
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Rose-Zerilli, M.J.J.
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Larrayoz, M.
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Clifford, R.
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Edelmann, J.
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Blakemore, S.
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Gibson, J.
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Wang, J.
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Ljungström, V.
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Roghanian, A.
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Davis, Z.
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Parker, A.
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Ntoufa, S.
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Ramos, S.
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Robbe, P.
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Alsolami, R.
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Steele, A.J.
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Packham, G.
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Rodriquez-Vicente, A.E.
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Brown, L.
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McNicholl, F.
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Forconi, F.
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Pettitt, A.
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Hillmen, P.
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Dyer, M.
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Cragg, M.S.
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Chelala, C.
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Oakes, C.C.
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Rosenquist, R.
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Stamatopoulos, K.
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Stilgenbauer, S.
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Knight, S.
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Schuh, A.
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Oscier, D.G.
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Strefford, J.C.
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Parker, H.
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Rose-Zerilli, M.J.J.
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Larrayoz, M.
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Clifford, R.
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Edelmann, J.
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Blakemore, S.
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Gibson, J.
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Wang, J.
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Ljungström, V.
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Roghanian, A.
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Davis, Z.
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Tausch, E.
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McNicholl, F.
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Forconi, F.
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Pettitt, A.
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Hillmen, P.
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Dyer, M.
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Cragg, M.S.
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Chelala, C.
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Oakes, C.C.
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Rosenquist, R.
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Stamatopoulos, K.
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Stilgenbauer, S.
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Knight, S.
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Schuh, A.
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Oscier, D.G.
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Strefford, J.C.
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Parker, H., Rose-Zerilli, M.J.J., Larrayoz, M., Clifford, R., Edelmann, J., Blakemore, S., Gibson, J., Wang, J., Ljungström, V., Wojdacz, T.K., Chaplin, T., Roghanian, A., Davis, Z., Parker, A., Tausch, E., Ntoufa, S., Ramos, S., Robbe, P., Alsolami, R., Steele, A.J., Packham, G., Rodriquez-Vicente, A.E., Brown, L., McNicholl, F., Forconi, F., Pettitt, A., Hillmen, P., Dyer, M., Cragg, M.S., Chelala, C., Oakes, C.C., Rosenquist, R., Stamatopoulos, K., Stilgenbauer, S., Knight, S., Schuh, A., Oscier, D.G. and Strefford, J.C. (2016) Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukemia. Leukemia, 30 (11), 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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Parker et al 26130 2 merged - Accepted Manuscript
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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: http://eprints.soton.ac.uk/id/eprint/394139
ISSN: 0887-6924
PURE UUID: 4852857e-d791-49d8-bae7-a78fd575ecc1
ORCID for H. Parker: ORCID iD orcid.org/0000-0001-8308-9781
ORCID for M.J.J. Rose-Zerilli: ORCID iD orcid.org/0000-0002-1064-5350
ORCID for J. Gibson: ORCID iD orcid.org/0000-0002-0973-8285
ORCID for A. Roghanian: ORCID iD orcid.org/0000-0003-1316-4218
ORCID for A.J. Steele: ORCID iD orcid.org/0000-0003-0667-1596
ORCID for G. Packham: ORCID iD orcid.org/0000-0002-9232-5691
ORCID for F. Forconi: ORCID iD orcid.org/0000-0002-2211-1831
ORCID for M.S. Cragg: ORCID iD orcid.org/0000-0003-2077-089X
ORCID for J.C. Strefford: ORCID iD orcid.org/0000-0002-0972-2881

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Date deposited: 12 May 2016 09:12
Last modified: 15 Mar 2024 05:34

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Contributors

Author: H. Parker ORCID iD
Author: M. Larrayoz
Author: R. Clifford
Author: J. Edelmann
Author: S. Blakemore
Author: J. Gibson ORCID iD
Author: J. Wang
Author: V. Ljungström
Author: T.K. Wojdacz
Author: T. Chaplin
Author: A. Roghanian ORCID iD
Author: Z. Davis
Author: A. Parker
Author: E. Tausch
Author: S. Ntoufa
Author: S. Ramos
Author: P. Robbe
Author: R. Alsolami
Author: A.J. Steele ORCID iD
Author: G. Packham ORCID iD
Author: A.E. Rodriquez-Vicente
Author: L. Brown
Author: F. McNicholl
Author: F. Forconi ORCID iD
Author: A. Pettitt
Author: P. Hillmen
Author: M. Dyer
Author: M.S. Cragg ORCID iD
Author: C. Chelala
Author: C.C. Oakes
Author: R. Rosenquist
Author: K. Stamatopoulos
Author: S. Stilgenbauer
Author: S. Knight
Author: A. Schuh
Author: D.G. Oscier
Author: J.C. Strefford ORCID iD

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