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Title: Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukaemia
Authors: 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.
Rodríguez-Vicente, A. E.
Brown, L.
McNicholl, F.
Forconi, F.
Pettitt, A.
Hillmen, P.
Dyer, Martin J. S.
Cragg, M. S.
Chelala, C.
Oakes, C. C.
Rosenquist, R.
Stamatopoulos, K.
Stilgenbauer, S.
Knight, S.
Schuh, A.
Oscier, D. G.
Strefford, J. C.
First Published: 10-Jun-2016
Publisher: Nature Publishing Group
Citation: Leukemia, 2016, 30 (11), pp. 2179-2186
Abstract: Histone methyltransferases (HMTs) are important epigenetic regulators of gene transcription and are disrupted at the genomic level in a spectrum of human tumours including haematological malignancies. Using high-resolution single nucleotide polymorphism (SNP) arrays, we identified recurrent deletions of the SETD2 locus in 3% (8/261) of chronic lymphocytic leukaemia (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 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 with cases wild type for all three genes. Consistent with its postulated role as a tumour suppressor, our data highlight SETD2 aberration as a recurrent, early loss-of-function event in CLL pathobiology linked to aggressive disease.
DOI Link: 10.1038/leu.2016.134
ISSN: 0887-6924
eISSN: 1476-5551
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © the authors, 2016. This is an open-access article distributed under the terms of the Creative Commons Attribution License ( ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Appears in Collections:Published Articles, College of Medicine, Biological Sciences and Psychology

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