Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukaemia.
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.
Academic Unit of Cancer Sciences, Faculty of Medicine, Cancer Research UK Centre and Experimental Cancer Medicine Centre, University of Southampton, Southampton, UK.
H
H
Parker
Academic Unit of Cancer Sciences, Faculty of Medicine, Cancer Research UK Centre and Experimental Cancer Medicine Centre, University of Southampton, Southampton, UK.
M J J
MJ
Rose-Zerilli
Academic Unit of Cancer Sciences, Faculty of Medicine, Cancer Research UK Centre and Experimental Cancer Medicine Centre, University of Southampton, Southampton, UK.
M
M
Larrayoz
Oxford National Institute for Health Research, Biomedical Research Centre/Molecular Diagnostic Centre, University of Oxford, Oxford, UK.
R
R
Clifford
Department of Internal Medicine III, Ulm University, Ulm, Germany.
J
J
Edelmann
Academic Unit of Cancer Sciences, Faculty of Medicine, Cancer Research UK Centre and Experimental Cancer Medicine Centre, University of Southampton, Southampton, UK.
S
0000-0003-2892-1162
S
Blakemore
Centre for Biological Sciences, Faculty of Natural and Environmental Sciences, University of Southampton, Southampton, UK.
J
0000-0002-0973-8285
J
Gibson
Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary's, University of London, London, UK.
J
J
Wang
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
V
V
Ljungström
Academic Unit of Cancer Sciences, Faculty of Medicine, Cancer Research UK Centre and Experimental Cancer Medicine Centre, University of Southampton, Southampton, UK.
T K
TK
Wojdacz
Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary's, University of London, London, UK.
T
T
Chaplin
Academic Unit of Cancer Sciences, Faculty of Medicine, Cancer Research UK Centre and Experimental Cancer Medicine Centre, University of Southampton, Southampton, UK.
A
A
Roghanian
Department of Molecular Pathology, Royal Bournemouth Hospital, Bournemouth, UK.
Z
Z
Davis
Department of Molecular Pathology, Royal Bournemouth Hospital, Bournemouth, UK.
A
A
Parker
Department of Internal Medicine III, Ulm University, Ulm, Germany.
E
E
Tausch
Institute of Applied Biosciences, Center for Research and Technology Hellas, Thessaloniki, Greece.
S
S
Ntoufa
Oxford National Institute for Health Research, Biomedical Research Centre/Molecular Diagnostic Centre, University of Oxford, Oxford, UK.
S
S
Ramos
Oxford National Institute for Health Research, Biomedical Research Centre/Molecular Diagnostic Centre, University of Oxford, Oxford, UK.
P
P
Robbe
Oxford National Institute for Health Research, Biomedical Research Centre/Molecular Diagnostic Centre, University of Oxford, Oxford, UK.
R
R
Alsolami
Academic Unit of Cancer Sciences, Faculty of Medicine, Cancer Research UK Centre and Experimental Cancer Medicine Centre, University of Southampton, Southampton, UK.
A J
AJ
Steele
Academic Unit of Cancer Sciences, Faculty of Medicine, Cancer Research UK Centre and Experimental Cancer Medicine Centre, University of Southampton, Southampton, UK.
G
G
Packham
Department of Haematology, University Hospital of Salamanca-Biomedical Research Institute of Salamanca, IBMCC, Comprehensive Cancer Center Research, University of Salamanca-CSIC, Salamanca, Spain.
A E
AE
Rodríguez-Vicente
Academic Unit of Cancer Sciences, Faculty of Medicine, Cancer Research UK Centre and Experimental Cancer Medicine Centre, University of Southampton, Southampton, UK.
L
L
Brown
Department of Haematology, Altnagelvin Area Hospital, Western Health and Social Care Trust, Londonderry, UK.
F
F
McNicholl
Academic Unit of Cancer Sciences, Faculty of Medicine, Cancer Research UK Centre and Experimental Cancer Medicine Centre, University of Southampton, Southampton, UK.
F
F
Forconi
Department of Molecular and Clinical Cancer Medicine, Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK.
A
A
Pettitt
Department of Haematology, St James's University Hospital, Leeds, UK.
P
P
Hillmen
College of Medicine, Biological Sciences and Psychology, University of Leicester, Leicester, UK.
M
M
Dyer
Academic Unit of Cancer Sciences, Faculty of Medicine, Cancer Research UK Centre and Experimental Cancer Medicine Centre, University of Southampton, Southampton, UK.
M S
MS
Cragg
Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary's, University of London, London, UK.
C
C
Chelala
Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
C C
CC
Oakes
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
R
R
Rosenquist
Institute of Applied Biosciences, Center for Research and Technology Hellas, Thessaloniki, Greece.
K
K
Stamatopoulos
Department of Internal Medicine III, Ulm University, Ulm, Germany.
S
S
Stilgenbauer
Oxford National Institute for Health Research, Biomedical Research Centre/Molecular Diagnostic Centre, University of Oxford, Oxford, UK.
S
S
Knight
Oxford National Institute for Health Research, Biomedical Research Centre/Molecular Diagnostic Centre, University of Oxford, Oxford, UK.
A
A
Schuh
Academic Unit of Cancer Sciences, Faculty of Medicine, Cancer Research UK Centre and Experimental Cancer Medicine Centre, University of Southampton, Southampton, UK.|Department of Molecular Pathology, Royal Bournemouth Hospital, Bournemouth, UK.
D G
DG
Oscier
Academic Unit of Cancer Sciences, Faculty of Medicine, Cancer Research UK Centre and Experimental Cancer Medicine Centre, University of Southampton, Southampton, UK.
J C
JC
Strefford
D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D016147:Genes, Tumor Suppressor; D023281:Genomics; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000201:enzymology / Q000235:genetics* / Q000401:mortality; D008297:Male; D009154:Mutation; D011379:Prognosis; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C521636:SETD2 protein, human; D064007:Ataxia Telangiectasia Mutated Proteins