Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukaemia.
Leukemia
; 30(11): 2179-2186, 2016 11.
Article
en En
| MEDLINE
| ID: mdl-27282254
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.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Leucemia Linfocítica Crónica de Células B
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N-Metiltransferasa de Histona-Lisina
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Genómica
/
Mutación
Tipo de estudio:
Clinical_trials
/
Prognostic_studies
Límite:
Female
/
Humans
/
Male
Idioma:
En
Revista:
Leukemia
Asunto de la revista:
HEMATOLOGIA
/
NEOPLASIAS
Año:
2016
Tipo del documento:
Article
País de afiliación:
Reino Unido