Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukaemia.
Leukemia
; 30(11): 2179-2186, 2016 11.
Article
em 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
Base de dados:
MEDLINE
Assunto principal:
Leucemia Linfocítica Crônica de Células B
/
Histona-Lisina N-Metiltransferase
/
Genômica
/
Mutação
Tipo de estudo:
Clinical_trials
/
Prognostic_studies
Limite:
Female
/
Humans
/
Male
Idioma:
En
Revista:
Leukemia
Assunto da revista:
HEMATOLOGIA
/
NEOPLASIAS
Ano de publicação:
2016
Tipo de documento:
Article
País de afiliação:
Reino Unido