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Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukaemia

AutorParker, H.; Rose-Zerilli, M. J. J.; Larrayoz, Mª José; Clifford, R.; Edelmann, J.; Blakemore, S.; Gibson, J.; Wang, J.; Ljungström, V.; Wojdacz, T. K.; Chaplin, T.; Roghanian, A.; Davis, Z.; Parker, Antón; Tausch, E.; Ntoufa, S.; Ramos, S. ; Robbe, P.; Alsolami, R.; Steele, A. J.; Packham, G.; Rodríguez-Vicente, Ana Eugenia; Brown, L.; McNicholl, F.; Forconi, F.; Pettitt, A.; Hillmen, P.; Dyer, M.; Cragg, M. S.; Chelala, C.; Oakes, C. C.; Rosenquist, Richard; Stamatopoulos, Kostas; Stilgenbauer, S.; Knight, S.; Schuh, A.; Oscier, David G.; Strefford, Jonathan C.
Fecha de publicación2016
EditorNature Publishing Group
CitaciónLeukemia 30(11): 2179-2186 (2016)
ResumenHistone 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.
Versión del editorhttps://doi.org/10.1038/leu.2016.134
URIhttp://hdl.handle.net/10261/168538
Identificadoresdoi: 10.1038/leu.2016.134
e-issn: 1476-5551
issn: 0887-6924
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