Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukaemia

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 deletion...

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Bibliografski detalji
Glavni autori: Parker, H, Rose-Zerilli, M, Larrayoz, M, Clifford, R, Edelmann, J, Blakemore, S, Gibson, J, Wang, J, Ljungström, V, Wojdacz, T, Chaplin, T, Roghanian, A, Davis, Z, Parker, A, Tausch, E, Ntoufa, S, Ramos, S, Robbe, P, Alsolami, R, Steele, A, Packham, G, Rodríguez-Vicente, A, Brown, L, McNicholl, F, Forconi, F, Pettitt, A, Hillmen, P, Dyer, M, Cragg, M, Chelala, C, Oakes, C, Rosenquist, R, Stamatopoulos, K, Stilgenbauer, S, Knight, S, Schuh, A, Oscier, D, Strefford, J
Format: Journal article
Jezik:English
Izdano: Nature Publishing Group 2016
Opis
Sažetak: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.Leukemia advance online publication, 10 June 2016; doi:10.1038/leu.2016.134.

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