Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukaemia

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Parker, H, Rose-Zerilli, MJJ, Larrayoz, M, Clifford, R, Edelmann, J, Blakemore, S, Gibson, J, Wang, J, Ljungstrom, V, Wojdacz, TK et al (show 28 more authors) , Chaplin, T, Roghanian, A, Davis, Z, Parker, A, Tausch, E, Ntoufa, S, Ramos, S, Robbe, P, Alsolami, R, Steele, AJ, Packham, G, Rodriguez-Vicente, AE, Brown, L, McNicholl, F, Forconi, F, Pettitt, A, Hillmen, P, Dyer, M, Cragg, MS, Chelala, C, Oakes, CC, Rosenquist, R, Stamatopoulos, K, Stilgenbauer, S, Knight, S, Schuh, A, Oscier, DG and Strefford, JC (2016) Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukaemia. Leukemia, 30 (11). pp. 2179-2186.

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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.

Item Type:	Article
Uncontrolled Keywords:	Cancer genetics, Cancer genomics, Chronic lymphocytic leukemia, Mutation, Transferases
Depositing User:	Symplectic Admin
Date Deposited:	04 Apr 2017 15:45
Last Modified:	19 Jan 2023 07:07
DOI:	10.1038/leu.2016.134
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3006787