Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukaemia



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) (2016) Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukaemia. Leukemia, 30. 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: 25 Oct 2021 11:14
DOI: 10.1038/leu.2016.134
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3006787