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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.

Original publication

DOI

10.1038/leu.2016.134

Type

Journal article

Journal

Leukemia

Publication Date

11/2016

Volume

30

Pages

2179 - 2186

Keywords

Ataxia Telangiectasia Mutated Proteins, Disease-Free Survival, Female, Genes, Tumor Suppressor, Genomics, Histone Methyltransferases, Histone-Lysine N-Methyltransferase, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Male, Mutation, Prognosis, Survival Rate, Tumor Suppressor Protein p53