Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukaemia
| Title: | Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukaemia |
|---|---|
| Authors: | Parker, H; Rose-Zerilli, MJJ; Larrayoz, M; Clifford, R; Edelmann, J; Blakemore, S; Gibson, J; Wang, J; Ljungström, V; Wojdacz, TK; Chaplin, T; Roghanian, A; Davis, Z; Parker, A; Tausch, E; Ntoufa, S; Ramos, S; Robbe, P; Alsolami, R; Steele, AJ; Packham, G; Rodríguez-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; Strefford, JC |
| Publisher Information: | Springer Science and Business Media LLC |
| Publication Year: | 2016 |
| Collection: | The University of Liverpool Repository |
| Description: | 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. |
| Document Type: | conference object |
| File Description: | text |
| Language: | English |
| Relation: | https://livrepository.liverpool.ac.uk/3004818/1/Genomic%20disruption%20of%20the%20histone%20methyltransferase%20SETD2%20in%20chronic%20lymphocytic%20leukaemia.pdf; Collapse authors list. Parker, H, Rose-Zerilli, MJJ, Larrayoz, M, Clifford, R, Edelmann, J, Blakemore, S orcid:0000-0003-2892-1162 , Gibson, J orcid:0000-0002-0973-8285 , Wang, J, Ljungström, 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, Rodríguez-Vicente, AE, Brown, L, McNicholl, F, Forconi, F, Pettitt, A orcid:0000-0002-0907-8950 , 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 , England. |
| DOI: | 10.1038/leu.2016.134 |
| Availability: | https://livrepository.liverpool.ac.uk/3004818/; https://doi.org/10.1038/leu.2016.134; https://livrepository.liverpool.ac.uk/3004818/1/Genomic%20disruption%20of%20the%20histone%20methyltransferase%20SETD2%20in%20chronic%20lymphocytic%20leukaemia.pdf |
| Accession Number: | edsbas.CB09CFE7 |
| Database: | BASE |