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...
| Autori principali: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Natura: | Journal article |
| Lingua: | English |
| Pubblicazione: |
Nature Publishing Group
2016
|
| _version_ | 1826300551471562752 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Parker, H |
| collection | OXFORD |
| 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.Leukemia advance online publication, 10 June 2016; doi:10.1038/leu.2016.134. |
| first_indexed | 2024-03-07T05:18:49Z |
| format | Journal article |
| id | oxford-uuid:de29329f-9de4-413c-a3ae-ff426675c510 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T05:18:49Z |
| publishDate | 2016 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | oxford-uuid:de29329f-9de4-413c-a3ae-ff426675c5102022-03-27T09:30:27ZGenomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukaemiaJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:de29329f-9de4-413c-a3ae-ff426675c510EnglishSymplectic Elements at OxfordNature Publishing Group2016Parker, HRose-Zerilli, MLarrayoz, MClifford, REdelmann, JBlakemore, SGibson, JWang, JLjungström, VWojdacz, TChaplin, TRoghanian, ADavis, ZParker, ATausch, ENtoufa, SRamos, SRobbe, PAlsolami, RSteele, APackham, GRodríguez-Vicente, ABrown, LMcNicholl, FForconi, FPettitt, AHillmen, PDyer, MCragg, MChelala, COakes, CRosenquist, RStamatopoulos, KStilgenbauer, SKnight, SSchuh, AOscier, DStrefford, JHistone 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. |
| spellingShingle | 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 Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukaemia |
| title | Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukaemia |
| title_full | Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukaemia |
| title_fullStr | Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukaemia |
| title_full_unstemmed | Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukaemia |
| title_short | Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukaemia |
| title_sort | genomic disruption of the histone methyltransferase setd2 in chronic lymphocytic leukaemia |
| work_keys_str_mv | AT parkerh genomicdisruptionofthehistonemethyltransferasesetd2inchroniclymphocyticleukaemia AT rosezerillim genomicdisruptionofthehistonemethyltransferasesetd2inchroniclymphocyticleukaemia AT larrayozm genomicdisruptionofthehistonemethyltransferasesetd2inchroniclymphocyticleukaemia AT cliffordr genomicdisruptionofthehistonemethyltransferasesetd2inchroniclymphocyticleukaemia AT edelmannj genomicdisruptionofthehistonemethyltransferasesetd2inchroniclymphocyticleukaemia AT blakemores genomicdisruptionofthehistonemethyltransferasesetd2inchroniclymphocyticleukaemia AT gibsonj genomicdisruptionofthehistonemethyltransferasesetd2inchroniclymphocyticleukaemia AT wangj genomicdisruptionofthehistonemethyltransferasesetd2inchroniclymphocyticleukaemia AT ljungstromv genomicdisruptionofthehistonemethyltransferasesetd2inchroniclymphocyticleukaemia AT wojdaczt genomicdisruptionofthehistonemethyltransferasesetd2inchroniclymphocyticleukaemia AT chaplint genomicdisruptionofthehistonemethyltransferasesetd2inchroniclymphocyticleukaemia AT roghaniana genomicdisruptionofthehistonemethyltransferasesetd2inchroniclymphocyticleukaemia AT davisz genomicdisruptionofthehistonemethyltransferasesetd2inchroniclymphocyticleukaemia AT parkera genomicdisruptionofthehistonemethyltransferasesetd2inchroniclymphocyticleukaemia AT tausche genomicdisruptionofthehistonemethyltransferasesetd2inchroniclymphocyticleukaemia AT ntoufas genomicdisruptionofthehistonemethyltransferasesetd2inchroniclymphocyticleukaemia AT ramoss genomicdisruptionofthehistonemethyltransferasesetd2inchroniclymphocyticleukaemia AT robbep genomicdisruptionofthehistonemethyltransferasesetd2inchroniclymphocyticleukaemia AT alsolamir genomicdisruptionofthehistonemethyltransferasesetd2inchroniclymphocyticleukaemia AT steelea genomicdisruptionofthehistonemethyltransferasesetd2inchroniclymphocyticleukaemia AT packhamg genomicdisruptionofthehistonemethyltransferasesetd2inchroniclymphocyticleukaemia AT rodriguezvicentea genomicdisruptionofthehistonemethyltransferasesetd2inchroniclymphocyticleukaemia AT brownl genomicdisruptionofthehistonemethyltransferasesetd2inchroniclymphocyticleukaemia AT mcnichollf genomicdisruptionofthehistonemethyltransferasesetd2inchroniclymphocyticleukaemia AT forconif genomicdisruptionofthehistonemethyltransferasesetd2inchroniclymphocyticleukaemia AT pettitta genomicdisruptionofthehistonemethyltransferasesetd2inchroniclymphocyticleukaemia AT hillmenp genomicdisruptionofthehistonemethyltransferasesetd2inchroniclymphocyticleukaemia AT dyerm genomicdisruptionofthehistonemethyltransferasesetd2inchroniclymphocyticleukaemia AT craggm genomicdisruptionofthehistonemethyltransferasesetd2inchroniclymphocyticleukaemia AT chelalac genomicdisruptionofthehistonemethyltransferasesetd2inchroniclymphocyticleukaemia AT oakesc genomicdisruptionofthehistonemethyltransferasesetd2inchroniclymphocyticleukaemia AT rosenquistr genomicdisruptionofthehistonemethyltransferasesetd2inchroniclymphocyticleukaemia AT stamatopoulosk genomicdisruptionofthehistonemethyltransferasesetd2inchroniclymphocyticleukaemia AT stilgenbauers genomicdisruptionofthehistonemethyltransferasesetd2inchroniclymphocyticleukaemia AT knights genomicdisruptionofthehistonemethyltransferasesetd2inchroniclymphocyticleukaemia AT schuha genomicdisruptionofthehistonemethyltransferasesetd2inchroniclymphocyticleukaemia AT oscierd genomicdisruptionofthehistonemethyltransferasesetd2inchroniclymphocyticleukaemia AT streffordj genomicdisruptionofthehistonemethyltransferasesetd2inchroniclymphocyticleukaemia |