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Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukaemia
Univ Southampton, Fac Med, Canc Res UK Ctr, Acad Unit Canc Sci, Southampton, Hants, England.;Univ Southampton, Expt Canc Med Ctr, Southampton, Hants, England..
Univ Southampton, Fac Med, Canc Res UK Ctr, Acad Unit Canc Sci, Southampton, Hants, England.;Univ Southampton, Expt Canc Med Ctr, Southampton, Hants, England..
Univ Southampton, Fac Med, Canc Res UK Ctr, Acad Unit Canc Sci, Southampton, Hants, England.;Univ Southampton, Expt Canc Med Ctr, Southampton, Hants, England..
Univ Oxford, Mol Diagnost Ctr, Biomed Res Ctr, Oxford Natl Inst Hlth Res, Oxford, England..
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2016 (English)In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 30, no 11, p. 2179-2186Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2016. Vol. 30, no 11, p. 2179-2186
National Category
Hematology Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-310770DOI: 10.1038/leu.2016.134ISI: 000387803100008PubMedID: 27282254OAI: oai:DiVA.org:uu-310770DiVA, id: diva2:1057916
Funder
German Research Foundation (DFG), SFB 1074 B1 B2Swedish Cancer SocietySwedish Research CouncilScience for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

De tre första författarna delar förstaförfattarskapet.

Available from: 2016-12-19 Created: 2016-12-19 Last updated: 2017-11-29Bibliographically approved

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