Pawlyn, C, Kaiser, MF, Heuck, C et al. (20 more authors) (2016) The spectrum and clinical impact of epigenetic modifier mutations in myeloma. Clinical Cancer Research, 22 (23). pp. 5783-5794. ISSN 1078-0432
Abstract
Epigenetic dysregulation is known to be an important contributor to myeloma pathogenesis but, unlike in other B cell malignancies, the full spectrum of somatic mutations in epigenetic modifiers has not been previously reported. We sought to address this using results from whole-exome sequencing in the context of a large prospective clinical trial of newly diagnosed patients and targeted sequencing in a cohort of previously treated patients for comparison.Whole-exome sequencing analysis of 463 presenting myeloma cases entered in the UK NCRI Myeloma XI study and targeted sequencing analysis of 156 previously treated cases from the University of Arkansas for Medical Sciences. We correlated the presence of mutations with clinical outcome from diagnosis and compared the mutations found at diagnosis with later stages of disease.In diagnostic myeloma patient samples we identify significant mutations in genes encoding the histone 1 linker protein, previously identified in other B-cell malignancies. Our data suggest an adverse prognostic impact from the presence of lesions in genes encoding DNA methylation modifiers and the histone demethylase KDM6A/UTX. The frequency of mutations in epigenetic modifiers appears to increase following treatment most notably in genes encoding histone methyltransferases and DNA methylation modifiers.Numerous mutations identified raise the possibility of targeted treatment strategies for patients either at diagnosis or relapse supporting the use of sequencing-based diagnostics in myeloma to help guide therapy as more epigenetic targeted agents become available.
Metadata
Item Type: | Article |
---|---|
Authors/Creators: |
|
Copyright, Publisher and Additional Information: | © 2016, American Association for Cancer Research. This is an author produced version of a paper published in Clinical cancer research. Uploaded in accordance with the publisher's self-archiving policy. |
Dates: |
|
Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > Institute of Molecular Medicine (LIMM) (Leeds) > Section of Oncology and Clinical Research (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 11 Jul 2016 10:10 |
Last Modified: | 18 Jul 2017 15:26 |
Published Version: | https://doi.org/10.1158/1078-0432.CCR-15-1790 |
Status: | Published |
Publisher: | American Association for Cancer Research |
Identification Number: | 10.1158/1078-0432.CCR-15-1790 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:102153 |