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Lookup NU author(s): Professor Graham Jackson
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Purpose: Epigenetic dysregulation is known to be an important contributor to myeloma pathogenesis but, unlike other B-cell malignancies, the full spectrum of somatic mutations in epigenetic modifiers has not been reported previously. We sought to address this using the 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.Experimental Design: 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 (Little Rock, AR). We correlated the presence of mutations with clinical outcome from diagnosis and compared the mutations found at diagnosis with later stages of disease.Results: 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.Conclusions: 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. (C) 2016 AACR.
Author(s): Pawlyn C, Kaiser MF, Heuck C, Melchor L, Wardell CP, Murison A, Chavan SS, Johnson DC, Begum DB, Dahir NM, Proszek PZ, Cairns DA, Boyle EM, Jones JR, Cook G, Drayson MT, Owen RG, Gregory WM, Jackson GH, Barlogie B, Davies FE, Walker BA, Morgan GJ
Publication type: Article
Publication status: Published
Journal: Clinical Cancer Research
Year: 2016
Volume: 22
Issue: 23
Pages: 5783-5794
Print publication date: 01/12/2016
Acceptance date: 01/01/1900
ISSN (print): 1078-0432
ISSN (electronic): 1557-3265
Publisher: American Association for Cancer Research
URL: http://dx.doi.org/10.1158/1078-0432.CCR-15-1790
DOI: 10.1158/1078-0432.CCR-15-1790
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