The Spectrum and Clinical Impact of Epigenetic Modifier Mutations in Myeloma.
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Date
2016-12-01Author
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
Type
Journal Article
Metadata
Show full item recordAbstract
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. Clin Cancer Res; 22(23); 5783-94. ©2016 AACR.
Collections
Subject
B-Lymphocytes
Humans
Multiple Myeloma
Neoplasm Recurrence, Local
Histone-Lysine N-Methyltransferase
Histones
Prospective Studies
DNA Methylation
Epigenesis, Genetic
Amino Acid Sequence
Mutation
Adult
Aged
Aged, 80 and over
Middle Aged
Female
Male
Epigenomics
Exome
Histone Methyltransferases
Research team
Myeloma Biology and Therapeutics
Myeloma Group
Language
eng
Date accepted
2016-04-27
License start date
2016-12
Citation
Clinical cancer research : an official journal of the American Association for Cancer Research, 2016, 22 (23), pp. 5783 - 5794
Publisher
AMER ASSOC CANCER RESEARCH