journal contribution
posted on 2023-03-31, 18:43 authored by Charlotte Pawlyn, Martin F. Kaiser, Christoph Heuck, Lorenzo Melchor, Christopher P. Wardell, Alex Murison, Shweta S. Chavan, David C. Johnson, Dil B. Begum, Nasrin M. Dahir, Paula Z. Proszek, David A. Cairns, Eileen M. Boyle, John R. Jones, Gordon Cook, Mark T. Drayson, Roger G. Owen, Walter M. Gregory, Graham H. Jackson, Bart Barlogie, Faith E. Davies, Brian A. Walker, Gareth J. Morgan Supplementary Tables: Supplementary table 1: Demographics of the 463 patients included in the Myeloma XI analysis Supplementary table 2: List of epigenetic modifier genes used to interrogate the list of mutations in the Myeloma XI dataset Supplementary table 3: Demographics of the 156 patients included in the UAMS dataset Supplementary table 4: List of epigenetic modifier genes sequenced in UAMS dataset Supplementary table 5: SIFT analysis of Histone 1 family gene mutations Supplementary table 6: Multivariate cox-regression model for overall survival in Myeloma XI patients Supplementary table 7: Percentage of patients with mutations in genes encoding epigenetic modifiers sequenced in both the MYXI and UAMS datasets (as shown in Supplementary table 4) - Supplementary Figures: Supplementary Figure 1: Epigenetic genes mutated in {greater than or equal to}5/463 patients (>1%) in Myeloma XI dataset - location of mutation with respect to protein functional domains Supplementary Figure 2: Translocation subgroup distribution by presence or absence of epigenetic modifier mutation in the Myeloma XI dataset Supplementary Figure 3: Survival curves for Histone 1 mutations in Myeloma XI dataset Supplementary Figure 4: A comparison of the variant allele frequency between the MyXI and UAMS mutations Supplementary Figure 5: The distribution of mutations in epigenetic modifiers in previously treated patients by GEP70 risk score Supplementary Figure 6: A comparison of the UAMS molecular subgroup distribution by presence of epigenetic modifier mutations in previously treated patients
Funding
Myeloma UK
Cancer Research UK CTAAC sample collection
Cancer Research UK Biomarkers and Imaging Discovery and Development
NIH Biomedical Research Centre
History
ARTICLE ABSTRACT
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.
