The Spectrum and Clinical Impact of Epigenetic Modifier Mutations in Myeloma

Abstract

Purpose 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. 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. 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.

Epigenetic regulatory mutations and epigenetic therapy for multiple myeloma

“…DNMT3A is aberrantly methylated early in MGUS and myeloma (29). DNMT3A mutations were significantly enriched at relapse in MM patients and found at a site frequently mutated in AML, E477K (2). These data are consistent with the finding that one of the most recurrent DNMT3A mutations impairs sensing and repair of DNA, resulting in chemo-resistance and increased mutagenesis (33).…”

“…KDM6A may be mutated in up to 7% of MM samples (67), and KDM6A mutations were associated with decreased survival (2, 66, 67). More, CNV indicates loss of this gene in about 25% MM cases (Figure 1).…”

“…Mutations cover a large variety of epigenetic modifying enzymes but none of them are present in a large proportion of patients (Figure 1). Furthermore, the comparison with targeted sequencing data from 156 previously relapsed cases demonstrated an increase in the frequency of some of these mutations suggesting a role for epigenetic changes in MM progression (2, 3). Although somatic mutations in many epigenetic modifiers are relatively rare, a large proportion of MM patients present copy number variations (CNV) in these genes (Figure 1).…”

UTX/KDM6A Loss Enhances the Malignant Phenotype of Multiple Myeloma and Sensitizes Cells to EZH2 inhibition

“…UTX mutations/deletions are found in 3-4% of primary MM specimens (Pawlyn et al, 2016, van Haaften et al, 2009) and are common features of MM cell lines, with 30-40% of them presenting damaging lesions of this gene (www.cbioportal.org, www.keatslab.org). Most MM cell lines were established from extramedullary MM and plasma cell leukemia cases, suggesting that UTX loss may contribute to disease progression.…”

Overexpression of EZH2 in multiple myeloma is associated with poor prognosis and dysregulation of cell cycle control

“…30, 31 No patients had mutations in EZH2 , but 3% of patients had potentially inactivating mutations or deletions in its partner demethylase KDM6A , with evidence of a negative effect on patient outcomes. Previous studies have shown an increase in EZH2 expression as disease progresses from monoclonal gammopathy of undetermined significance (MGUS) through smouldering myeloma to myeloma and that genes underexpressed in multiple myeloma (MM) are associated with H3K27me3 targets in embryonic stem cells.…”