Abstract 839: Whole genome DNA methylation analysis of multiple myeloma identifies pervasive hypomethylation and biomarkers of survival

Multiple myeloma is a malignancy of terminally differentiated, antibody secreting B cells known as plasma cells. Normal plasma cell differentiation and cell fate are coupled to epigenetic and transcriptional reprogramming, including a proliferation-dependent global loss of DNA methylation. However, relatively little is known about the epigenetic changes that underlie myelomagenesis and how these contribute to disease etiology. To this end, we have analyzed the DNA methylome of 119 myeloma specimens from the CoMMpass study (NCT01454297) by whole genome bisulfite sequencing (WGBS) and more than 90% of these same specimens were also characterized for structural variants (long-insert whole genome sequencing) and gene expression (RNA-seq). Unsupervised hierarchical clustering grouped together specimens with t(4;14) translocations that upregulate the H3K36 dimethyltransferase NSD2 (also known as MMSET and WHSC1), which likely impacts the DNA methylation state through epigenetic cross-talk. These data also revealed a dramatic genome-wide hypomethylation where myeloma samples had a median global CpG methylation level of 41% as compared to 71% and 89% in normal plasma cells and B cells, respectively. Demethylation of the myeloma methylome occurred in large megabase domains encompassing genes that were devoid of gene expression. Conversely, DNA methylation remained mostly unchanged in the bodies of genes that were highly expressed. Although the majority of these hypomethylated domains were common across myelomas, many regions of variable methylation exist and these differences corresponded with proximal gene expression differences. These variably methylated regions were compared to PFS and OS and this identified 6,314 CpG loci where the level of DNA methylation was prognostic of outcome (P≤0.00001). These loci were clustered into discrete regions and in the majority of cases (79%), reduced DNA methylation at these loci corresponded with poor outcome. For example, several loci in the gene bodies of PRKCE, MGMT, FHIT, WWOX were prognostic of poor survival. Interestingly, myeloma t(14;16) translocations disrupt the tumor suppressor WWOX and induce the oncogene MAF. These data suggest that WWOX expression may also be lost by epigenetic mechanisms. Finally, we analyzed the DNA methylome of primary and relapsed samples for 22 patients, including multiple relapsed samples for 2 patients. These data identified genome-wide DNA methylation remodeling with a median of 1.9 million differential methylated CpGs between the newly diagnosed and relapsed specimens. These relapse differentially methylated loci coincided at the same regions in several patients and significantly overlapped loci where the DNA methylation level was prognostic of outcome. Integrative genetic, epigenetic, and transcriptional analyses for 120 myeloma samples will be presented. Citation Format: Benjamin G. Barwick, Doris R. Powell, Daniel Penaherrera, Sheri Skerget, Jonathan J. Keats, Daniel Auclair, Sagar Lonial, Lawrence H. Boise, Paula M. Vertino. Whole genome DNA methylation analysis of multiple myeloma identifies pervasive hypomethylation and biomarkers of survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 839.