Genome-wide DNA methylation patterns define 2 subtypes of WM with transcriptional signatures reminiscent of normal plasma and MBCs. (A) PCA of the 10 000 most-variable CpG methylation levels from Illumina EPIC arrays across 35 WM patients. Samples are colored according to hierarchical clustering in panel B (orange, MBC-like; blue, PC-like). (B) Heat map showing the methylation levels of the top 1000 most-variable CpGs across patients. WM patients are arranged by hierarchical clustering (blue, methylated; white, unmethylated). (C) Pie chart displaying the number of CpGs that displays relative hypomethylation between subgroups defined by mean difference >20%, false-discovery rate q < 0.05. The number of CpGs is indicated (D) GSEA output showing highly significant enrichment of a plasma vs MBC expression signature between WM methylation subgroups. NES, normalized enrichment score. (E) Correlation of differential expression between WM subgroups and normal MBCs compared with PCs. A set of 19 genes previously defined to be important for PC differentiation was extracted from RNA sequencing data. (F) Histograms showing the expression levels of 9 of 19 genes significantly differentially expressed between MBCs and PCs in both normal and WM subtypes. Significance assessed by Student t test; *P < .05; **P < .01; ***P < .001. RPKM, reads per kilobase of transcript, per million mapped reads.