Overview of the study. (A) Discovery cohort (CHOP-O study). Paired PB-CLL (FF) and RS (FFPE) samples. (B) Validation cohort (patients with RS). Paired nodal CLL (FFPE) and RS (FFPE) samples. SNVs, InDels, and CNAs were identified in pairs of peripheral blood CLL (PB-CLL) and Richter diagnostic biopsies (tissue-RS) (from 17 CHOP-O patients)²¹  using whole-genome sequencing. Based on these data, we conducted integrated analysis of mutational burden, analysis of clonal structure, and analysis of noncoding mutations. We validated our findings through differential gene expression and gene-set enrichment analysis on transcriptomic data from an independent cohort of 12 subjects with RS.