Genome-wide clustering reveals changes in mutation profiles. (A-C) Grouping of somatic mutation profiles for all single nucleotide variants (SNVs). Absolute white blood cell (WBC) and lymphocyte (LY) counts are shown at the top of each figure. The bottom panels show genome-wide SNV frequencies plotted against the 5 time points. Mutation profiles for coding genes are shown as black lines. (A) CLL003; a indicates before chlorambucil; b, before fludarabine, cyclophosphamide, rituximab; c, immediately after 6 cycles of fludarabine, cyclophosphamide, rituximab; d, before ofatumumab; and e, after ofatumumab. Coding mutations: red plot SLC9A11, NLRP3, SF3B1, ADAD1, IL11RA, TRIM58, HERC2, RPGRIP1, MUC16, SHROOM1; green plot ATM, PLEKHG5, NFATC1, FCGBP, BPIL2, AMTN, MTUS1, SPTAN1; purple plot SLITRK4, SEMA3E, ASXL1, MUSK, NPY, CHRNB2, ZNF534, FAT3; and blue plot: noncoding mutations only. (B) CLL077; a indicates before chlorambucil; b, before fludarabine, cyclophosphamide; c, immediately after 4 cycles of fludarabine, cyclophosphamide; d, before ofatumumab; and e, relapse 9 months after ofatumumab. Coding mutations: green plot: OCA2, SLC12A1, PLA2G16, DAZAP1, EXOC6B, LRRC16A; orange plot: NAMPTL, BCL2L13, GHDC; red plot: SAMHD1, IRF2BP2, GPR158; blue plot: MAP2K1, ZFHX4, HMCN1, DDX1, KLHDC2, NOD1, ZNF566, COL24A1; and purple plot: noncoding mutations only. (C) CLL006; a indicates before fludarabine, cyclophosphamide; b, before Rituximab; c, before Ofatmumab; d, immediately after Ofatumumab; and e, relapse 12 months after Ofatumumab. Coding mutations: red plot: MED12, KLHL4, CNOT7, SLK1, U2AF1, C3orf43, PILRB, ARHGAP29, KIAA0182, MAP4, TMPRSS9; blue plot: PCLO, IRF4, LRRC37B, KIAA0319L; and green plot: RBPJ. (D) Mutation profiles based on deep sequencing in patient CLL003. Colored boxes to the right of each plot indicate mutation profile type (HH^F indicates red box, HL, yellow box, LH, green box, and 0H, blue box). See supplemental Table 5.