Extended Data Fig. 5: Landscape of driver alterations and chromosomal aberrations in IGHV subtypes.

a. The genomic landscape of CLL IGHV subtypes. Driver genes, U1 and IGLV3-21^R110 mutations are labeled according to their genomic location (outside ring, numbered by chromosome). The tracks show the frequency and locations of driver genes in M-CLL (purple) vs. U-CLL (orange) (track 1; outermost), focal sCNAs (track 2; gains, red; losses, blue), and density of SV breakpoints of deletions (track 3) and translocations (track 4) (M-CLL n = 88; U-CLL n = 87; WGS, windows of 1-Mb). Innermost plot highlights translocations in which either one or both breakpoints are recurrent in at least 3 cases (windows of 1-Mb considered to define recurrence) in M-CLL (purple) and U-CLL (orange). Deletions, inversions, and tandem duplications where both breakpoints were found in at least 2 cases and did not overlap with a driver sCNA are shown (Note: only focal deletion in SP140 in two U-CLL cases met this criterion. b. Schema of recurrent IG-BCL2 translocation and IGH-ZFP36L1 deletion in the WGS cohort. All 5 BCL2 translocations were in M-CLL with immunoglobulin (IG) breakpoints in J or D genes, suggesting mediation by aberrant V(D)J recombination. In contrast, 4 U-CLL cases carried IGH-ZFP36L1 truncating deletions, which were all clonal (CCF = 1). Breakpoints in IGH class-switch regions suggested mediation by aberrant class-switch recombination (CSR). c. Immunoglobulin (IG) SVs in 177 WGS and 984 WES. In WES, 9 of 10 BCL2 translocations were in M-CLL and mediated by aberrant V(D)J recombination in IGH (n = 7) or IGK (n = 2). The sole BCL2 translocation in U-CLL was due to aberrant CSR. One CSR-mediated IGH-ZFP36L1 deletion was observed in a case with unclassified IGHV status due to presence of two populations (one M-CLL, one U-CLL; the latter was more prevalent). Of note, in WES, U-CLLs carry a higher number of non-recurrent IG events than M-CLL.