ED Fig 5. Landscape of driver alterations and chromosomal aberrations in IGHV subtypes.
a. The genomic landscape of CLL IGHV subtypes. Driver genes, U1 and IGLV3–21R110 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.