Previous studies found kilobase sized regions of hypermutation, termed “kataegis”, that tend to co-occur with genomic rearrangements in cancer44,60. Importantly, our data suggest that the mutational mechanism underlying the association between CBS mutations and DNA breakpoints is distinct from that of kataegis. While kataegis is characterized by C>T and C>G substitutions, CBS mutations are mostly T>G and T>C substitutions. In addition, kataegis is defined by mutation clusters with inter-mutation distance <1 kb. CBS hotspots are confined focal regions of <30 bps including the CTCF motif and its 5′ flanking sequence.