CTCF is a DNA-binding protein essential for the maintenance of genome architecture by mediating both short and long-range chromosomal contacts11,12. Together with the cohesin complex, CTCF organizes chromatin into large topologically associating domains (TADs), insulating the local chromosomal neighborhoods from adjacent regions. Disruption of CTCF binding can therefore lead to dysregulation of gene expression11,12. In cancer, CTCF binding is disrupted through various mechanisms, such as DNA copy number alterations spanning domain boundaries13, microdeletions within CBSs13, and hypermethylation of CBSs14. These alterations at CBSs may drive cancer progression by allowing ectopic expression of oncogenes. Notably, recent studies have reported a genome-wide elevated somatic mutation rate across CBSs in several cancer types15–18. This suggests that mutational and DNA repair processes may act differently at CBSs relative to other genomic regions, thereby resulting in an overall elevated mutational burden at such sites in cancer. However, no study to date has rigorously tested the hypothesis that even amidst this elevated mutational burden, positive selection may still act on specific CBSs to drive cancer in individual tumor types. To accurately identify such genomic sites under positive selection, statistical tests must take into account regional biases in the mutation burden.