Overall a large fraction of the candidate TFBSs from both SNVs and INDELs are either CTCF, RAD21, or SMC3 binding sites (25 of 91; Supplementary Table 2; Fig. 2a14–21), which are associated with the cohesin complex.33 Recently, an elevated SNV rate at binding sites of the cohesin complex have been reported for several cancer types.34,35 The cohesin complex is a key player in formation and maintenance of topological chromatin domains,36,37 suggesting that non-coding mutations could play a role shaping the chromatin structure during cancer development. Here, RAD21 is linked to cancer.