The pan-cancer mutation rate profiles, stratified by signature (averaged over gene expression bins, Figure 1B and Supplementary Figure S1) revealed a strong and consistent mutation rate depletion at the 5′ gene end, occurring mainly for the following signatures: SBS1, associated with the deamination of methylated cytosines; SBS15 and SBS6, associated with MMR deficiencies (microsatellite instability, MSI), and SBS10a, SBS10b and SBS28, associated with mutations in the proofreading domain of the replicative DNA polymerase ε (POLE) (52,53). This evidence concerns the gene POLE and cancer.