Although inactivating framshift not likely leads to a hypermutation profile, Poulos et al.24 observed the presence of coding mutation hotspots in POLE-mutant cancers at highly-methylated CpGs in the tumor-suppressor genes APC and TP53. This finding points to the links between methylation and mutations and DNA repair, and these mechanisms define a key part of the mutational background of cancer genomes. Here, POLE is linked to neoplasm.