The PER-POLE-P286R error signature most closely resembles the mutational profile of a group of ‘POLEd and MMRd’ samples of patients with cancer that have a pathogenic mutation in the POLE proofreading domain and defects in MMR, the major postreplicative DNA repair pathway (Mann–Whitney U test of cosine similarities between groups: P = 2 × 10−8; Fig. 2a–c). This evidence concerns the gene POLE and cancer.