High mutation loads have been associated with exogenous carcinogens, such as tobacco smoking in lung adenocarcinoma (LUAD) and UV radiation in skin melanoma (SKCM), as well as with defects of the DNA repair machinery, such as mismatch repair deficiency in micro-satellite unstable tumors (MSI) or specific mutations affecting the polymerase-ε encoding gene POLE. MSI and especially POLE-mutant tumors in our dataset exhibited over one order of magnitude more mutations than lung or melanoma tumors (Fig 2A—left panel), however they were characterized by fewer clones (Fig 2A—right panel). This evidence concerns the gene POLE and cutaneous melanoma.