Highly mutated CRC (∼ 16%) was split into two major groups: (1) hypermutated cancers (∼ 13%) with microsatellite instability (MSI) due to defective mismatch repair (dMMR) or (2) ultramutated cancers (∼ 3%) with DNA polymerase epsilon (POLE) exonuclease domain mutations that inactivate the proofreading function. Here, POLE is linked to cancer.