While the three major biological CRC phenotypes CIN, MSI, and CIMP and their clinical implications have been elucidated during the last 20 years, it was only recently noted that a subset of MSS CRC patients harbor germline mutations in the exonuclease domain of POLD and POLE [8], which account for the exonuclease catalytic activities of these DNA polymerases [27]. This evidence concerns the gene POLE and colorectal carcinoma.