Using a combination of whole-genome sequencing of highly selected multiple adenoma patients, linkage analysis, and studies of loss-of-heterozygosity (LOH) in tumors, followed by replication in a large set of familial CRC cases [31••] we identified one germline mutation in POLE (p.Leu424Val) and one in POLD1 (p.Ser478Asn) that were not present in nearly 7000 UK controls or in public databases of controls. Here, POLD1 is linked to colorectal carcinoma.