Recently, a novel germline mutation in the POLD1 gene that encodes the catalytic subunit of DNA polymerase δ was described in several families with multiple cases of endometrial cancer.
Germline mutations in the exonuclease (proofreading) domains of 2 DNA polymerases (POLE and POLD1) have been associated with a dominantly inherited, highly penetrant syndrome of oligo adenomatous polyposis and early-age-of-diagnosis colorectal cancer and endometrial cancer.
Here, we present the evidence for POLE and POLD1 as important contributors to the pathogenesis of CRC and EC, and highlight some of the key questions in this emerging field.
The variants associated with susceptibility, POLE p.Leu424Val and POLD1p.Ser478Asn, have high penetrance, and POLD1 mutation was also associated with endometrial cancer predisposition.
We have recently shown that germline POLE and POLD1 exonuclease domain mutations (EDMs) predispose to colorectal cancer (CRC) and, in the latter case, to endometrial cancer (EC).