Refinement of estimates of CRC risk for POLD1 carriers is needed; however, clinical management recommendations could follow those made for POLE carriers.
Eleven of the 132 study subjects (8.3%) carried either a POLD1 or a POLE mutation: 7 of 68 (10.3%) subjects with multiple colorectal adenomas and 4 of 64 (6.2%) subjects with early-onset mismatch repair proficient colorectal cancer.
Mutations in the POLD1 and POLE genes encoding DNA polymerases δ (Polδ) and ɛ (Polɛ) cause hereditary colorectal cancer (CRC) and have been found in many sporadic colorectal and endometrial tumors.
Beyond deficient-MMR tumors, somatic or germline DNA polymerase D1 (POLD1) or DNA polymerase E (POLE) alterations cause a hypermutated phenotype in CRC.
In addition to the POLE p.L424V recurrent mutation in a patient with polyposis, CRC and oligodendroglioma, six novel or rare POLD1 variants (four of them, p.D316H, p.D316G, p.R409W, and p.L474P, with strong evidence for pathogenicity) were identified in nonpolyposis CRC families.
Notably, germline mutations in either POLE/POLD1 were seen in 8.5% of patients who will require appropriate genetic counseling regarding risk of developing colorectal carcinoma and on the need for additional surveillance for colonic changes.
We examined 1188 familial CRC and polyposis index patients for POLE p.(Leu424Val) and POLD1p.(Ser478Asn) variants using competitive allele-specific PCR.
Most of the approximately 13 high-penetrance genes that predispose to CRC primarily predispose to colorectal polyps, and each gene is associated with a specific type of polyp, whether conventional adenomas (APC, MUTYH, POLE, POLD1, NTHL1), juvenile polyps (SMAD4, BMPR1A), Peutz-Jeghers hamartomas (LKB1/STK11) and mixed polyps of serrated and juvenile types (GREM1).
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.
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).
A new study reports the identification of germline CRC risk variants that adversely affect the proofreading function of DNA polymerases encoded by POLE and POLD1.
Using whole-genome sequencing, supplemented by linkage and association analysis, we identified specific heterozygous POLE or POLD1 germline variants in several multiple-adenoma and/or CRC cases but in no controls.
These results suggest that an increase in the expression of cdk2/cdc2 in colorectal cancer may have prevented pRB from braking the cell cycle through phosphorylation.