Genetic, structural, and functional characterization of POLE polymerase proofreading variants allows cancer risk prediction

Purpose Polymerase proofreading-associated polyposis is a dominantly inherited colorectal cancer syndrome caused by exonuclease domain missense variants in the DNA polymerases POLE and POLD1 . Manifestations may also include malignancies at extracolonic sites. Cancer risks in this syndrome are not yet accurately quantified. Methods We sequenced POLE and POLD1 exonuclease domains in 354 individuals with early/familial colorectal cancer (CRC) or adenomatous polyposis. We assessed the pathogenicity of POLE variants with yeast fluctuation assays and structural modeling. We estimated the penetrance function for each cancer site in variant carriers with a previously published nonparametric method based on survival analysis approach, able to manage unknown genotypes. Results Pathogenic POLE exonuclease domain variants P286L, M294R, P324L, N363K, D368N, L424V, K425R, and P436S were found in ten families. The estimated cumulative risk of CRC at 30, 50, and 70 years was 11.1% (95% confidence interval [CI]: 4.2–17.5), 48.5% (33.2–60.3), and 74% (51.6–86.1). Cumulative risk of glioblastoma was 18.7% (3.2–25.8) at 70 years. Variants interfering with DNA binding (P286L and N363K) had a significantly higher mutagenic effect than variants disrupting ion metal coordination at the exonuclease site. Conclusion The risk estimates derived from this study provide a rational basis on which to provide genetic counseling to POLE variant carriers.