Sensitivity to radiotherapy and selected chemotherapeutics was compared between <i>Pole</i>-mutant mouse-derived embryonic stem (mES) cells, generated using CRISPR-Cas9 (<i>Pole</i> mutations D275A/E275A, and cancer-associated P286R, S297F, V411L) and isogenic wild-type cell lines.<b>Results:</b> In the observation arm of the PORTEC-1 trial (<i>N</i> = 245), women with <i>POLE</i>-mutant endometrial cancers (<i>N</i> = 16) had an improved recurrence-free survival (10-year recurrence-free survival 100% vs. 80.1% for <i>POLE-</i>wild-type; HR, 0.143; 95% confidence interval, 0.001-0.996; <i>P</i> = 0.049).
The variants associated with susceptibility, POLE p.Leu424Val and POLD1 p.Ser478Asn, have high penetrance, and POLD1 mutation was also associated with endometrial cancer predisposition.