Abstract IA014: POLE mutations in endometrial cancer: Consequences and mechanisms

Abstract

Abstract Mutations in the POLE gene encoding DNA polymerase ϵ (Pol ϵ) drive the development of ultramutated endometrial tumors. We aim to understand the mechanisms through which POLE defects cause ultramutation and establish approaches to identify functionally significant variants. Because POLE mutations preferentially affect conserved amino acid residues in the exonuclease domain of Pol ϵ, a concept has initially formed that defective proofreading of replication errors triggers ultramutation. However, genetic and biochemical studies of the most common POLE variants suggested that their pathogenicity is determined by functional alterations other than loss of proofreading. When modeled in yeast, most of the exonuclease domain changes seen in tumors produce mutator effects far exceeding the effect of Polϵ exonuclease deficiency. The magnitude of the mutator effect is allele-specific and does not correlate with the severity of the exonuclease defect. A yeast mimic of the most common variant, P286R, shows greatly increased DNA polymerase activity, in addition to the exonuclease defect, which likely underlies the high mutagenicity. We discuss the implications of POLE status for tumor progression and the design of therapeutic strategies. We also discuss current approaches to assess the functional significance of the multitude of reported POLE mutations and present the most up-to-date list of experimentally confirmed significant variants. Citation Format: Polina V. Shcherbakova. POLE mutations in endometrial cancer: Consequences and mechanisms [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr IA014.