Defining the subset of mutations in Polymerase Epsilon (POLE) associated with Loss-of-Proofreading (LOP) functionality.

Mutation in the gene Polymerase Epsilon (POLE) mutation has been associated with a hypermutant phenotype, improved prognosis, and more recently, investigated as a predictive biomarker for immunotherapy response 1 Rousseau B. Bieche I. Pasmant E. et al. PD-1 Blockade in Solid Tumors with Defects in Polymerase Epsilon. Cancer Discov. 2022; 12: 1435-1448 Crossref PubMed Scopus (27) Google Scholar . However, there is currently ongoing confusion in the oncology community regarding which specific POLE mutations drive the hypermutant phenotype and immune response, with some authors arguing that this applies to all nonsynonymous mutations in the coding regions of POLE2 Wang F. Zhao Q. Wang Y.N. et al. Evaluation of POLE and POLD1 Mutations as Biomarkers for Immunotherapy Outcomes Across Multiple Cancer Types. JAMA Oncol. 2019; 5: 1504-1506 Crossref PubMed Scopus (277) Google Scholar . POLE is a unique DNA polymerase that in addition to its primary function as a polymerase also has the ability to proofread and remove mismatched base pairs via an exonuclease domain. Selective loss-of-proofreading (LOP) function leads to error prone synthesis which drives elevated Tumor Mutational Burden (TMB) with a characteristic mutational signature 3 Hodel K.P. Sun M.J.S. Ungerleider N. et al. POLE Mutation Spectra Are Shaped by the Mutant Allele Identity, Its Abundance, and Mismatch Repair Status. Mol Cell. 2020; 78 (e1166): 1166-1177 Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar . Here we sought to end the controversy regarding which specific POLE mutant alleles predict response to immune therapy by generating for the first time a comprehensive list of POLE mutant alleles causing selective loss-of-proofreading (LOP) function.