Emerging role of DNA polymerase epsilon non-exonuclease domain mutations in colorectal cancer: From sequence variants to clinical implications.

This editorial highlights the emerging significance of non-exonuclease domain mutations (non-EDMs) in DNA polymerase epsilon (POLE) in colorectal cancer (CRC), inspired by the recent study by Taskiran et al. Their study revealed an exceptionally high frequency of POLE mutations (53.65%) in a Turkish CRC cohort, primarily attributed to a specific frameshift variant (p.V1446fs3) with undetermined pathogenic significance. Notably, the non-EDMs showed significant co-occurrence with mutations in critical genes, such as MLH3, MSH3, KRAS, PIK3CA, and BRAF, implying a potential synergistic interaction between impaired DNA repair mechanisms and activation of oncogenic pathways. Although POLE-mutant tumors rarely display high microsatellite instability, their hypermutator phenotype may make them more responsive to immunotherapy. This commentary underscores the need for functional assays and validation through multi-center studies to establish the pathogenicity and clinical relevance of non-EDMs. Furthermore, it advocates for the incorporation of comprehensive POLE sequencing, including non-EDM regions, into standard molecular subtyping frameworks for CRC to refine personalized treatment strategies.