Letter to the Editor: From colorectal to pan-gastrointestinal cancer: Unlocking the therapeutic potential of DNA polymerase epsilon mutations

Abstract

A recent investigation by Taskiran et al published in the World Journal of Gastroenterology on DNA polymerase epsilon (POLE) mutations in colorectal cancer prompted a broader discussion on the role of pathogenic variants as pan-gastrointestinal therapeutic biomarkers. Pathogenic exonuclease domain mutations (EDMs) in POLE have been identified in other digestive system malignancies including gastric, pancreatic, biliary, and hepatocellular carcinomas. Although rare, POLE EDMs consistently confer a hypermutator phenotype and high tumor mutational burden, irrespective of the tissue of origin. This shared biological consequence serves as a powerful predictor of response to immune checkpoint inhibitors, offering a vital, tissue-agnostic therapeutic option for patients with advanced or refractory diseases with established tumor mutational burden-high approvals. Therefore, to ensure that these rare but highly actionable opportunities are not missed, broader implementation of comprehensive genomic profiling, including POLE analysis, is warranted for all patients with advanced pan-gastrointestinal cancers.

Keywords: DNA polymerase epsilon; Pan-gastrointestinal cancer; Immune checkpoint inhibitors; Tumor mutational burden; Biomarker; Mismatch repair deficiency

Core Tip: To maximize the identification of immunotherapy candidates in gastrointestinal cancer, we advocate for a paradigm of concurrent mismatch repair and DNA polymerase epsilon testing. This dual strategy provides a crucial second pathway to therapy for patients with proficient mismatch repair tumors who harbor pathogenic DNA polymerase epsilon mutations, ensuring these “hidden hot tumors” are not overlooked by conventional screening.