DNA polymerase epsilon-mutant colorectal cancers: Insights into non-exonuclease domain mutation variants, microsatellite instability status, and co-mutation profiles

Abstract

BACKGROUND

Although the relationship between somatic DNA polymerase epsilon (POLE) exonuclease domain mutations (EDMs) and colorectal cancer (CRC) is well established, the role of POLE non-EDMs in CRC remains unclear.

AIM

To identify POLE non-EDMs and EDMs in CRC, and to determine their associations with accompanying mutations and microsatellite instability (MSI).

METHODS

In this retrospective study, next-generation sequencing was performed using a targeted colon cancer panel (Qiagen, DHS-003Z) on 356 CRC patients. Of these, 191 patients were found to carry POLE mutations. For these patients, MSI status was assessed using both real-time PCR (EasyPGX^® Ready MSI kit) and immunohistochemistry, and accompanying somatic mutations were investigated.

RESULTS

POLE mutations were identified in 53.65% of the CRC patients. Among the POLE-mutant patients, 87.96% were classified as pMMR (MSI-L), and 12.04% as dMMR (MSI-H). The most frequently observed POLE non-EDM variant was exon 34 c.4337_4338delTG p.V1446fs*3. The POLE EDMs were present in exon 14, with two specific variants p.Y458F (0.52%) and p.Y468N (0.52%). The most common pathogenic variants accompanying the POLE mutations were in MLH3, MSH3, KRAS, PIK3CA, and BRAF genes. POLE mutations were associated with a high mutational burden and MSI in CRC, particularly in the dMMR phenotype. This association suggests that POLE mutations may serve as important biomarkers for understanding the genetic profile of the disease and may be used in the clinical management of CRC.

CONCLUSION

POLE mutations, especially non-EDMs, are frequent in MSI-L CRC and often co-occur with MLH3, MSH3, KRAS, PIK3CA, and BRAF, highlighting their potential role in tumor biology and as biomarkers for personalized treatment. Functional validation and multicenter studies are needed.

Keywords: DNA polymerase epsilon mutation; Non-exonuclease domain variants; Microsatellite instability; Colorectal cancer; Next-generation sequencing; Somatic co-mutations

Core Tip: This study highlights the overlooked role of DNA polymerase epsilon (POLE) non-exonuclease domain mutations in colorectal cancer. By integrating next-generation sequencing with microsatellite instability testing, we show that POLE mutations are frequent, particularly in microsatellite-low tumors, and are often accompanied by co-mutations in MLH3, MSH3, KRAS, PIK3CA, and BRAF. These findings extend beyond the classical exonuclease domain hotspots, suggesting that both exonuclease and non-exonuclease POLE variants may serve as valuable biomarkers for prognosis and support the development of personalized treatment strategies in colorectal cancer management.