Polymerase Mutations and Immune Response in Colorectal Cancer

Colorectal cancers harbouring mutations in the exonuclease domains of DNA polymerases ε (POLE) and δ (POLD1) exhibit an ‘ultramutated’ phenotype characterised by exceptionally high numbers of somatic base substitutions. These mutations disrupt the proofreading function that normally corrects replication errors, leading to abundant tumour neoantigens and a pronounced cytotoxic T-cell infiltrate. The consequent immune-active microenvironment renders a subset of these tumours particularly susceptible to immune checkpoint blockade, even in the absence of classical mismatch repair deficiency. Beyond germline variants that confer hereditary predisposition, somatic polymerase mutations arise early in tumourigenesis, shaping the driver landscape and influencing clonal neoantigen burden. Advances in computational pathology and harmonised biomarkers such as tumour mutational burden are refining patient selection for immunotherapy, while studies of polymerase-mutation signatures inform both diagnostic screening and therapeutic stratification. Collectively, these insights underscore the dual role of polymerase defects as both oncogenic drivers and facilitators of antitumour immunity.

Research from Nature Portfolio

No recent Nature Portfolio content available.

Polymerase Mutations and Immune Response in Colorectal Cancer publication trend

The graph below shows the total number of articles in polymerase mutations and immune response in colorectal cancer across all publications each year (not limited to Nature Index journals).

Technical terms

Exonuclease domain: Protein region responsible for proofreading newly synthesised DNA during replication, ensuring high fidelity.

Tumour mutational burden: Total number of somatic mutations per megabase of tumour DNA, used as a biomarker for immunotherapy response.

Microsatellite instability: Condition of length variation in short repetitive DNA sequences caused by defective mismatch repair.

Neoantigen: Novel peptide derived from tumour-specific mutations that can be presented to and recognised by T cells.

Immune checkpoint inhibitor: Therapeutic agent that blocks inhibitory pathways in T cells to potentiate antitumour immune responses.

References

1. Deep learning for dual detection of microsatellite instability and POLE mutations in colorectal cancer histopathology. npj Precision Oncology (2024).
2. Tumor mutational burden in colorectal cancer: Implications for treatment. Critical Reviews in Oncology/Hematology (2024).
3. Mutational Signatures in Colorectal Cancer: Translational Insights, Clinical Applications, and Limitations. Cancers (2024).
4. Somatic POLE exonuclease domain mutations are early events in sporadic endometrial and colorectal carcinogenesis, determining driver mutational landscape, clonal neoantigen burden and immune response. The Journal of Pathology (2018).