Non-exonuclease domain POLE mutations and their biological significance in colorectal cancer

Table 1 Classification of DNA polymerase epsilon mutations in colorectal cancer

Feature	Exonuclease domain mutations	Non-exonuclease domain mutations
Location	Exonuclease (proofreading) domain	Outside exonuclease domain
Mechanism	Loss of proofreading activity	Indirect effects (replication stress, altered polymerase dynamics)
Tumor mutational burden	Ultra-high (> 100 mut/Mb)	Intermediate to high (context-dependent)
Mutational signature	COSMIC signature 10	Heterogeneous/less defined
MSI status	Often MSI-H or independent	Predominantly MSS/MSI-L
Immunogenicity	High (strong neoantigen load)	Variable, potentially increased in subsets
Clinical relevance	Established biomarker for immunotherapy	Emerging, not yet standardized
Role in tumorigenesis	Early driver event	Likely modifier, context-dependent

MSI-H: High levels of microsatellite instability; MSI-L: Low levels of microsatellite instability; MSS: Microsatellite stable.