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

Table 1 Key co-mutation partners in polymerase epsilon-mutant colorectal cancer and their potential clinical relevance

Co-mutated gene	Functional category	Potential biological consequence	Potential clinical relevance
MLH3/MSH3	DNA mismatch repair (accessory proteins)	Potential synergistic (“double-hit”) effect on genomic instability with POLE mutations; may further elevate tumor mutational burden[27,35]	Requires validation; may identify a subset with enhanced response to ICIs[27]
KRAS	Oncogenic signaling (MAPK pathway)	Constitutive activation of proliferation/survival signals[30]	Suggests resistance to anti-EGFR therapy[30]; may necessitate KRAS-targeted strategies (e.g., KRAS G12C inhibitors)
PIK3CA	Oncogenic signaling (PI3K/AKT pathway)	Activation of growth and metabolic pathways[31]	Potential sensitivity to PI3K/AKT/mTOR pathway inhibitors (in research settings)[31]
BRAF	Oncogenic signaling (MAPK pathway)	Constitutive MAPK pathway activation; often associated with specific subtypes[30,32]	BRAF V600E mutation confers poor prognosis; may guide use of BRAF/EGFR/MEK inhibitor combinations[33]
TP53	Tumor suppressor	Loss of cell cycle control and apoptosis; promotes genomic instability[34]	Associated with tumor progression and worse prognosis; a common event in advanced CRC[34]

The clinical relevance summarized here is primarily hypothetical and based on the established roles of these genes in colorectal cancer biology and general therapeutic principles. Prospective clinical validation is required to confirm these associations in the specific context of polymerase epsilon-mutant colorectal cancer. MAPK: Mitogen-activated protein kinase; PI3K: Phosphatidylinositol 3-kinase; AKT: Protein kinase B; POLE: Polymerase epsilon; ICI: Immune checkpoint inhibitor; EGFR: Epidermal growth factor receptor; mTOR: Mammalian target of rapamycin; MEK: Mitogen-activated extracellular signal-regulated kinase; CRC: Colorectal cancer.