A POLE mutation refers to a pathogenic variant in the POLE gene, which encodes the catalytic subunit of DNA polymerase epsilon, a key enzyme responsible for DNA replication and proofreading.
Most clinically significant POLE mutations occur within the exonuclease or proofreading domain, leading to loss of proofreading activity and resulting in a markedly increased rate of base substitution mutations—an ultramutated phenotype in affected cells.
Germline POLE exonuclease domain mutations cause a dominantly inherited cancer predisposition syndrome known as polymerase proofreading-associated polyposis (PPAP).
It is characterized by a high risk of colorectal adenomas, colorectal cancer, and, to a lesser extent, other malignancies such as endometrial and brain tumors.
Somatic POLE exonuclease domain mutations are also found in sporadic tumors, particularly endometrial and colorectal cancers, and are associated with high tumor mutational burden, increased neoantigen load, prominent lymphocytic infiltrate, and favorable prognosis.
Pathogenic POLE mutations in colorectal cancer are associated with a hypermutated phenotype and a more favorable prognosis, and may have implications for immunotherapy responsiveness, similar to mismatch repair-deficient or microsatellite instability-high tumors.
A POLE mutation is a pathogenic alteration most often in the exonuclease domain of the POLE gene, resulting in defective DNA proofreading, genomic hypermutation, and increased cancer risk or distinct tumor biology.