Polymerase epsilon mutations and concomitant β2-microglobulin mutations in cancer

Abstract

Mutations in the exonuclease domain of polymerase epsilon (POLE), an enzyme of DNA synthesis, are involved in a newly described syndrome of colorectal polyposis and cancer, and have been associated with a high mutation burden with or without microsatellite instability (MSI) phenotype. The exonuclease domain of POLE executes a proofreading function that decreases the mutation rate during DNA replication by an estimated of one to two orders. The high mutation burden resulting from its loss of function could create a load of neo-antigens that would put the neoplastic cells in severe disadvantage of an immune attack if properly presented to the immune system. This paper investigates the mutagenic effect of different POLE mutations in various cancers, in published genomic studies and the effect that these POLE mutations have in selecting for mutations of the β2 microglobulin (B2M) gene involved in antigen presentation.