The role of mutations in the MUTYH gene in the development of colorectal cancer

Abstract

Mutations in the MUTYH gene, which encodes a DNA glycosylase, are associated with an increased risk of colorectal cancer (CRC), particularly in individuals with hereditary MUTYH-associated polyposis (MAP). MUTYH is an essential component of the base excision repair (BER) pathway, where it removes adenine resi-dues that are mispaired with 8-oxoguanine (8-oxoG), a major product of oxidative DNA damage. Loss of MUTYH function caused by pathogenic variants promotes the accumulation of oxidative DNA damage-associated mutations, including G:C→T:A transversions, thereby contributing to genomic instability and colo-rectal tumorigenesis. This review examines the pathogenic mechanisms underlying MAP and its characteristic phenotypic features. Structural and functional studies indicate that many pathogenic MUTYH variants result in reduced adenine DNA glycosylase activity, leading to impaired base excision repair. Potential therapeutic strate-gies aimed at restoring or compensating for defective MUTYH function are being investigated, including ap-proaches based on synthetic lethality. Increasing attention is also being paid to molecular genetic testing for bial-lelic pathogenic variants in the MUTYH gene, particularly in individuals with clinical or family histories sug-gestive of hereditary colorectal cancer or polyposis. Identification of such variants may enable more precise risk assessment and facilitate personalized surveillance and preventive management. Overall, advances in under-standing the role of MUTYH in genome maintenance have provided important insights into the pathogenesis of MAP and created opportunities for improving the diagnosis, risk stratification, and management of colorectal cancer.