Heterozygous deleterious MUTYH variants as a driver for tumorigenesis

Abstract MUTYH is a glycosylase involved in the base excision repair of the DNA. Biallelic mutations in the MUTYH gene cause the autosomal recessive condition known as MUTYH-associated adenomatous polyposis and increase colorectal cancer risk. However, the cancer risk associated with germline variants in individuals carrying only one MUTYH defective allele is controversial and based on studies involving few samples. Here, we described a comprehensive investigation of monoallelic deleterious MUTYH carriers among approximately 10,400 patients across 33 different tumor types and more than 117 thousand samples of normal individuals. Our results indicate MUTYH deficiency in heterozygosity can lead to tumorigenesis through a mechanism of Loss Of Heterozygosity (LOH) of the functional MUTYH allele. We confirmed that the frequency of damaging MUTYH monoallelic variant carriers is higher in individuals with cancer than in the general population, though its frequency is not homogeneous among tumor types. We also demonstrate that MUTYH related mutational signature is elevated only in those patients with loss of the functional allele. We also find that MUTYH characteristic base substitution (C>A) increases stop codon generation and we identify key genes affected during tumorigenesis. In conclusion, we propose that deleterious germline monoallelic MUTYH variant carriers are at a higher risk of developing tumors, especially those types with frequent LOH events, such as adrenal adenocarcinoma.