Heterozygous deleterious MUTYH variants as a driver for tumorigenesis

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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The authors acknowledge the National Council for Scientific and Technological Development (CNPq) and the Sao Paulo Research Foundation (FAPESP, grants 2018/15579-8, 2019/04927-8 and 2020/06091-1) for financial support. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Not applicable. All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes We have used only public data.