A germline heterozygous POLQ nonsense mutation causes hereditary colorectal cancer

The causal genes for a large proportion of hereditary colorectal adenomas and early-onset colorectal cancer (CRC) remain to be identified. Here, we identified a germline heterozygous stop-gain mutation p.Arg1953X (rs150312701) of the POLQ (DNA Polymerase Theta) gene, which is co-segregated with disease status, by whole-exome sequencing of twelve hereditary CRC pedigrees. The mutation was validated in an independent pedigree, resulting in ten p.Arg1953X carriers from two CRC families. Mechanically, the heterozygous nonsense mutation led to compensated overexpression of the mRNA with wild-type POLQ allele under DNA damage stress, resulting in hyperactivation of the error-prone theta mediated end-joining (TMEJ) DNA repair pathway, which enables the survival of mutation-enriched cells. Concordantly, tumor tissues from p.Arg1953X mutation carriers showed microsatellite instability and hypermutation, and were resistant to radiotherapy. We found that an FDA-approved antibiotic Novobiocin inhibits the POLQ-mediated TMEJ pathway, eliminates the p.Arg1953X mutation-related resistance to DNA damage, finally benefits tumor radiotherapy. Collectively, we defined a POLQ-mutated CRC type and suggested for a mutation-based potential target therapeutic strategy. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The study was supported by the National Natural Science Foundation of China and the Applied Basic Research Foundation of Yunnan Province. ### 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: All studies were conducted with the approval of the ethics committee of Kunming Medical University (2017-3), and all participants provided written informed consent. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. 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, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.