A germline heterozygousPOLQnonsense 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.