Identification and Targeting of POLQ-Associated Hereditary Colorectal Cancer

Abstract Purpose: Hereditary colorectal cancer syndromes remain incompletely understood, with many cases lacking defined genetic causes. This study aimed to identify pathogenic mutations associated with hereditary colorectal cancer and explore their potential for targeted therapies. Experimental Design: This observational study was conducted in Yunnan Province, China. We analyzed 43 individuals from 12 families with hereditary colorectal cancer using whole-exome sequencing, screened 84 families with polyposis and 310 sporadic colorectal cancer cases, and analyzed an expanded cohort of 285 individuals with potential hereditary colorectal cancer. A series of in vivo and in vitro assays were conducted to evaluate the mutation’s effects on tumorigenesis. Results: A germline heterozygous stop-gain mutation, p.Arg1953X in the polymerase θ (POLQ) gene, was identified in two families with colorectal cancer, showing cosegregation with disease status. A third POLQ mutation–positive family was identified in the expanded validation cohort. Cells carrying the mutation showed potential of tumorigenesis. The mutation hyperactivates error-prone θ-mediated end-joining (TMEJ), leading to high tumor mutational burden and resistance to DNA-damaging treatments. Indeed, the probands exhibited mismatch repair–deficient/microsatellite instability–high status that indicates high tumor mutational burden. Treatment with the POLQ inhibitor novobiocin suppressed TMEJ activity and restored tumor sensitivity to DNA damage, providing a combined medication scheme for drug-resistant POLQ-type colorectal cancer. Conclusions: This study identifies POLQ as a pathogenic gene in hereditary colorectal cancer, unveiling a novel POLQ-type colorectal cancer driven by TMEJ hyperactivation. Screening for POLQ mutations in patients with hereditary adenomas or early-onset colorectal cancer would benefit early diagnosis and personalized therapy for POLQ-associated colorectal cancer; however, further clinical validation is warranted.