Xu Ning, Zhang Deng-Feng, Shi Xiao-Xiao, Yang Ke-Xin, Gan Bei-Bei, Fan Yu, Huang Feng-Chang, Ren Jun-Yu, Bi Rui, Li Yu, Ye Mao-Sen, Xu Min, Zhou Yong-Chun, Li Wen-Hui, Yao Yong-Gang, Li Wen-Liang
The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Peking University Cancer Hospital Yunnan, Kunming, China.
The First Affiliated Hospital of Kunming Medical University, Kunming, China.
Clin Cancer Res. 2025 Aug 1;31(15):3215-3228. doi: 10.1158/1078-0432.CCR-25-0379.
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.
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.
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.
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.
遗传性结直肠癌综合征仍未被完全理解，许多病例缺乏明确的遗传病因。本研究旨在识别与遗传性结直肠癌相关的致病突变，并探索其靶向治疗的潜力。
本观察性研究在中国云南省进行。我们使用全外显子组测序分析了来自12个遗传性结直肠癌家族的43名个体，筛查了84个息肉病家族和310例散发性结直肠癌病例，并分析了一个扩大的队列，其中包括285名可能患有遗传性结直肠癌的个体。进行了一系列体内和体外试验以评估该突变对肿瘤发生的影响。
在两个结直肠癌家族中鉴定出一种生殖系杂合性终止获得突变，即聚合酶θ（POLQ）基因中的p.Arg1953X，显示与疾病状态共分离。在扩大的验证队列中鉴定出第三个POLQ突变阳性家族。携带该突变的细胞显示出肿瘤发生的潜力。该突变过度激活易出错的θ介导的末端连接（TMEJ），导致高肿瘤突变负担和对DNA损伤治疗的抗性。事实上，先证者表现出错配修复缺陷/微卫星不稳定性高状态，这表明高肿瘤突变负担。使用POLQ抑制剂新生霉素治疗可抑制TMEJ活性并恢复肿瘤对DNA损伤的敏感性，为耐药性POLQ型结直肠癌提供了联合用药方案。
本研究将POLQ鉴定为遗传性结直肠癌中的致病基因，揭示了一种由TMEJ过度激活驱动的新型POLQ型结直肠癌。对遗传性腺瘤或早发性结直肠癌患者进行POLQ突变筛查将有助于POLQ相关结直肠癌的早期诊断和个性化治疗；然而，需要进一步的临床验证。
