摘要
目的:探讨低误差第二代测序(next-generation sequencing,NGS)技术在肿瘤研究和药物致突变性评价领域的进展。方法:通过查阅文献、收集资料等方法,汇总近年来低误差NGS技术进展、优缺点以及在肿瘤研究和药物致突变性/致癌性评价的应用。结果:传统的NGS技术的背景误差率较高,限制其在低频率突变检测方面的应用。近年开发的多种低误差NGS技术(即校正测序错误的NGS,errorcorrected next-generation sequencing,ecNGS)可将NGS的检测误差率降低至10^(-7)~10^(-4)或甚至更低,满足肿瘤临床监测和指导用药的需求。此外,HiFi-Seq和PECC-Seq等技术的最低误差率可降低至10^(-8),可检出药物短期暴露导致的细胞/组织的超低频突变,有助于在药物研发早期评估其致癌性风险。结论:ecNGS技术目前处于开发阶段,尚未标准化,且未在临床、毒理学、风险评估领域推广应用。然而,该方法可直接检出肿瘤早期病变组织中的突变和药物诱导的组织/细胞突变,有望取代或补充现有的致突变性试验方法,纳入相关指导原则,成为药物早期遗传毒性、致癌性筛查的金标准。
Objective:To explore the advances of low-error next-generation sequencing(NGS)technology in cancer research and drug mutagenicity evaluation.Methods:The technical progress,advantages and disadvantages of low-error NGS and its application in cancer research and drug mutagenicity/carcinogenicity evaluation were summarized by reviewing literatures and collecting data in recent years.Results:The background error rate of traditional NGS technique is high,which limits its application in low frequency mutation detection.Several low-error NGS technologies developed in recent years(i.e.,error-corrected next generation sequencing,ecNGS)can reduce the error rate of NGS to 10^(-7)to 10^(-4)or even lower,meeting the needs of clinical tumor monitoring and drug regulation.In addition,the minimum error rate of ecNGS technologies such as HiFi-Seq and PECC-Seq can be reduced to 10^(-8),which can detect ultra-low frequency mutations in cell/tissue caused by short-term exposure to drugs,helping to assess their carcinogenicity risk in the early stage of drug development.Conclusion:The ecNGS technology is currently in the development stage,it has not been standardized,and has not been popularized in clinical,toxicology and risk assessment fields.However,these can directly detect druginduced tissue/cell mutations and obtain the specific mutation spectrum of drugs,which can be an alternative or supplement method of the existing mutagenicity tests,incorporate relevant guidelines,and become the gold standard for early drug genetic toxicity and carcinogenicity screening.
作者
寇小旋
耿兴超
文海若
Kou Xiaoxuan;Geng Xingchao;Wen Hairuo(National Center for Safety Evaluation of Drugs,National Institutes for Food and Drug Control,Key Laboratory of Beijing for Nonclinical Safety Evaluation Research of Drugs,Beijing 100176,China;China Pharmaceutical University,Nanjing 210009,China)
出处
《中国药事》
CAS
2024年第7期831-838,共8页
Chinese Pharmaceutical Affairs
基金
药品监管科学全国重点实验室课题“药品杂质遗传毒性评价新技术和生物标志物研究”(编号2023SKLDRS0128)。
关键词
第二代测序技术
致突变性
致癌性
肿瘤研究
超低频测序
药品监管
next-generation sequencing technology
mutagenicity
carcinogenicity
cancer research
ultra-low frequency sequencing
drug regulation
