Department of Analytical, Environmental and Forensic Sciences, MRC-PHE Centre for Environment and Health, King's College London, 150 Stamford Street, London SE1 9NH, UK.
Academic Department of Medical Genetics, School of Clinical Medicine, University of Cambridge, Cambridge CB2 9NB, UK; MRC Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, UK; Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
Cell. 2019 May 2;177(4):821-836.e16. doi: 10.1016/j.cell.2019.03.001. Epub 2019 Apr 11.
Whole-genome-sequencing (WGS) of human tumors has revealed distinct mutation patterns that hint at the causative origins of cancer. We examined mutational signatures in 324 WGS human-induced pluripotent stem cells exposed to 79 known or suspected environmental carcinogens. Forty-one yielded characteristic substitution mutational signatures. Some were similar to signatures found in human tumors. Additionally, six agents produced double-substitution signatures and eight produced indel signatures. Investigating mutation asymmetries across genome topography revealed fully functional mismatch and transcription-coupled repair pathways. DNA damage induced by environmental mutagens can be resolved by disparate repair and/or replicative pathways, resulting in an assortment of signature outcomes even for a single agent. This compendium of experimentally induced mutational signatures permits further exploration of roles of environmental agents in cancer etiology and underscores how human stem cell DNA is directly vulnerable to environmental agents. VIDEO ABSTRACT.
全基因组测序（WGS）揭示了人类肿瘤中独特的突变模式，这些模式暗示了癌症的致病起源。我们在 324 个人类诱导多能干细胞中研究了 79 种已知或可疑的环境致癌物的突变特征，这些细胞暴露于这些环境致癌物中。其中 41 种产生了特征性的替代突变特征。其中一些与在人类肿瘤中发现的特征相似。此外，六种试剂产生了双取代特征，八种试剂产生了插入缺失特征。通过对基因组拓扑结构上的突变不对称性进行研究，揭示了完全功能的错配和转录偶联修复途径。环境诱变剂引起的 DNA 损伤可以通过不同的修复和/或复制途径来解决，即使对于单个试剂，也会产生各种特征性的结果。这套实验诱导的突变特征集允许进一步探索环境因素在癌症病因学中的作用，并强调了人类干细胞 DNA是如何直接易受环境因素影响的。视频摘要。
