A compendium of mutational signatures of environmental and chemotherapeutic agents Kucab et al.

Whole-genome-sequencing (WGS) of human tumours has revealed distinct mutation patterns that hint at the causative origins of cancer. We examined mutational signatures in 324 WGS of human induced pluripotent stem cells (iPSCs) following exposure to known or suspected environmental carcinogens. 79 agents were tested at concentrations that produced measurable cytotoxicity; 41 yielded characteristic substitution mutational signatures. Some exhibited similarity with signatures found in human tumours. Additionally, 6 agents produced double-substitution signatures and 8 produced indel signatures. Investigating mutation asymmetries across genome topography revealed fully functional mismatch and transcription-coupled repair pathways in iPSCs. Primary adducts induced by environmental carcinogens can be resolved by disparate repair/replicative pathways, resulting in an assortment of signature outcomes even for a single mutagen. This compendium of experimentally-induced mutational signatures permits further exploration of roles of environmental agents in cancer aetiology, and underscores how human stem cell DNA is directly vulnerable to environmental agents.全基因组测序（Whole-genome-sequencing, WGS）技术在人类肿瘤研究中的应用已揭示出多种独特的突变模式，这些模式可为癌症的致病起源提供线索。本研究对324例经已知或疑似环境致癌物暴露处理的人类诱导多能干细胞（induced pluripotent stem cells, iPSCs）的全基因组测序样本开展了突变特征分析。研究共测试了79种受试物，其使用浓度均能产生可检测的细胞毒性；其中41种受试物可诱导产生特征性的碱基替换突变特征，部分特征与人类肿瘤中发现的突变特征具有相似性。此外，有6种受试物可诱导产生双碱基替换突变特征，另有8种可产生插入缺失（indel）突变特征。通过分析全基因组范围内的突变不对称性，本研究证实人类诱导多能干细胞中存在功能完备的错配修复与转录偶联修复通路。环境致癌物诱导形成的DNA初级加合物可通过不同的修复或复制通路进行清除，即便仅针对单一诱变剂，也可产生多样化的突变特征结局。本项实验诱导突变特征汇编数据集，可为进一步探究环境因子在癌症病因学中的作用提供研究基础，同时也凸显了人类干细胞DNA对环境因子的直接易感性。