A compendium of mutational signatures of environmental 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 human induced pluripotent stem cells exposed to 79 known or suspected environmental carcinogens. 41 yielded characteristic substitution mutational signatures. Some were similar to 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. DNA damage induced by environmental mutagens can be resolved by disparate repair/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 aetiology, and underscores how human stem cell DNA is directly vulnerable to environmental agents.

全基因组测序（WGS）在人类肿瘤研究中揭示了独特的突变模式，这些模式暗示了癌症的致病起源。我们对324例暴露于79种已知或疑似环境致癌物的人源诱导多能干细胞（hiPSCs）的突变特征进行了分析。其中41例产生了典型的替换突变特征，部分特征与人类肿瘤中的特征相似。此外，6种化学物质产生了双替换突变特征，而8种产生了插入/缺失（indel）突变特征。通过对基因组拓扑结构中突变非对称性的研究，揭示了完全功能的错配修复和转录偶联修复途径。由环境诱变剂引起的DNA损伤可以通过不同的修复/复制途径得到解决，导致即使是单一化学物质也可能产生多种特征性结果。这份由实验诱导的突变特征汇编为进一步探索环境因素在癌症病因学中的作用提供了可能，并强调了人类干细胞DNA直接易受环境因素的影响。