Mutational signatures of environmental carcinogens in human tissue organoids revealed by duplex sequencing

Environmental exposures play a pivotal role in carcinogenesis, yet their molecular imprints in human tissues remain incompletely understood. Here, we present an extensive catalogue of mutational signatures induced by a panel of environmental carcinogens using human tissue-derived organoids coupled with high-fidelity duplex sequencing (NanoSeq). This unique combination enables direct detection of mutations without clonal expansion and reveals consistent, carcinogen-specific signatures across multiple organ types (i.e. colon, stomach, liver, kidney and pancreas). We identify mutational signatures for agents such as benzo[a]pyrene, aflatoxin B1, aristolochic acid I and alkylating agents, some of which show strong concordance with known tumour signatures (e.g., SBS4, SBS11, SBS22, SBS24) and previous, experimentally-derived signatures. Our findings validate organoid models as physiologically relevant platforms for chemical mutagenesis and provide a foundational resource for decoding the environmental origins of human cancer.