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Published on: December 23, 2022
Mutational signatures of environmental carcinogens in human tissue organoids revealed by duplex sequencing
Jill E Kucab1, Shuvro P Nandi2, Halh Al-Serori1
1Department of Analytical, Environmental and Forensic Sciences, School of Cancer and Pharmaceutical Sciences, King's College London, 150 Stamford Street, London SE1 9NH, UK.
Abstract:
Environmental exposures play a pivotal role in carcinogenesis, yet their molecular imprints in human tissues remain incompletely understood. Here, we present an extensive catalog 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 tumor signatures (e.g., SBS4, SBS11, SBS22, and 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.
Insights
Environmental exposures cause cancer, but their molecular damage is unclear. This study catalogs cancer-causing agent mutations in human organoids, revealing consistent, specific signatures across organs.
Area of Science:
- Environmental carcinogenesis
- Genomic instability
- Cancer molecular epidemiology
Background:
- Environmental exposures are key drivers of cancer development.
- The precise molecular alterations induced by environmental carcinogens in human tissues are not fully understood.
- Identifying these alterations is crucial for understanding cancer origins.
Purpose of the Study:
- To create a comprehensive catalog of mutational signatures caused by environmental carcinogens.
- To investigate the molecular imprints of specific carcinogens in human tissue-derived organoids.
- To validate organoid models for studying chemical mutagenesis and its role in cancer.
Main Methods:
- Utilized human tissue-derived organoids from multiple organs (colon, stomach, liver, kidney, pancreas).
- Employed high-fidelity duplex sequencing (NanoSeq) for direct mutation detection without clonal expansion.
- Exposed organoids to a panel of environmental carcinogens, including benzo[a]pyrene, aflatoxin B1, aristolochic acid I, and alkylating agents.
Main Results:
- Identified consistent and distinct mutational signatures specific to each tested environmental carcinogen.
- Observed these carcinogen-induced signatures across various human organoid models.
- Found strong concordance between identified signatures and known tumor mutational signatures (e.g., SBS4, SBS11, SBS22, SBS24).
Conclusions:
- Human organoid models are validated as physiologically relevant platforms for studying chemical mutagenesis.
- The study provides a foundational resource for understanding the environmental origins of human cancers.
- This work advances the ability to decode the molecular links between environmental exposures and cancer development.
