Assessing the Mutational Consequences of Chronic Arsenic Exposure Using Patient-Derived Tumor Samples and In Vitro Systems.
14 affiliations
- 1Department of Public Health Sciences, University of Chicago, Chicago, Illinois, USA.
- 2Committee on Genetics, Genomics, Systems Biology, University of Chicago, Chicago, Illinois, USA.
- 3Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
- 4UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA.
- 5Center for Research Informatics Bioinformatics Core, University of Chicago, Chicago, Illinois, USA.
- 6Institute for Population and Precision Health (IPPH), Biological Sciences Division, University of Chicago, Chicago, Illinois, USA.
- 7Section of Dermatology, Department of Medicine, University of Chicago, Chicago, Illinois, USA.
- 8UChicago Research Bangladesh, Dhaka, Bangladesh.
- 9Bangladesh Medical University (BMU), Dhaka, Bangladesh.
- 10Ahsania Mission Cancer & General Hospital, Dhaka, Bangladesh.
- 11National Institute of Cancer Research and Hospital (NICRH), Dhaka, Bangladesh.
- 12Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois, USA.
- 13Department of Human Genetics, University of Chicago, Chicago, Illinois, USA.
- 14Comprehensive Cancer Center, University of Chicago, Chicago, Illinois, USA.
Abstract
Inorganic arsenic, a naturally occurring metalloid found in groundwater, is a well-established human carcinogen. Epidemiological studies from highly contaminated regions link chronic arsenic exposure to increased risks of skin, lung, bladder, and kidney cancer. However, studies investigating the mechanisms driving arsenic-related mutagenicity in human tumors remain limited. To improve our understanding, we analyzed whole-exome sequencing (WES) data from tumor samples of 17 cancer patients treated in Dhaka, Bangladesh, with known or suspected exposure based on toenail arsenic concentrations. These patients included bladder (n = 9), kidney (n = 6), and lung (n = 2) cancers. The mutational burden (mutations per megabase) across all exomes ranged from 23 to 117 for single-base substitutions (SBS) and 2 to 13 for small insertions and deletions (indel). We showed that SBS and indel signatures, including SBS5, SBS6, ID6, and ID19 contributed the highest mutation load across all exomes. However, we did not observe associations between arsenic exposure levels and any mutational signature. We additionally analyzed WES data from two cell line models of chronic arsenic exposure, HaCaT skin epithelial and BEAS-2B lung epithelial cells exposed to low-dose of arsenite (100 nM) for 28 weeks. Consistent with the patient-derived results, we observed no exposure-related mutational burden or signature. Taken together, our findings suggest that arsenic alone may have limited independent mutagenic effects and instead may act through co-carcinogenic mechanisms. However, limited sensitivity to detect low-frequency mutations and small sample sizes potentially reduced our ability to capture mutational processes that may be associated with chronic arsenic exposure.
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BibTeX
@article{jain2026assessing,
title = {{Assessing the Mutational Consequences of Chronic Arsenic Exposure Using Patient-Derived Tumor Samples and In Vitro Systems.}},
author = {Niyati Jain and Kathryn Demanelis and Evan Wu and Muhammad G Kibriya and Farzana Jasmine and Emma Wilkinson and Syed Emdadul Haque and Mohammed Kamal and Saequa Habib and Qamruzzaman Chowdhury and Farida Arjuman and Habibul Ahsan and Lixing Yang and Yu-Ying He and Brandon L Pierce},
journal = {Environmental and molecular mutagenesis},
year = {2026},
month = oct,
doi = {10.1002/em.70079},
url = {https://europepmc.org/article/MED/42920328},
note = {CC BY},
}
RIS
TY - JOUR
TI - Assessing the Mutational Consequences of Chronic Arsenic Exposure Using Patient-Derived Tumor Samples and In Vitro Systems.
AU - Niyati Jain
AU - Kathryn Demanelis
AU - Evan Wu
AU - Muhammad G Kibriya
AU - Farzana Jasmine
AU - Emma Wilkinson
AU - Syed Emdadul Haque
AU - Mohammed Kamal
AU - Saequa Habib
AU - Qamruzzaman Chowdhury
AU - Farida Arjuman
AU - Habibul Ahsan
AU - Lixing Yang
AU - Yu-Ying He
AU - Brandon L Pierce
PY - 2026
DA - 2026/10/01
JO - Environmental and molecular mutagenesis
DO - 10.1002/em.70079
UR - https://europepmc.org/article/MED/42920328
AB - Inorganic arsenic, a naturally occurring metalloid found in groundwater, is a well-established human carcinogen. Epidemiological studies from highly contaminated regions link chronic arsenic exposure to increased risks of skin, lung, bladder, and kidney cancer. However, studies investigating the mechanisms driving arsenic-related mutagenicity in human tumors remain limited. To improve our understanding, we analyzed whole-exome sequencing (WES) data from tumor samples of 17 cancer patients treated in Dhaka, Bangladesh, with known or suspected exposure based on toenail arsenic concentrations. These patients included bladder (n = 9), kidney (n = 6), and lung (n = 2) cancers. The mutational burden (mutations per megabase) across all exomes ranged from 23 to 117 for single-base substitutions (SBS) and 2 to 13 for small insertions and deletions (indel). We showed that SBS and indel signatures, including SBS5, SBS6, ID6, and ID19 contributed the highest mutation load across all exomes. However, we did not observe associations between arsenic exposure levels and any mutational signature. We additionally analyzed WES data from two cell line models of chronic arsenic exposure, HaCaT skin epithelial and BEAS-2B lung epithelial cells exposed to low-dose of arsenite (100 nM) for 28 weeks. Consistent with the patient-derived results, we observed no exposure-related mutational burden or signature. Taken together, our findings suggest that arsenic alone may have limited independent mutagenic effects and instead may act through co-carcinogenic mechanisms. However, limited sensitivity to detect low-frequency mutations and small sample sizes potentially reduced our ability to capture mutational processes that may be associated with chronic arsenic exposure.
SN - 0893-6692
SN - 1098-2280
ER -