Mutational spectra of aflatoxin B
Author(s)
Fox, Edward J.; Loeb, Lawrence A.; Chawanthayatham, Supawadee; Valentine III, Charles Clinton; Fedeles, Bogdan I; Levine, Stuart S.; Slocum, Stephen L.; Wogan, Gerald N; Croy, Robert G; Essigmann, John M; ... Show more Show less
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Aflatoxin B₁ (AFB₁) and/or hepatitis B and C viruses are risk factors for human hepatocellular carcinoma (HCC). Available evidence supports the interpretation that formation of AFB₁-DNA adducts in hepatocytes seeds a population of mutations, mainly G:C→T:A, and viral processes synergize to accelerate tumorigenesis, perhaps via inflammation. Responding to a need for early-onset evidence predicting disease development, highly accurate duplex sequencing was used to monitor acquisition of high-resolution mutational spectra (HRMS) during the process of hepatocarcinogenesis. Four-day-old male mice were treated with AFB₁ using a regimen that induced HCC within 72 wk. For analysis, livers were separated into tumor and adjacent cellular fractions. HRMS of cells surrounding the tumors revealed predominantly G:C→T:A mutations characteristic of AFB₁ exposure. Importantly, 25% of all mutations were G→T in one trinucleotide context (CGC; the underlined G is the position of the mutation), which is also a hotspot mutation in human liver tumors whose incidence correlates with AFB₁ exposure. The technology proved sufficiently sensitive that the same distinctive spectrum was detected as early as 10 wk after dosing, well before evidence of neoplasia. Additionally, analysis of tumor tissue revealed a more complex pattern than observed in surrounding hepatocytes; tumor HRMS were a composite of the 10-wk spectrum and a more heterogeneous set of mutations that emerged during tumor outgrowth. We propose that the 10-wk HRMS reflects a short-term mutational response to AFB₁, and, as such, is an early detection metric for AFB₁-induced liver cancer in this mouse model that will be a useful tool to reconstruct the molecular etiology of human hepatocarcinogenesis.
Date issued
2017-03Department
Massachusetts Institute of Technology. Center for Environmental Health Sciences; Massachusetts Institute of Technology. Department of Biological Engineering; Massachusetts Institute of Technology. Department of ChemistryJournal
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences (U.S.)
Citation
Chawanthayatham, Supawadee et al. “Mutational Spectra of Aflatoxin B1in Vivo Establish Biomarkers of Exposure for Human Hepatocellular Carcinoma.” Proceedings of the National Academy of Sciences 114, 15 (March 2017): E3101–E3109 © 2017 National Academy of Sciences
Version: Final published version
ISSN
0027-8424
1091-6490