Whole exome and transcript profiling of liver following aflatoxin B1 exposure in rats

Whole exome and transcript profiling of liver following aflatoxin B1 exposure in rats

We recently developed a rat whole exome sequencing (WES) panel and used it to evaluate early somatic mutations in archival liver tissues from F344/N rats exposed to the hepatocarcinogen, Aflatoxin B1 (AFB1), a widely studied, potent mutagen and hepatocarcinogen associated with hepatocellular carcino...

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Published in:Journal of applied toxicology Vol. 43; no. 9; pp. 1293 - 1305
Main Authors: Foley, Julie F., Elgart, Brian, Phadke, Dhiral, Mav, Deepak, Tripodi, Ignacio, Clausen, Nicholas, Weick, Madeleine, Gladwell, Wes, Gerrish, Kevin, Shah, Ruchir, Merrick, B. Alex
Format: Journal Article
Language:English
Published: England Wiley Subscription Services, Inc 01-09-2023
Subjects:
Aflatoxin B1
Aflatoxins
Apoptosis
Cancer
Cell cycle
Cell death
Cell proliferation
Deoxyribonucleic acid
DNA
DNA damage
DNA repair
E2F protein
Exposure
Gene expression
Gene set enrichment analysis
Genes
Genetic transformation
hepatocarcinogen
Hepatocellular carcinoma
Impact analysis
Impact damage
Liver
Liver cancer
Mutation
Myc protein
Nucleotide sequence
Reactive oxygen species
Recovery
Transformations
whole exome sequencing
hepatocarcinogen
whole exome sequencing
aflatoxin b1
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Summary:We recently developed a rat whole exome sequencing (WES) panel and used it to evaluate early somatic mutations in archival liver tissues from F344/N rats exposed to the hepatocarcinogen, Aflatoxin B1 (AFB1), a widely studied, potent mutagen and hepatocarcinogen associated with hepatocellular carcinoma (HCC). Rats were exposed to 1‐ppm AFB1 in feed for 14, 90, and 90 days plus a recovery 60‐day, non‐exposure period (150‐day) timepoint. Isolated liver DNA was exome sequenced. We identified 172 sequence variants across all timepoints, of which 101 were non‐synonymous variants. Well‐annotated genes carried a diverse set of 29 non‐synonymous mutations at 14 days, increasing to 39 mutations at 90 days and then decreasing to 33 mutations following the 60‐day recovery. Gene Set Enrichment Analysis conducted on previously reported, available RNA expression data of the same exome sequenced archival samples identified altered transcripts in pathways associated with malignant transformation. These included HALLMARK gene sets associated with cell proliferation (MYC Targets Version 1 and Version 2, E2F targets), cell cycle (G2M checkpoint, mitotic spindle), cell death (apoptosis), and DNA damage (DNA repair, UV response Up, Reactive oxygen species) pathways. DriverNet Impact analysis integrated exome‐seq and expression data to reveal somatic mutations in Mcm8, Bdp1, and Cct6a that may drive cancer formation. Connectivity with transcript expression changes identified these genes as the top‐ranked candidate driver genes associated with hepatocellular transformation. In conclusion, exome sequencing revealed early somatic mutations that may play a role in cancer cell transformation that are translatable to aflatoxin‐induced HCC. Whole exome sequencing revealed early somatic mutations that may play a role in cancer cell transformation that are translatable to aflatoxin‐induced HCC. Integration of exome‐sequencing with transcript expression changes identified Mcm8, Bdp1, and Cct6a as the top‐ranked candidate driver genes associated with hepatocellular transformation following short term (14‐day) and sub‐chronic (90‐day) AFB1 exposure.
Bibliography:Funding information
This research was supported in part by the NIH, National Institute of Environmental Health Sciences through Intramural Research Program Project ES103383‐01.
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ISSN:0260-437X
1099-1263
DOI:10.1002/jat.4463