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Title: Somatic mutation signatures in primary liver tumors of workers exposed to ionizing radiation

Abstract

Liver cancer is associated with genetic mutations caused by environmental exposures, including occupational exposure to alpha radiation emitted by plutonium. We used whole exome sequencing (WES) to characterize somatic mutations in 3 histologically distinct primary liver tumors (angiosarcoma of the liver (ASL), cholangiocarcinoma (CCA) and hepatocellular carcinoma (HCC)) from Mayak worker subjects occupationally exposed to ionizing radiation (IR) to investigate the contribution of IR to the mutational landscape of liver cancer. DNA sequence analysis revealed these tumors harbor an excess of deletions, with a deletions:substitutions ratio similar to that previously reported in radiation-associated tumors. These tumors were also enriched for clustered mutations, a signature of radiation exposure. Multiple tumors displayed similarities in abrogated gene pathways including actin cytoskeletal signaling and DNA double-strand break (DSB) repair. WES identified novel candidate driver genes in ASL involved in angiogenesis and PIK3CA/AKT/mTOR signaling. We confirmed known driver genes of CCA, and identified candidate driver genes involved in chromatin remodeling. In HCC tumors we validated known driver genes, and identified novel putative driver genes involved in Wnt/β-catenin signaling, chromatin remodeling, PIK3CA/AKT/mTOR signaling, and angiogenesis. This pilot study identifies several novel candidate driver mutations that are likely to be caused by IR exposure, and provides themore » first data on the mutational landscape of liver cancer after IR exposure.« less

Authors:
; ; ; ; ORCiD logo; ; ; ; ;
Publication Date:
Research Org.:
Georgetown Univ., Washington, DC (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1619612
Alternate Identifier(s):
OSTI ID: 1624513
Grant/Contract Number:  
FC01-08HS08032
Resource Type:
Published Article
Journal Name:
Scientific Reports
Additional Journal Information:
Journal Name: Scientific Reports Journal Volume: 9 Journal Issue: 1; Journal ID: ISSN 2045-2322
Publisher:
Nature Publishing Group
Country of Publication:
United Kingdom
Language:
English
Subject:
Science & Technology - Other Topics

Citation Formats

Goerlitz, David S., Blancato, Jan, Ramesh, Archana, Islam, Md., Graham, Garrett T., Revina, Valentina, Kallakury, Bhaskar, Zeck, Jay, Kirillova, Evgeniya, and Loffredo, Christopher A.. Somatic mutation signatures in primary liver tumors of workers exposed to ionizing radiation. United Kingdom: N. p., 2019. Web. https://doi.org/10.1038/s41598-019-54773-z.
Goerlitz, David S., Blancato, Jan, Ramesh, Archana, Islam, Md., Graham, Garrett T., Revina, Valentina, Kallakury, Bhaskar, Zeck, Jay, Kirillova, Evgeniya, & Loffredo, Christopher A.. Somatic mutation signatures in primary liver tumors of workers exposed to ionizing radiation. United Kingdom. https://doi.org/10.1038/s41598-019-54773-z
Goerlitz, David S., Blancato, Jan, Ramesh, Archana, Islam, Md., Graham, Garrett T., Revina, Valentina, Kallakury, Bhaskar, Zeck, Jay, Kirillova, Evgeniya, and Loffredo, Christopher A.. Tue . "Somatic mutation signatures in primary liver tumors of workers exposed to ionizing radiation". United Kingdom. https://doi.org/10.1038/s41598-019-54773-z.
@article{osti_1619612,
title = {Somatic mutation signatures in primary liver tumors of workers exposed to ionizing radiation},
author = {Goerlitz, David S. and Blancato, Jan and Ramesh, Archana and Islam, Md. and Graham, Garrett T. and Revina, Valentina and Kallakury, Bhaskar and Zeck, Jay and Kirillova, Evgeniya and Loffredo, Christopher A.},
abstractNote = {Liver cancer is associated with genetic mutations caused by environmental exposures, including occupational exposure to alpha radiation emitted by plutonium. We used whole exome sequencing (WES) to characterize somatic mutations in 3 histologically distinct primary liver tumors (angiosarcoma of the liver (ASL), cholangiocarcinoma (CCA) and hepatocellular carcinoma (HCC)) from Mayak worker subjects occupationally exposed to ionizing radiation (IR) to investigate the contribution of IR to the mutational landscape of liver cancer. DNA sequence analysis revealed these tumors harbor an excess of deletions, with a deletions:substitutions ratio similar to that previously reported in radiation-associated tumors. These tumors were also enriched for clustered mutations, a signature of radiation exposure. Multiple tumors displayed similarities in abrogated gene pathways including actin cytoskeletal signaling and DNA double-strand break (DSB) repair. WES identified novel candidate driver genes in ASL involved in angiogenesis and PIK3CA/AKT/mTOR signaling. We confirmed known driver genes of CCA, and identified candidate driver genes involved in chromatin remodeling. In HCC tumors we validated known driver genes, and identified novel putative driver genes involved in Wnt/β-catenin signaling, chromatin remodeling, PIK3CA/AKT/mTOR signaling, and angiogenesis. This pilot study identifies several novel candidate driver mutations that are likely to be caused by IR exposure, and provides the first data on the mutational landscape of liver cancer after IR exposure.},
doi = {10.1038/s41598-019-54773-z},
journal = {Scientific Reports},
number = 1,
volume = 9,
place = {United Kingdom},
year = {2019},
month = {12}
}

Journal Article:
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Publisher's Version of Record
https://doi.org/10.1038/s41598-019-54773-z

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