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Experimental analysis of exome-scale mutational signature of glycidamide, the reactive metabolite of acrylamide

Maria Zhivagui, Maude Ardin, Alvin W.T. Ng, Mona I. Churchwell, Manuraj Pandey, Stephanie Villar, Vincent Cahais, Alexis Robitaille, Liacine Bouaoun, Adriana Heguy, Kathryn Guyton, Martha R. Stampfer, James McKay, Monica Hollstein, Magali Olivier, Steven G. Rozen, Frederick A. Beland, Michael Korenjak, Jiri Zavadil
doi: https://doi.org/10.1101/254664
Maria Zhivagui
1Molecular Mechanisms and Biomarkers Group, International Agency for Research on Cancer, Lyon 69008, France
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Maude Ardin
1Molecular Mechanisms and Biomarkers Group, International Agency for Research on Cancer, Lyon 69008, France
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Alvin W.T. Ng
2Centre for Computational Biology, Duke-NUS Medical School, Singapore 169857, Singapore
3Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, 169857, Singapore
4NUS Graduate School for Integrative Sciences and Engineering, 117456, Singapore
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Mona I. Churchwell
5Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079, USA
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Manuraj Pandey
1Molecular Mechanisms and Biomarkers Group, International Agency for Research on Cancer, Lyon 69008, France
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Stephanie Villar
1Molecular Mechanisms and Biomarkers Group, International Agency for Research on Cancer, Lyon 69008, France
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Vincent Cahais
6Epigenetics Group, International Agency for Research on Cancer, Lyon 69008, France
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Alexis Robitaille
7Infections and Cancer Biology Group, International Agency for Research on Cancer, Lyon 69008, France
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Liacine Bouaoun
8Environment and Radiation Section, International Agency for Research on Cancer, Lyon 69008, France
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Adriana Heguy
9Department of Pathology and Genome Technology Center, New York University, Langone Medical Center, New York, NY 10016, USA
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Kathryn Guyton
10IARC Monographs Section, International Agency for Research on Cancer, Lyon 69008, France
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Martha R. Stampfer
11Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA
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James McKay
12Genetic Cancer Susceptibility Group, International Agency for Research on Cancer, Lyon 69008, France
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Monica Hollstein
1Molecular Mechanisms and Biomarkers Group, International Agency for Research on Cancer, Lyon 69008, France
13Deutsches Krebsforschungszentrum, 69120 Heidelberg, Germany
14Faculty of Medicine and Health, University of Leeds, LIGHT Laboratories, Leeds LS2 9JT, United Kingdom
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Magali Olivier
1Molecular Mechanisms and Biomarkers Group, International Agency for Research on Cancer, Lyon 69008, France
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Steven G. Rozen
2Centre for Computational Biology, Duke-NUS Medical School, Singapore 169857, Singapore
3Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, 169857, Singapore
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Frederick A. Beland
5Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079, USA
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Michael Korenjak
1Molecular Mechanisms and Biomarkers Group, International Agency for Research on Cancer, Lyon 69008, France
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Jiri Zavadil
1Molecular Mechanisms and Biomarkers Group, International Agency for Research on Cancer, Lyon 69008, France
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Abstract

Acrylamide, a probable human carcinogen, is ubiquitously present in the human environment, with sources including heated starchy foods, coffee and cigarette smoke. Humans are also exposed to acrylamide occupationally. Acrylamide is genotoxic, inducing gene mutations and chromosomal aberrations in various experimental settings. Covalent haemoglobin adducts were reported in acrylamide-exposed humans and DNA adducts in experimental systems. The carcinogenicity of acrylamide has been attributed to the effects of glycidamide, its reactive and mutagenic metabolite capable of inducing rodent tumors at various anatomical sites. In order to characterize the pre-mutagenic DNA lesions and global mutation spectra induced by acrylamide and glycidamide, we combined DNA-adduct and whole-exome sequencing analyses in an established exposure-clonal immortalization system based on mouse embryonic fibroblasts. Sequencing and computational analysis revealed a unique mutational signature of glycidamide, characterized by predominant T:A>A:T transversions, followed by T:A>C:G and C:G>A:T mutations exhibiting specific trinucleotide contexts and significant transcription strand bias. Computational interrogation of human cancer genome sequencing data indicated that a combination of the glycidamide signature and an experimental benzo[a]pyrene signature are nearly equivalent to the COSMIC tobacco-smoking related signature 4 in lung adenocarcinomas and squamous cell carcinomas. We found a more variable relationship between the glycidamide‐ and benzo[a]pyrene-signatures and COSMIC signature 4 in liver cancer, indicating more complex exposures in the liver. Our study demonstrates that the controlled experimental characterization of specific genetic damage associated with glycidamide exposure facilitates identifying corresponding patterns in cancer genome data, thereby underscoring how mutation signature laboratory experimentation contributes to the elucidation of cancer causation.

A 40-word summary Innovative experimental approaches identify a novel mutational signature of glycidamide, a metabolite of the probable human carcinogen acrylamide. The results may elucidate the cancer risks associated with exposure to acrylamide, commonly found in tobacco smoke, thermally processed foods and beverages.

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Posted January 27, 2018.
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Experimental analysis of exome-scale mutational signature of glycidamide, the reactive metabolite of acrylamide
Maria Zhivagui, Maude Ardin, Alvin W.T. Ng, Mona I. Churchwell, Manuraj Pandey, Stephanie Villar, Vincent Cahais, Alexis Robitaille, Liacine Bouaoun, Adriana Heguy, Kathryn Guyton, Martha R. Stampfer, James McKay, Monica Hollstein, Magali Olivier, Steven G. Rozen, Frederick A. Beland, Michael Korenjak, Jiri Zavadil
bioRxiv 254664; doi: https://doi.org/10.1101/254664
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Experimental analysis of exome-scale mutational signature of glycidamide, the reactive metabolite of acrylamide
Maria Zhivagui, Maude Ardin, Alvin W.T. Ng, Mona I. Churchwell, Manuraj Pandey, Stephanie Villar, Vincent Cahais, Alexis Robitaille, Liacine Bouaoun, Adriana Heguy, Kathryn Guyton, Martha R. Stampfer, James McKay, Monica Hollstein, Magali Olivier, Steven G. Rozen, Frederick A. Beland, Michael Korenjak, Jiri Zavadil
bioRxiv 254664; doi: https://doi.org/10.1101/254664

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