PT - JOURNAL ARTICLE AU - Maria Zhivagui AU - Maude Ardin AU - Alvin W.T. Ng AU - Mona I. Churchwell AU - Manuraj Pandey AU - Stephanie Villar AU - Vincent Cahais AU - Alexis Robitaille AU - Liacine Bouaoun AU - Adriana Heguy AU - Kathryn Guyton AU - Martha R. Stampfer AU - James McKay AU - Monica Hollstein AU - Magali Olivier AU - Steven G. Rozen AU - Frederick A. Beland AU - Michael Korenjak AU - Jiri Zavadil TI - Experimental analysis of exome-scale mutational signature of glycidamide, the reactive metabolite of acrylamide AID - 10.1101/254664 DP - 2018 Jan 01 TA - bioRxiv PG - 254664 4099 - http://biorxiv.org/content/early/2018/01/27/254664.short 4100 - http://biorxiv.org/content/early/2018/01/27/254664.full AB - 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.