Experimental and pan-cancer genome analyses reveal widespread contribution of acrylamide exposure to carcinogenesis in humans

Zhivagui, Maria; Ng, Alvin W.T.; Ardin, Maude; Churchwell, Mona I.; Pandey, Manuraj; Renard, Claire-Angélique; Villar, Stéphanie; Cahais, Vincent; Robitaille, Alexis; Bouaoun, Liacine; Heguy, Adriana; Guyton, Kathryn Z.; Stampfer, Martha R.; McKay, James; Hollstein, Monica; Olivier, Magalí; Rozen, Steven G.; Beland, Frederick A.; Korenjak, Michael; Zavadil, Jiří

doi:10.1101/gr.242453.118

Cited by 73 publications

(87 citation statements)

References 62 publications

(89 reference statements)

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“…Thus, the further development of methods for deciphering and attributing mutational signatures is warranted, ideally supported by signatures derived from experimental systems in which the causes are known. Nevertheless, signatures with many similarities and some differences can be found by different mathematical approaches, and these can be confirmed in several ways, including experimentally elucidated signatures 5,31,39,42,43,[54][55][56][57][58][59][60][61][62] and tumours dominated by a single signature (syn12016215).…”

Section: Discussionmentioning

confidence: 95%

The repertoire of mutational signatures in human cancer

Alexandrov

Kim

Haradhvala

et al. 2020

Nature

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2,564

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3,078

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Somatic mutations in cancer genomes are caused by multiple mutational processes, each of which generates a characteristic mutational signature 1. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium 2 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we characterized mutational signatures using 84,729,690 somatic mutations from 4,645 whole-genome and 19,184 exome sequences that encompass most types of cancer. We identified 49 single-base-substitution, 11 doublet-base-substitution, 4 clustered-base-substitution and 17 small insertion-and-deletion signatures. The substantial size of our dataset, compared with previous analyses 3-15 , enabled the discovery of new signatures, the separation of overlapping signatures and the decomposition of signatures into components that may represent associated-but distinct-DNA damage, repair and/or replication mechanisms. By estimating the contribution of each signature to the mutational catalogues of individual cancer genomes, we revealed associations of signatures to exogenous or endogenous exposures, as well as to defective DNA-maintenance processes. However, many signatures are of unknown cause. This analysis provides a systematic perspective on the repertoire of mutational processes that contribute to the development of human cancer. Somatic mutations in cancer genomes are caused by mutational processes of both exogenous and endogenous origin that operate during the cell lineage between the fertilized egg and the cancer cell 16. Each mutational process may involve components of DNA damage or modification, DNA repair and DNA replication (which may be normal or abnormal), and generates a characteristic mutational signature that potentially includes base substitutions, small insertions and deletions (indels), genome rearrangements and chromosome copy-number changes 1. The mutations in an individual cancer genome may have been generated by multiple mutational processes, and thus incorporate multiple superimposed mutational signatures. Therefore, to systematically characterize the mutational processes that contribute to cancer, mathematical methods have previously been used to decipher mutational signatures from somatic mutation catalogues, estimate the number of mutations that are attributable to each signature in individual samples and annotate each mutation class in each tumour with the probability that it arose from each signature 6,9,17-27. Previous studies of multiple types of cancer have identified more than 30 single-base substitution (SBS) signatures, some of knownbut many of unknown-aetiologies, some ubiquitous and others rare, some part of normal cell biology and others associated with abnormal exposures or neoplastic progression 3-5,7-15. Genome rearrangement signatures have also previously been described 11,25,28-30. However, the analysis of other classes of mutation has been relatively limited 3,11,31-33 .

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Section: Discussionmentioning

confidence: 95%

The repertoire of mutational signatures in human cancer

Alexandrov

Kim

Haradhvala

et al. 2020

Nature

Self Cite

2,564

117

3,078

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“…The recall bias and confounding effect of tobacco smoking may play a role in these observed associations. Recently, some debates are ignited about the acrylamide formed early in the roasting process of coffee beans, a carcinogen in both animals and human [30]. However, we did not have enough evidence to attribute the positive associations between coffee and these two types of cancers to the acrylamide because such a low exposure of acrylamide in coffee is unlikely to cause any cancers in human body [31,32].…”

Section: Discussionmentioning

confidence: 70%

Coffee drinking and cancer risk: an umbrella review of meta-analyses of observational studies

Zhao

Guo

et al. 2020

BMC Cancer

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Background: Epidemiological studies on the association between coffee intake and cancer risk have yielded inconsistent results. To summarize and appraise the quality of the current evidence, we conducted an umbrella review of existing findings from meta-analyses of observational studies. Methods: We searched PubMed, Embase, Web of Science and the Cochrane database to obtain systematic reviews and meta-analyses of associations between coffee intake and cancer incidence. For each association, we estimated the summary effect size using the fixed-and random-effects model, the 95% confidence interval, and the 95% prediction interval. We also assessed heterogeneity, evidence of small-study effects, and excess significance bias. Results: Twenty-eight individual meta-analyses including 36 summary associations for 26 cancer sites were retrieved for this umbrella review. A total of 17 meta-analyses were significant at P ≤ 0.05 in the random-effects model. For the highest versus lowest categories, 4 of 26 associations had a more stringent P value (P ≤ 10 − 6). Associations for five cancers were significant in dose-response analyses. Most studies (69%) showed low heterogeneity (I 2 ≤ 50%). Three and six associations had evidence of excessive significance bias and publication bias, respectively. Coffee intake was inversely related to the risk of liver cancer and endometrial cancer and was characterized by dose-response relationships. There were no substantial changes when we restricted analyses to meta-analysis of cohort studies. Conclusions: There is highly suggestive evidence for an inverse association between coffee intake and risk of liver and endometrial cancer. Further research is needed to provide more robust evidence for cancer at other sites.

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“…Lastly, the HIMA coupled with next generation sequencing and DNA adduct analysis has yielded a novel mutational signature of glycidamide, the reactive metabolite of acrylamide present in human diet and in tobacco smoke. Tailored computational analyses of the vast pan-cancer data were then able to identify the glycidamide signature in an unexpectedly large number of cancer types [54]. Collectively, these studies exemplify the future potential of the HIMA assay for systematic screening of carcinogenic compounds for robust mutagenic effects and functional impact, and they signal new in-depth insights into aetiology and development of cancer while generating important mechanistic evidence for adopting relevant preventive measures.…”

Section: Future Perspectives: Investigating Mutational Signatures By mentioning

confidence: 82%

Characterising Mutational Spectra of Carcinogens in the Tumour Suppressor Gene TP53 Using Human TP53 Knock-in (Hupki) Mouse Embryo Fibroblasts

Hölzl-Armstrong

Kucab

Korenjak

et al. 2019

MPs

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DNA in dividing cells is prone to mutagenesis, with mutations making key contributions to human disease including cancer. The tumour suppressor gene TP53 is the most frequently mutated gene in human tumours. Here, we present a robust protocol for studying TP53 mutagenesis utilising human TP53 knock-in (Hupki) mouse embryonic fibroblasts (HUFs). In the HUF immortalisation assay (HIMA), primary HUFs are treated with known or suspected carcinogens at 3% oxygen and then transferred to 20% atmospheric oxygen to induce senescence. Cells containing mutations (e.g., in TP53) that allow bypassing of senescence eventually emerge as immortalised clonal cell lines after 2–3 months of serial passaging. As not all immortalised HUF cells contain TP53 mutations, we developed a Nutlin-3a counter-screen to select for TP53-mutated clones prior to sequencing. TP53 mutation spectra generated can be compared with those of human tumours recorded in the International Agency for Research on Cancer TP53 mutation database. Environmental mutagens that have demonstrated and validated the utility of the HIMA include ultraviolet radiation, aristolochic acid, and benzo[a]pyrene. The TP53 mutation patterns induced by these mutagens in the HIMA corresponded to those found in human tumours from patients exposed to these mutagens. The approach presented helps to deepen our understanding of human cancer aetiology.

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Experimental and pan-cancer genome analyses reveal widespread contribution of acrylamide exposure to carcinogenesis in humans

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Cited by 73 publications

References 62 publications

The repertoire of mutational signatures in human cancer

The repertoire of mutational signatures in human cancer

Coffee drinking and cancer risk: an umbrella review of meta-analyses of observational studies

Characterising Mutational Spectra of Carcinogens in the Tumour Suppressor Gene TP53 Using Human TP53 Knock-in (Hupki) Mouse Embryo Fibroblasts

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