The genome as a record of environmental exposure

Nik-Zainal, Serena; Kucab, Jill E.; Morganella, Sandro; Glodzik, Dominik; Alexandrov, Ludmil B.; Arlt, Volker M.; Weninger, Annette; Hollstein, Monica; Stratton, Michael R.; Phillips, David H.

doi:10.1093/mutage/gev073

Cited by 167 publications

(223 citation statements)

References 34 publications

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“…Mouse models and cells derived from mice are often used to study experimental AAN and mechanisms related to AA carcinogenesis (Arlt et al 2011; Baudoux et al 2012; Krais et al 2015; Nik-Zainal et al 2015; Odell et al 2013; Wang et al 2012). Thus, it is also important to understand the role of murine Sults on AA bioactivation.…”

Section: Discussionmentioning

confidence: 99%

“…The major AA-DNA adducts have been identified as: 7-(deoxyadenosin- N 6 -yl)aristolactam I (dA-AAI); 7-(deoxyguanosin- N 2 -yl)aristolactam I (dG-AAI); 7-(deoxyadenosin- N 6 -yl)aristolactam II (dA-AAII); and 7-(deoxyguanosin- N 2 -yl)aristolactam II (dG-AAII) (Schmeiser et al 2009, 2014). Characteristic AT to TA transversion mutations have been found in urothelial tumours of AAN patients highlighting the role of dA-AAI adducts as critical premutagenic lesions in AA malignancy (Arlt et al 2007; Lord et al 2004; Nik-Zainal et al 2015; Poon et al 2013). …”

Section: Introductionmentioning

confidence: 99%

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Impact of genetic modulation of SULT1A enzymes on DNA adduct formation by aristolochic acids and 3-nitrobenzanthrone

et al. 2016

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Exposure to aristolochic acid (AA) causes aristolochic acid nephropathy (AAN) and Balkan endemic nephropathy (BEN). Conflicting results have been found for the role of human sulfotransferase 1A1 (SULT1A1) contributing to the metabolic activation of aristolochic acid I (AAI) in vitro. We evaluated the role of human SULT1A1 in AA bioactivation in vivo after treatment of transgenic mice carrying a functional human SULT1A1-SULT1A2 gene cluster (i.e. hSULT1A1/2 mice) and Sult1a1(−/−) mice with AAI and aristolochic acid II (AAII). Both compounds formed characteristic DNA adducts in the intact mouse and in cytosolic incubations in vitro. However, we did not find differences in AAI-/AAII-DNA adduct levels between hSULT1A1/2 and wild-type (WT) mice in all tissues analysed including kidney and liver despite strong enhancement of sulfotransferase activity in both kidney and liver of hSULT1A1/2 mice relative to WT, kidney and liver being major organs involved in AA metabolism. In contrast, DNA adduct formation was strongly increased in hSULT1A1/2 mice compared to WT after treatment with 3-nitrobenzanthrone (3-NBA), another carcinogenic aromatic nitro compound where human SULT1A1/2 is known to contribute to genotoxicity. We found no differences in AAI-/AAII-DNA adduct formation in Sult1a1(−/−) and WT mice in vivo. Using renal and hepatic cytosolic fractions of hSULT1A1/2, Sult1a1(−/−) and WT mice, we investigated AAI-DNA adduct formation in vitro but failed to find a contribution of human SULT1A1/2 or murine Sult1a1 to AAI bioactivation. Our results indicate that sulfo-conjugation catalysed by human SULT1A1 does not play a role in the activation pathways of AAI and AAII in vivo, but is important in 3-NBA bioactivation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Impact of genetic modulation of SULT1A enzymes on DNA adduct formation by aristolochic acids and 3-nitrobenzanthrone

et al. 2016

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“…There are now 30 widely accepted signatures, with a variety of known, suspected, or unknown causes (http ://cancer.sanger.ac.uk/cosmic/signatures). These signatures hold promise in molecular cancer epidemiology because they bear witness to mutagenic exposures and because they illuminate endogenous mutagenic processes and mechanisms of DNA damage and repair Helleday et al 2014;Poon et al 2014;Nik-Zainal et al 2015;Hollstein et al 2016).…”

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confidence: 99%

“…While exome-or genome-wide extended mutational signatures from several metazoan experimental systems have been reported (Meier et al 2014;Olivier et al 2014;Severson et al 2014;Nik-Zainal et al 2015;Poon et al 2015;Blokzijl et al 2016;Zamborszky et al 2016), development of systems that robustly recapitulate in vivo human mutagenesis remains a challenge.…”

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confidence: 99%

Genome-scale mutational signatures of aflatoxin in cells, mice, and human tumors

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et al. 2017

Genome Res.

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Aflatoxin B1 (AFB1) is a mutagen and IARC (International Agency for Research on Cancer) Group 1 carcinogen that causes hepatocellular carcinoma (HCC). Here, we present the first whole-genome data on the mutational signatures of AFB1 exposure from a total of >40,000 mutations in four experimental systems: two different human cell lines, in liver tumors in wild-type mice, and in mice that carried a hepatitis B surface antigen transgene—this to model the multiplicative effects of aflatoxin exposure and hepatitis B in causing HCC. AFB1 mutational signatures from all four experimental systems were remarkably similar. We integrated the experimental mutational signatures with data from newly sequenced HCCs from Qidong County, China, a region of well-studied aflatoxin exposure. This indicated that COSMIC mutational signature 24, previously hypothesized to stem from aflatoxin exposure, indeed likely represents AFB1 exposure, possibly combined with other exposures. Among published somatic mutation data, we found evidence of AFB1 exposure in 0.7% of HCCs treated in North America, 1% of HCCs from Japan, but 16% of HCCs from Hong Kong. Thus, aflatoxin exposure apparently remains a substantial public health issue in some areas. This aspect of our study exemplifies the promise of future widespread resequencing of tumor genomes in providing new insights into the contribution of mutagenic exposures to cancer incidence.

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“…76, 83, 84, 85, 86, 87, 88, 89, 90 For example, exposure of normal murine embryonic fibroblasts (MEF) to known human carcinogens and sequencing of clones following immortalization is a rapid procedure that can generate mutational signatures corresponding to signatures in human tumours from patients exposed to the same agents (Figure 2). 91, 92 This simple experimental procedure 93, 94 is also suited to investigation of signatures linked to endogenous mutational processes. As proof of principle, we compared mutational signatures in immortalized MEF clones derived from MEFs isolated from mice harbouring an activation-induced cytidine deaminase (AID) transgene against signatures in non-transgenic mice, and demonstrated the expected excess of AID signature mutations in the clones derived from AID-expressing mice.…”

Section: Orphan Signatures and The Call For More Mutagenesis Studies mentioning

confidence: 99%

Base changes in tumour DNA have the power to reveal the causes and evolution of cancer

et al. 2016

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Next-generation sequencing (NGS) technology has demonstrated that the cancer genomes are peppered with mutations. Although most somatic tumour mutations are unlikely to have any role in the cancer process per se, the spectra of DNA sequence changes in tumour mutation catalogues have the potential to identify the mutagens, and to reveal the mutagenic processes responsible for human cancer. Very recently, a novel approach for data mining of the vast compilations of tumour NGS data succeeded in separating and precisely defining at least 30 distinct patterns of sequence change hidden in mutation databases. At least half of these mutational signatures can be readily assigned to known human carcinogenic exposures or endogenous mechanisms of mutagenesis. A quantum leap in our knowledge of mutagenesis in human cancers has resulted, stimulating a flurry of research activity. We trace here the major findings leading first to the hypothesis that carcinogenic insults leave characteristic imprints on the DNA sequence of tumours, and culminating in empirical evidence from NGS data that well-defined carcinogen mutational signatures are indeed present in tumour genomic DNA from a variety of cancer types. The notion that tumour DNAs can divulge environmental sources of mutation is now a well-accepted fact. This approach to cancer aetiology has also incriminated various endogenous, enzyme-driven processes that increase the somatic mutation load in sporadic cancers. The tasks now confronting the field of molecular epidemiology are to assign mutagenic processes to orphan and newly discovered tumour mutation patterns, and to determine whether avoidable cancer risk factors influence signatures produced by endogenous enzymatic mechanisms. Innovative research with experimental models and exploitation of the geographical heterogeneity in cancer incidence can address these challenges.

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The genome as a record of environmental exposure

Cited by 167 publications

References 34 publications

Impact of genetic modulation of SULT1A enzymes on DNA adduct formation by aristolochic acids and 3-nitrobenzanthrone

Impact of genetic modulation of SULT1A enzymes on DNA adduct formation by aristolochic acids and 3-nitrobenzanthrone

Genome-scale mutational signatures of aflatoxin in cells, mice, and human tumors

Base changes in tumour DNA have the power to reveal the causes and evolution of cancer

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