Chemically induced mutations in a MutaMouse reporter gene inform mechanisms underlying human cancer mutational signatures

Marc A Beal,Jason M O’Brien,Clotilde Maurice,Francesco Marchetti,Matthew J Meier,Danielle P Leblanc,Carole L Yauk

doi:10.1038/s42003-020-01174-y

Marc A Beal, Jason M O’Brien + Show 5 more

Open Access

https://doi.org/10.1038/s42003-020-01174-y

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Abstract

Transgenic rodent (TGR) models use bacterial reporter genes to quantify in vivo mutagenesis. Pairing TGR assays with next-generation sequencing (NGS) enables comprehensive mutation pattern analysis to inform mutational mechanisms. We used this approach to identify 2751 independent lacZ mutations in the bone marrow of MutaMouse animals exposed to four chemical mutagens: benzo[a]pyrene, N-ethyl-N-nitrosourea, procarbazine, and triethylenemelamine. We also collected published data for 706 lacZ mutations from eight additional environmental mutagens. We report that lacZ gene sequencing generates chemical-specific mutation signatures observed in human cancers with established environmental causes. For example, the mutation signature of benzo[a]pyrene, a carcinogen present in tobacco smoke, matched the signature associated with tobacco-induced lung cancers. Our results suggest that the analysis of chemically induced mutations in the lacZ gene shortly after exposure provides an effective approach to characterize human-relevant mechanisms of carcinogenesis and propose novel environmental causes of mutation signatures observed in human cancers.

Highlights

Transgenic rodent (TGR) models use bacterial reporter genes to quantify in vivo mutagenesis
Mutation patterns were generated from plaques collected during experiments aimed at evaluating the induction of mutations in the bone marrow of MutaMouse males exposed to either BaP, ENU, PRC, or TEM using the lacZ assay[5]
We show that in vivo next-generation sequencing (NGS)–TGR data can be used to extract mutagenic mechanisms that may contribute to human cancers through the application of Catalogue of Somatic Mutations in Cancer (COSMIC) signature analysis

Summary

Introduction

Transgenic rodent (TGR) models use bacterial reporter genes to quantify in vivo mutagenesis. Pairing TGR assays with next-generation sequencing (NGS) enables comprehensive mutation pattern analysis to inform mutational mechanisms We used this approach to identify 2751 independent lacZ mutations in the bone marrow of MutaMouse animals exposed to four chemical mutagens: benzo[a]pyrene, N-ethyl-N-nitrosourea, procarbazine, and triethylenemelamine. Our results suggest that the analysis of chemically induced mutations in the lacZ gene shortly after exposure provides an effective approach to characterize human-relevant mechanisms of carcinogenesis and propose novel environmental causes of mutation signatures observed in human cancers. A major advantage of TGR models is the possibility to sequence mutants in order to characterize mutation patterns This information is necessary to understand mutational mechanisms associated with mutagen exposure and response in different tissues, life stages, genetic backgrounds or other contexts. We argue that analysis of COSMIC signatures observed in exposed animals can be used to generate or test hypotheses of mutagenic mechanisms associated with human mutational signatures of unknown etiology

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