title: Modelling mutational landscapes of human cancers in vitro.
abstract: Experimental models that recapitulate mutational landscapes of human cancers are needed to decipher the rapidly expanding data on human somatic mutations. We demonstrate that mutation patterns in immortalised cell lines derived from primary murine embryonic fibroblasts (MEFs) exposed in vitro to carcinogens recapitulate key features of mutational signatures observed in human cancers. In experiments with several cancer-causing agents we obtained high genome-wide concordance between human tumour mutation data and in vitro data with respect to predominant substitution types, strand bias and sequence context. Moreover, we found signature mutations in well-studied human cancer driver genes. To explore endogenous mutagenesis, we used MEFs ectopically expressing activation-induced cytidine deaminase (AID) and observed an excess of AID signature mutations in immortalised cell lines compared to their non-transgenic counterparts. MEF immortalisation is thus a simple and powerful strategy for modelling cancer mutation landscapes that facilitates the interpretation of human tumour genome-wide sequencing data.
authors.affiliation: Molecular Mechanisms and Biomarkers Group, International Agency for Research on Cancer, 69008 Lyon, France.
authors.forename: Magali
authors.initials: M
authors.lastname: Olivier
authors.affiliation: German Cancer Research Center (Deutsches Krebsforschungszentrum), D69120 Heidelberg, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Weninger
authors.affiliation: Molecular Mechanisms and Biomarkers Group, International Agency for Research on Cancer, 69008 Lyon, France.
authors.forename: Maude
authors.initials: M
authors.lastname: Ardin
authors.affiliation: Molecular Mechanisms and Biomarkers Group, International Agency for Research on Cancer, 69008 Lyon, France.
authors.forename: Hana
authors.initials: H
authors.lastname: Huskova
authors.affiliation: Molecular Mechanisms and Biomarkers Group, International Agency for Research on Cancer, 69008 Lyon, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Castells
authors.affiliation: Genetic Cancer Susceptibility Group, International Agency for Research on Cancer, 69008 Lyon, France.
authors.forename: Maxime P
authors.initials: MP
authors.lastname: Vallée
authors.affiliation: Genetic Cancer Susceptibility Group, International Agency for Research on Cancer, 69008 Lyon, France.
authors.forename: James
authors.initials: J
authors.lastname: McKay
authors.affiliation: German Cancer Research Center (Deutsches Krebsforschungszentrum), D69120 Heidelberg, Germany.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Nedelko
authors.affiliation: German Cancer Research Center (Deutsches Krebsforschungszentrum), D69120 Heidelberg, Germany.
authors.forename: Karl-Rudolf
authors.initials: KR
authors.lastname: Muehlbauer
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Marusawa
authors.affiliation: Faculty of Medicine and Health, University of Leeds, Leeds LS2 9JT, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Alexander
authors.affiliation: Faculty of Medicine and Health, University of Leeds, Leeds LS2 9JT, United Kingdom.
authors.forename: Lee
authors.initials: L
authors.lastname: Hazelwood
authors.affiliation: Biostatistics Group, International Agency for Research on Cancer, 69008 Lyon, France.
authors.forename: Graham
authors.initials: G
authors.lastname: Byrnes
authors.affiliation: 1] German Cancer Research Center (Deutsches Krebsforschungszentrum), D69120 Heidelberg, Germany [2] Faculty of Medicine and Health, University of Leeds, Leeds LS2 9JT, United Kingdom.
authors.forename: Monica
authors.initials: M
authors.lastname: Hollstein
authors.affiliation: Molecular Mechanisms and Biomarkers Group, International Agency for Research on Cancer, 69008 Lyon, France.
authors.forename: Jiri
authors.initials: J
authors.lastname: Zavadil
mesh_terms: D000818:Animals; D002461:Cell Line, Transformed; D019295:Computational Biology; D004252:DNA Mutational Analysis / Q000379:methods; D059472:Exome; D055106:Genome-Wide Association Study; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*