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dc.contributor.authorSzikriszt, Bernadetten_US
dc.contributor.authorPóti, Ádámen_US
dc.contributor.authorPipek, Orsolyaen_US
dc.contributor.authorKrzystanek, Marcinen_US
dc.contributor.authorKanu, Nnennayaen_US
dc.contributor.authorMolnár, Jánosen_US
dc.contributor.authorRibli, Dezsően_US
dc.contributor.authorSzeltner, Zoltánen_US
dc.contributor.authorTusnády, Gábor E.en_US
dc.contributor.authorCsabai, Istvánen_US
dc.contributor.authorSzallasi, Zoltanen_US
dc.contributor.authorSwanton, Charlesen_US
dc.contributor.authorSzüts, Dáviden_US
dc.date.accessioned2016-06-14T18:51:53Z
dc.date.issued2016en_US
dc.identifier.citationSzikriszt, B., Á. Póti, O. Pipek, M. Krzystanek, N. Kanu, J. Molnár, D. Ribli, et al. 2016. “A comprehensive survey of the mutagenic impact of common cancer cytotoxics.” Genome Biology 17 (1): 99. doi:10.1186/s13059-016-0963-7. http://dx.doi.org/10.1186/s13059-016-0963-7.en
dc.identifier.issn1474-7596en
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:27320271
dc.description.abstractBackground: Genomic mutations caused by cytotoxic agents used in cancer chemotherapy may cause secondary malignancies as well as contribute to the evolution of treatment-resistant tumour cells. The stable diploid genome of the chicken DT40 lymphoblast cell line, an established DNA repair model system, is well suited to accurately assay genomic mutations. Results: We use whole genome sequencing of multiple DT40 clones to determine the mutagenic effect of eight common cytotoxics used for the treatment of millions of patients worldwide. We determine the spontaneous mutagenesis rate at 2.3 × 10–10 per base per cell division and find that cisplatin, cyclophosphamide and etoposide induce extra base substitutions with distinct spectra. After four cycles of exposure, cisplatin induces 0.8 mutations per Mb, equivalent to the median mutational burden in common leukaemias. Cisplatin-induced mutations, including short insertions and deletions, are mainly located at sites of putative intrastrand crosslinks. We find two of the newly defined cisplatin-specific mutation types as causes of the reversion of BRCA2 mutations in emerging cisplatin-resistant tumours or cell clones. Gemcitabine, 5-fluorouracil, hydroxyurea, doxorubicin and paclitaxel have no measurable mutagenic effect. The cisplatin-induced mutation spectrum shows good correlation with cancer mutation signatures attributed to smoking and other sources of guanine-directed base damage. Conclusion: This study provides support for the use of cell line mutagenesis assays to validate or predict the mutagenic effect of environmental and iatrogenic exposures. Our results suggest genetic reversion due to cisplatin-induced mutations as a distinct mechanism for developing resistance. Electronic supplementary material The online version of this article (doi:10.1186/s13059-016-0963-7) contains supplementary material, which is available to authorized users.en
dc.language.isoen_USen
dc.publisherBioMed Centralen
dc.relation.isversionofdoi:10.1186/s13059-016-0963-7en
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4862131/pdf/en
dash.licenseLAAen_US
dc.subjectWhole genome sequencingen
dc.subjectMutagenesisen
dc.subjectCisplatinen
dc.subjectCyclophosphamideen
dc.subjectEtoposideen
dc.subjectCytotoxicsen
dc.subjectCancer chemotherapyen
dc.subjectChemotherapy resistanceen
dc.subjectBRCA2en
dc.subjectSpontaneous mutagenesisen
dc.subjectDT40en
dc.titleA comprehensive survey of the mutagenic impact of common cancer cytotoxicsen
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden
dc.relation.journalGenome Biologyen
dash.depositing.authorSzallasi, Zoltanen_US
dc.date.available2016-06-14T18:51:53Z
dc.identifier.doi10.1186/s13059-016-0963-7*
dash.authorsorderedfalse
dash.contributor.affiliatedSzallasi, Zoltan


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