Journal Article

A comprehensive survey of the mutagenic impact of common cancer cytotoxics

Csabai, István, Krzystanek, Marcin, Szallasi, Zoltan, Póti, Ádám, Szeltner, Zoltán, Swanton, Charles, Szüts, Dávid, Pipek, Orsolya, Ribli, Dezső, Tusnády, Gábor E., Szikriszt, Bernadett, Kanu, Nnennaya, Molnár, János

2016

Overview

Background 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.

• Publisher: BioMed Central,Springer Nature B.V
• Subject: 5-Fluorouracil / Animal Genetics and Genomics / Animals / Antineoplastic Agents - adverse effects / Antineoplastic Agents - pharmacology / Antineoplastic Agents - toxicity / Bioinformatics / Biomedical and Life Sciences / BRCA2 protein / Cancer / Cancer therapies / Cell division / Cell growth / Cell Line, Tumor / Chemotherapy / Chickens / Chromosomes / Cisplatin / Cisplatin - adverse effects / Cisplatin - pharmacology / Cisplatin - toxicity / Cloning / crosslinking / Cyclophosphamide / Cytotoxic agents / Cytotoxicity / Cytotoxins - adverse effects / Cytotoxins - pharmacology / Cytotoxins - toxicity / Deoxyribonucleic acid / diploidy / DNA / DNA damage / DNA repair / Doxorubicin / Drug dosages / Drug Screening Assays, Antitumor - methods / drug therapy / Etoposide / evolution / Evolutionary Biology / fluorouracil / Gemcitabine / Genes, BRCA2 / Genome / Genomes / Guanine / Human Genetics / Hydroxyurea / Leukemia / Life Sciences / Microbial Genetics and Genomics / Mutagenesis / mutagens / Mutagens - adverse effects / Mutagens - pharmacology / Mutagens - toxicity / Mutation / Mutation Rate / neoplasm cells / neoplasms / Paclitaxel / patients / Plant Genetics and Genomics / Reversion / sequence analysis / Smoking / Studies / surveys / tumor suppressor proteins / Tumors