A comprehensive survey of the mutagenic impact of common cancer cytotoxics

Abstract

BackgroundGenomic 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.ResultsWe 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.ConclusionThis 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 materialThe online version of this article (doi:10.1186/s13059-016-0963-7) contains supplementary material, which is available to authorized users.

Whole exome sequencing of independent lung adenocarcinoma, lung squamous cell carcinoma, and malignant peritoneal mesothelioma

“…It is also known that chemotherapy might affect the mutational status of eukaryote cells. [29] Despite the only 2 cycles of carboplatin, considering the interval between treatment and SCC tumor collection (about 14 months), we cannot exclude the mutagenic effect induced by carboplatin.…”

Clonal selection and double-hit events involving tumor suppressor genes underlie relapse in myeloma

“…33 In the scenario of relapse after Total Therapy, multiagent chemotherapy could potentially cause harmful DNA damage, increasing the likelihood of driver abnormalities within resistant "units of selection," which could therefore enhance relapse risk. Indeed, we found significantly more mutations and an enrichment for a novel signature, characterized by peaks at "C.T GCA" and "C.T GCC" motifs at relapse.…”

Chemotherapy weakly contributes to predicted neoantigen expression in ovarian cancer

“…While signatures for exposure to the carboplatin/paclitaxel combination that is standard first line therapy in ovarian cancer have not been established, two recent reports provide data on mutations detected in cisplatin-exposed Caenorhabditis elegans [22] and a Gallus gallus (chicken) cell line exposed to several chemotherapies including cisplatin, chyclophosphamide, and etoposide [23]. As cisplatin is thought to induce the same DNA adducts as carboplatin, we reasoned that the mutational signatures of these related compounds are likely similar [24].…”