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Contribution of genotoxic anticancer treatments to the development of multiple primary tumours in the context of germline TP53 mutations

Abstract : Introduction Li-Fraumeni syndrome (LFS), due to TP53 germline mutations, is characterised by a remarkably high incidence of multiple primary cancers (MPCs), and the key role of p53 in response to DNA damage questions the contribution of anticancer treatments to MPCs development. Materials and methods We first evaluated genotoxicity of X-rays and different classes of conventional chemotherapies, thanks to genotoxicity assays, based on the measurement of transcriptional response to DNA damage and performed in murine splenocytes, either exposed ex vivo or extracted from exposed mice. We then exposed a total of 208 Trp53Δ /Δ, wt/Δ or wt/wt mice to clinical doses of X-rays or genotoxic or non-genotoxic chemotherapies. Tumour development was monitored using whole-body magnetic resonance imaging and pathological examination at death. Results: X-rays and conventional chemotherapies, except mitotic spindle poisons, were found to be genotoxic in both p53 genotoxicity assays. Exposition to X-rays and the topoisomerase inhibitor etoposide, analysed as genotoxic anticancer treatment, drastically increase the tumour development risk in Trp53Δ /Δ and wt/Δ mice (hazard ration [HR] = 4.4, 95% confidence interval [CI] [2.2–8.8], p < 0.001*** and HR = 4.7, 95% CI [2.4–9.3], p < 0.001***, respectively). In contrast, exposure to the non-genotoxic mitotic spindle poison, docetaxel, had no impact on tumour development. Conclusions This study shows that radiotherapy and genotoxic chemotherapies significantly increase the risk of tumour development in a LFS mice model. These results strongly support the contribution of genotoxic anticancer treatments to MPC development in LFS patients. Therefore, to reduce the risk of MPCs in germline TP53 mutation carriers, radiotherapy should be avoided whenever possible, surgical treatment prioritised, and non-genotoxic treatments considered.
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Submitted on : Friday, November 22, 2019 - 10:46:10 AM
Last modification on : Monday, May 11, 2020 - 2:49:07 PM

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Edwige Kasper, Émilie Angot, Elodie Colasse, Lionel Nicol, Jean-Christophe Sabourin, et al.. Contribution of genotoxic anticancer treatments to the development of multiple primary tumours in the context of germline TP53 mutations. European Journal of Cancer, Elsevier, 2018, 101, pp.254-262. ⟨10.1016/j.ejca.2018.06.011⟩. ⟨hal-02375757⟩

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