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

Autor: Edwige Kasper, Camille Charbonnier, Sabine Raad, Jean-Michel Flaman, Gaëlle Bougeard, Emilie Angot, Jean-Christophe Sabourin, Yann Lacoume, Lionel Nicol, Thierry Frebourg, Sahil Adriouch, Elodie Colasse
Přispěvatelé: Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Normandie Université (NU)-Normandie Université (NU), Endothélium, valvulopathies et insuffisance cardiaque (EnVI), CHU Rouen, Normandie Université (NU), Physiopathologie et biothérapies des maladies inflammatoires et autoimmunes, Génétique du cancer et des maladies neuropsychiatriques (GMFC)
Rok vydání: 2018
Předmět:
0301 basic medicine
Cancer Research
medicine.drug_class
DNA damage
Context (language use)
Antineoplastic Agents
X-Ray Therapy
medicine.disease_cause
Germline
Multiple primary cancers
Li-Fraumeni Syndrome
Neoplasms
Multiple Primary
03 medical and health sciences
0302 clinical medicine
Germline mutation
Risk Factors
medicine
Animals
Humans
Genetic Predisposition to Disease
Anticancer treatments
Etoposide
Survival analysis
ComputingMilieux_MISCELLANEOUS
Germ-Line Mutation
Mice
Knockout
business.industry
Magnetic Resonance Imaging
Survival Analysis
3. Good health
Mice
Inbred C57BL
030104 developmental biology
Oncology
[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics
030220 oncology & carcinogenesis
Cancer research
[SDV.IMM]Life Sciences [q-bio]/Immunology
Genotoxicity
Tumor Suppressor Protein p53
business
Topoisomerase inhibitor
Whole-Body Irradiation
medicine.drug
Zdroj: HAL
European Journal of Cancer
European Journal of Cancer, Elsevier, 2018, ⟨10.1016/j.ejca.2018.06.011⟩
European Journal of Cancer, Elsevier, 2018, 101, pp.254-262. ⟨10.1016/j.ejca.2018.06.011⟩
ISSN: 1879-0852
0959-8049
DOI: 10.1016/j.ejca.2018.06.011⟩
Popis: International audience; IntroductionLi-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 methodsWe 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.ConclusionsThis 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.
Databáze: OpenAIRE
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