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Differential mutation profiles and similar intronic TP53 polymorphisms in asbestos-related lung cancer and pleural mesothelioma

Pascal Andujar 1, 2 Jean-Claude Pairon 1, 2 Annie Renier 3 Alexis Descatha 4 Ilir Hysi 5, 4 Issam Abd-Alsamad 6 Marie-Annick Billon-Galland 7 Hélène Blons 8 Bénédicte Clin 9 Claire Danel 10 Denis Debrosse 11 Françoise Galateau-Salle 12 Bruno Housset 1 Pierre Laurent-Puig 13 Françoise Le Pimpec-Barthes 4 Marc Letourneux 14 Isabelle Monnet 15 Jean-François Régnard 16 Pierre Validire 11 Jessica Zucman-Rossi 4 Marie-Claude Jaurand 4 Didier Jean 4
1 IMRB - Institut Mondor de Recherche Biomédicale
2 Service de Pneumologie et de Pathologie Professionnelle [CHI Créteil]
3 Oncogenèse des tumeurs respiratoires et urogénitales
4 U674 - Génomique fonctionnelle des tumeurs solides
5 CHRU Lille - Centre Hospitalier Régional Universitaire [Lille]
6 Service d'Anatomo-Pathologie
7 LEPI - Laboratoire d'Etude des Particules Inhalées
8 U775 (IFR95) - Bases moléculaires de la réponse aux xénobiotiques
9 Service de Santé au Travail et Pathologie Professionnellel [CHU Caen]
10 Service d'Anatomie et cytologie pathologique
11 IMM - Institut Mutualiste de Montsouris
12 Laboratoire d'Anatomie Pathologique [CHU Caen]
13 U490 - Toxicologie Moleculaire
14 Cancers et Populations : Facteurs de Risque, Depistage, Pratiques Diagnostiques et Therapeutiques
15 CIMAP - UMR 6252 - Centre de recherche sur les Ions, les MAtériaux et la Photonique
16 Dpt of thoracic surgery
Abstract : Given the interest in defining biomarkers of asbestos exposure and to provide insights into asbestos-related and cell-specific mechanisms of neoplasia, the identification of gene alterations in asbestos-related cancers can help to a better understanding of exposure risk. To understand the aetiology of asbestos-induced malignancies and to increase our knowledge of mesothelial carcinogenesis, we compared genetic alterations in relevant cancer genes between lung cancer, induced by asbestos and tobacco smoke, and malignant pleural mesothelioma (MPM), a cancer related to asbestos, but not to tobacco smoke. TP53, KRAS, EGFR and NF2 gene alteration analyses were performed in 100 non-small cell lung cancer (NSCLC) patients, 50 asbestos-exposed and 50 unexposed patients, matched for age, gender, histology and smoking habits. Detailed assessment of asbestos exposure was based on both specific questionnaires and asbestos body quantification in lung tissue. Genetic analyses were also performed in 34 MPM patients. TP53, EGFR and KRAS mutations were found in NSCLC with no link with asbestos exposure. NF2 was only altered in MPM. Significant enhancement of TP53 G:C to T:A transversions was found in NSCLC from asbestos-exposed patients when compared with unexposed patients (P = 0.037). Interestingly, TP53 polymorphisms in intron 7 (rs12947788 and rs12951053) were more frequently identified in asbestos-exposed NSCLC (P = 0.046) and MPM patients than in unexposed patients (P < 0.001 and P = 0.012, respectively). These results emphasise distinct genetic alterations between asbestos-related thoracic tumours, but identify common potential susceptibility factors, i.e. single nucleotide polymorphisms in intron 7 of TP53. While genetic changes in NSCLC are dominated by the effects of tobacco smoke, the increase of transversions in TP53 gene is consistent with a synergistic effect of asbestos. These results may help to define cell-dependent mechanisms of action of asbestos and identify susceptibility factors to asbestos.
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https://www.hal.inserm.fr/inserm-02478590
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Submitted on : Friday, February 14, 2020 - 12:52:12 AM
Last modification on : Friday, March 27, 2020 - 2:41:54 AM

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IMRB | DSM-IRAMIS | UPEC-UPEM | UPEC | CEA | IRAMIS-CIMAP | IRSET-10 | UNIV-PARIS5 | COMUE-NORMANDIE | CEA-DRF | ENSICAEN | UNIV-PARIS7 | UNICAEN | USPC | CNRS

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Pascal Andujar, Jean-Claude Pairon, Annie Renier, Alexis Descatha, Ilir Hysi, et al.. Differential mutation profiles and similar intronic TP53 polymorphisms in asbestos-related lung cancer and pleural mesothelioma. Mutagenesis, Oxford University Press (OUP), 2013, 28 (3), pp.323-331. ⟨10.1093/mutage/get008⟩. ⟨inserm-02478590⟩

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