title: Differential mutation profiles and similar intronic TP53 polymorphisms in asbestos-related lung cancer and pleural mesothelioma.
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.
authors: Centre Hospitalier Intercommunal de Créteil, Service de Pneumologie et de Pathologie Professionnelle, Créteil F-94000, France. pascal.andujar@chicreteil.fr
authors: Pascal
authors: P
authors: Andujar
authors: Jean-Claude
authors: JC
authors: Pairon
authors: Annie
authors: A
authors: Renier
authors: Alexis
authors: A
authors: Descatha
authors: Ilir
authors: I
authors: Hysi
authors: Issam
authors: I
authors: Abd-Alsamad
authors: Marie-Annick
authors: MA
authors: Billon-Galland
authors: Hélène
authors: H
authors: Blons
authors: Bénédicte
authors: B
authors: Clin
authors: Claire
authors: C
authors: Danel
authors: Denis
authors: D
authors: Debrosse
authors: Françoise
authors: F
authors: Galateau-Sallé
authors: Bruno
authors: B
authors: Housset
authors: Pierre
authors: P
authors: Laurent-Puig
authors: Françoise
authors: F
authors: Le Pimpec-Barthes
authors: Marc
authors: M
authors: Letourneux
authors: Isabelle
authors: I
authors: Monnet
authors: Jean-François
authors: JF
authors: Régnard
authors: Pierre
authors: P
authors: Validire
authors: Jessica
authors: J
authors: Zucman-Rossi
authors: Marie-Claude
authors: MC
authors: Jaurand
authors: Didier
authors: D
authors: Jean
mesh_terms: D000368:Aged; D001194:Asbestos / Q000009:adverse effects*; D002289:Carcinoma, Non-Small-Cell Lung / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D006801:Humans; D007438:Introns; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D008297:Male; D008654:Mesothelioma / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D009154:Mutation; D025581:Neurofibromin 2 / Q000235:genetics; D010997:Pleural Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D011110:Polymorphism, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D012907:Smoking; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D018631:ras Proteins / Q000235:genetics
chemical_list: C117307:KRAS protein, human; D025581:Neurofibromin 2; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D001194:Asbestos; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins