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

Our plain-English summary of Differential mutation profiles and similar intronic TP53 polymorphisms in asbestos-related lung cancer and pleural mesothelioma, by P. Andujar, J.C. Pairon, A. Renier, et al (Mutagenesis, 2013).

The study

• Authors: P. Andujar, J.C. Pairon, A. Renier, A. Descatha, I. Hysi, I. Abd-Alsamad, M.A. Billon-Galland, H. Blons, B. Clin, C. Danel, D. Debrosse, F. Galateau-Sallé, B. Housset, P. Laurent-Puig, F. Le Pimpec-Barthes, M. Letourneux, I. Monnet, J.F. Régnard, P. Validire, J. Zucman-Rossi, M.C. Jaurand, D. Jean
• Journal: Mutagenesis
• Published: 2013;28(3):323-31
• Cited by: 27 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

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.

In plain English

The authors compared gene changes in lung cancer and malignant pleural mesothelioma. They analysed tumours from 100 patients who had surgery for non-small cell lung cancer at five French hospitals. Fifty had definite occupational asbestos exposure, assessed by questionnaire and lung tissue asbestos body counts. The other 50 were unexposed patients matched for age, gender, tumour type and smoking. They also analysed 34 mesothelioma cell cultures. In lung cancer, TP53, EGFR and KRAS mutation rates did not differ significantly by asbestos exposure. NF2 mutations were found in 13 of 34 mesothelioma cases but no lung cancers. Among lung cancers with TP53 mutations, a G:C to T:A transversion occurred in 13 of 19 exposed and 7 of 20 unexposed cases (P = 0.037). Two TP53 intron 7 variants were each found in 16% of exposed and 4% of unexposed lung cancer patients (P = 0.046). Among 59 mesothelioma cases, these variants appeared only in patients with high estimated exposure. The authors concluded that tobacco dominates lung cancer gene changes, and that the TP53 changes are consistent with a synergistic effect of asbestos.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory genetic study comparing tumour mutations and TP53 polymorphisms in asbestos-exposed versus matched unexposed non-small cell lung cancer patients, plus malignant pleural mesothelioma primary cell cultures
• Who was studied: 100 non-small cell lung cancer (NSCLC) patients treated surgically in five French hospitals from 1994 through 2007: 50 asbestos-exposed and 50 unexposed. Also 34 malignant pleural mesothelioma (MPM) primary cell cultures from four French hospitals from 1985 through 2007, plus an additional 25 MPM cases used for the intron 7 polymorphism and NF2 analyses (59 MPM in total).
• Exposure: Asbestos (fibre types not specified). In NSCLC patients, definite occupational exposure meant either more than 10 years of occupational exposure on questionnaire or more than 1000 asbestos bodies per gram of dry lung tissue. Unexposed patients had no identified exposure and fewer than 1000 asbestos bodies per gram. In MPM patients, an occupational hygienist estimated a cumulative exposure index (high, moderate, low or null) from clinical reports.
• Main results:
  • TP53 mutations in NSCLC: 19 of 50 asbestos-exposed cases (38%) and 20 of 50 unexposed cases (40%); the difference was not significant.
  • EGFR mutations in NSCLC: 2 asbestos-exposed and 6 unexposed cases; the difference was not significant. No EGFR mutation was found in MPM.
  • KRAS mutations in NSCLC: 5 asbestos-exposed and 8 unexposed cases; the difference was not significant. No KRAS mutation was found in MPM.
  • NF2 mutations: none in NSCLC patients; found in 38.2% (13/34) of MPM cases.
  • In MPM, a link between NF2 mutations and asbestos exposure (P = 0.043) was not confirmed in the larger series of 59 MPM cases (P = 0.372).
  • Among NSCLC patients with TP53 mutations, at least one G:C to T:A transversion was found in 13/19 (68%) asbestos-exposed and 7/20 (35%) unexposed cases (P = 0.037).
  • Counting all 50 cases per group, the share of NSCLC patients with a G:C to T:A transversion was not significantly different: 26% exposed versus 14% unexposed (P = 0.134).
  • TP53 intron 7 polymorphism rs12947788 (minor allele) was found in 16% of asbestos-exposed and 4% of unexposed NSCLC cases (P = 0.046). The difference remained significant after adjustment for age, gender, tobacco status and histological type.
  • TP53 intron 7 polymorphism rs12951053 (minor allele) was found in 16% of asbestos-exposed and 4% of unexposed NSCLC cases (P = 0.046).
  • Across all 59 MPM cases, the two intron 7 minor alleles were found in 39.3% (rs12947788) and 25.0% (rs12951053) of patients with high cumulative exposure index, and in none with moderate or low exposure or no exposure (P less than 0.001 and P = 0.012).
  • Four TP53 mutations (11.8%) were found among the MPM cases.
• The authors' conclusion: The authors concluded that in NSCLC the effects of tobacco smoke dominate the genetic changes, and that the TP53 alterations are consistent with a synergistic effect of asbestos. They also concluded that the shared intron 7 TP53 polymorphisms should be examined as possible susceptibility factors for asbestos-related thoracic cancer.
• Limitations the authors state:
  • Asbestos exposure assessment was based on clinical reports and is often less accurate in MPM than in NSCLC.
  • A negative asbestos body count does not definitively exclude past asbestos exposure.
  • The rs12951053 result could not be fully adjusted for age, gender, tobacco status and histological type.
  • The role of the intron 7 polymorphisms in TP53 function is unknown.
  • Studies of normal tissues would be needed to confirm the hypothesis that the polymorphisms act as susceptibility factors.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Lung Cancer, Pleural Mesothelioma, Biomarker, Asbestos Exposure, Carcinogenesis, EGFR, Non-Small Cell Lung Cancer, Histology.

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