Genetic variants associated with increased risk of malignant pleural mesothelioma: a genome-wide association study

Our plain-English summary of Genetic variants associated with increased risk of malignant pleural mesothelioma: a genome-wide association study, by G. Matullo, S. Guarrera, M. Betti, et al (PloS One, 2013).

The study

• Authors: G. Matullo, S. Guarrera, M. Betti, G. Fiorito, D. Ferrante, F. Voglino, G. Cadby, C. Di Gaetano, F. Rosa, A. Russo, A. Hirvonen, E. Casalone, S. Tunesi, M. Padoan, M. Giordano, A. Aspesi, C. Casadio, F. Ardissone, E. Ruffini, P.G. Betta, R. Libener, R. Guaschino, E. Piccolini, M. Neri, A.W. Musk, N.H. de Klerk, J. Hui, J. Beilby, A.L. James, J. Creaney, B.W. Robinson, S. Mukherjee, L.J. Palmer, D. Mirabelli, D. Ugolini, S. Bonassi, C. Magnani, I. Dianzani
• Journal: PloS One
• Published: 2013;8(4):e61253
• Cited by: 48 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Asbestos exposure is the main risk factor for malignant pleural mesothelioma (MPM), a rare aggressive tumor. Nevertheless, only 5-17% of those exposed to asbestos develop MPM, suggesting the involvement of other environmental and genetic risk factors. To identify the genetic risk factors that may contribute to the development of MPM, we conducted a genome-wide association study (GWAS; 370,000 genotyped SNPs, 5 million imputed SNPs) in Italy, among 407 MPM cases and 389 controls with a complete history of asbestos exposure. A replication study was also undertaken and included 428 MPM cases and 1269 controls from Australia. Although no single marker reached the genome-wide significance threshold, several associations were supported by haplotype-, chromosomal region-, gene- and gene-ontology process-based analyses. Most of these SNPs were located in regions reported to harbor aberrant alterations in mesothelioma (SLC7A14, THRB, CEBP350, ADAMTS2, ETV1, PVT1 and MMP14 genes), causing at most a 2-3-fold increase in MPM risk. The Australian replication study showed significant associations in five of these chromosomal regions (3q26.2, 4q32.1, 7p22.2, 14q11.2, 15q14). Multivariate analysis suggested an independent contribution of 10 genetic variants, with an Area Under the ROC Curve (AUC) of 0.76 when only exposure and covariates were included in the model, and of 0.86 when the genetic component was also included, with a substantial increase of asbestos exposure risk estimation (odds ratio, OR: 45.28, 95% confidence interval, CI: 21.52-95.28). These results showed that genetic risk factors may play an additional role in the development of MPM, and that these should be taken into account to better estimate individual MPM risk in individuals who have been exposed to asbestos.

In plain English

This genome-wide association study looked for inherited genetic variants linked to malignant pleural mesothelioma. The authors tested 330,879 genetic markers in 392 cases and 367 controls from northern Italy, counted after quality checks. Each person's asbestos exposure was classed as no/unlikely, low or high. The authors then checked the results in 428 cases and 1,269 controls from Australia; the Australian controls had no exposure information. No single marker reached genome-wide significance. None of the 12 top Italian markers replicated individually in Australia, although five chromosomal regions showed significant associations there. The authors reported that the top variants were linked to at most a 2–3-fold increase in risk. Compared with no exposure, high asbestos exposure had an odds ratio of 17.33 (95% CI 9.28–32.37). Adding 10 selected variants to the model raised this to 45.28 (95% CI 21.52–95.28) and improved prediction (average AUC from 0.76 to 0.86). The authors concluded that genetic background plays a complementary role. They noted their limited sample size, differences between the two populations, and missing exposure data for the Australian controls.

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: Genome-wide association study (case-control) in Italy, with a replication study in Australia
• Who was studied: Italian discovery sample: 407 malignant pleural mesothelioma cases and 389 controls from three case-control studies in Casale Monferrato, Turin, and Genoa/La Spezia. Recruitment periods fell between 1996 and 2008. After quality control, 392 cases and 367 controls remained. Australian replication sample: 428 mesothelioma cases who had been exposed to asbestos and attended a hospital clinic in Perth between 1988 and 2010 (GUARD study), plus 1,269 population controls from the Busselton Health Study.
• Exposure: Asbestos exposure in the Italian subjects was reviewed from occupational histories by one expert. It was classed as no/unlikely, low, or high. High meant definite and high exposure: asbestos-cement and asbestos-textile workers, insulators, shipyard workers and dockers. No fiber types are named. The Australian controls had no exposure information.
• Main results:
  • In the Italian analysis, no single genetic marker reached the genome-wide significance threshold.
  • Most of the top genetic signals lay in chromosomal regions reported to be altered in mesothelioma. According to the authors, they caused at most a 2–3-fold increase in risk.
  • Model without genetic variants, adjusted for age, gender, centre and genetic cluster: high asbestos exposure versus no exposure had an odds ratio of 17.33 (95% CI 9.28–32.37).
  • Same model without genetic variants: low asbestos exposure versus no exposure had an odds ratio of 8.01 (95% CI 4.41–14.54).
  • Model that also included 10 selected genetic variants: high asbestos exposure versus no exposure had an odds ratio of 45.28 (95% CI 21.52–95.28).
  • Same model with the 10 genetic variants: low asbestos exposure versus no exposure had an odds ratio of 15.31 (95% CI 7.78–30.14).
  • Across 10,000 random splits of the Italian sample, the average AUC (a measure of how well a model predicts) was 0.76 for the model without genetic variants and 0.86 for the model with them.
  • None of the individual top Italian variants replicated in the Australian sample.
  • A regional analysis in the Australian sample found significant associations in five chromosomal regions: 3q26.2, 4q32.1, 7p22.2, 14q11.2 and 15q14.
• The authors' conclusion: The authors concluded that their results support a complementary role of genetic background in asbestos-related cancer of the pleura. In their view, genetic risk factors should be taken into account to understand the disease and to better define the mesothelioma risk profile of people highly exposed to asbestos.
• Limitations the authors state:
  • The sample size is small for a genome-wide association study.
  • Genome-wide association studies do not capture rare genetic variants.
  • The Italian and Australian samples differed markedly from each other (heterogeneity).
  • There was no asbestos exposure assessment for the Australian controls.

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Asbestos Exposure, Mesothelioma, Multivariate Analysis, Odds Ratio, confidence interval.

Related studies

• A genome-wide association study for malignant mesothelioma risk — G. Cadby, S. Mukherjee, et al. (2013)
• XRCC1 and ERCC1 variants modify malignant mesothelioma risk: a case-control study — M. Betti, D. Ferrante, et al. (2011)
• Genome-wide Gene-Asbestos Exposure Interaction Association Study Identifies a Common Susceptibility Variant on 22q13.31 Associated with Lung Cancer Risk — C.Y. Liu, I. Stücker, et al. (2015)
• Pooled analysis of NAT2 genotypes as risk factors for asbestos-related malignant mesothelioma — M. Betti, M. Neri, et al. (2009)
• Gene-asbestos interaction in malignant pleural mesothelioma susceptibility — S. Tunesi, D. Ferrante, et al. (2015)
• CDKN2A and BAP1 germline mutations predispose to melanoma and mesothelioma — M. Betti, A. Aspesi, et al. (2016)

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