Gene-asbestos interaction in malignant pleural mesothelioma susceptibility

Our plain-English summary of Gene-asbestos interaction in malignant pleural mesothelioma susceptibility, by S. Tunesi, D. Ferrante, D. Mirabelli, et al (Carcinogenesis, 2015).

The study

• Authors: S. Tunesi, D. Ferrante, D. Mirabelli, S. Andorno, M. Betti, G. Fiorito, S. Guarrera, E. Casalone, M. Neri, D. Ugolini, S. Bonassi, G. Matullo, I. Dianzani, C. Magnani
• Journal: Carcinogenesis
• Published: 2015;36(10):1129-35
• Cited by: 30 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Asbestos exposure is the main risk factor for malignant pleural mesothelioma (MPM), a rare aggressive tumor. Nevertheless, on average less than 10% of subjects highly exposed to asbestos develop MPM, suggesting the possible involvement of other risk factors. To identify the genetic factors that may modulate the risk of MPM, we conducted a gene-environment interaction analysis including asbestos exposure and 15 single nucleotide polymorphisms (SNPs) previously identified through a genome-wide association study on Italian subjects. In the present study, we assessed gene-asbestos interaction on MPM risk using relative excess risk due to interaction and synergy index for additive interaction and V index for multiplicative interaction. Generalized multifactor dimensionality reduction (GMDR) analyses were also performed. Positive deviation from additivity was found for six SNPs (rs1508805, rs2501618, rs4701085, rs4290865, rs10519201, rs763271), and four of them (rs1508805, rs2501618, rs4701085, rs10519201) deviated also from multiplicative models. However, after Bonferroni correction, deviation from multiplicative model was still significant for rs1508805 and rs4701085 only. GMDR analysis showed a strong MPM risk due to asbestos exposure and suggested a possible synergistic effect between asbestos exposure and rs1508805, rs2501618 and rs5756444. Our results suggested that gene-asbestos interaction may play an additional role on MPM susceptibility, given that asbestos exposure appears as the main risk factor.

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In plain English

This Italian case-control study looked at whether 15 genetic variants (SNPs), linked to malignant pleural mesothelioma in an earlier genome-wide study, changed the risk linked to asbestos exposure. It included 759 people (392 mesothelioma cases and 367 controls) from Casale Monferrato, Turin, Genoa and La Spezia in Northern Italy. An expert classified occupational and environmental asbestos exposure from interview histories and counted low or high exposure as exposed. Exposure was unknown for 36 cases, and the interaction analyses used only people with known exposure and genotype. For one variant (rs2236304), exposed people who carried the variant had an odds ratio of 28.87 (95% CI 9.95 to 83.78) compared with unexposed non-carriers. Six variants showed statistically significant positive interaction on the additive scale, but after correction for multiple testing none remained significant by one of the two additive measures (RERI). On the multiplicative scale, two variants (rs1508805 and rs4701085) remained significant after correction. The authors concluded that a person's genetic background may modulate asbestos-related cancer of the pleura, but that asbestos remains the major risk factor. They noted limited statistical power, because few cases were unexposed.

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: Gene-environment interaction analysis of pooled case-control data (one population-based and two hospital-based case-control studies), using genotype data from an earlier genome-wide association study
• Who was studied: 759 subjects (392 malignant pleural mesothelioma cases and 367 controls), all of Italian origin, from Casale Monferrato and Turin (Piedmont) and Genoa and La Spezia (Liguria), Northern Italy; matched by age and gender. Interaction analyses included only subjects with known asbestos exposure and genotype.
• Exposure: Asbestos exposure was classified by an expert, after review of occupational histories from questionnaire-based interviews, as absent/unlikely (no acknowledged occupational or environmental exposure), low or high. For the analysis, low and high were counted as exposed. High exposure corresponded in principle to asbestos-cement and asbestos-textile workers, insulators, shipyard workers and dockers. Exposure was not available for 36 cases (Table I). No fiber types were specified. Exposure was analyzed together with 15 candidate SNPs.
• Main results:
  • For SNP rs2236304, compared with unexposed people without the minor allele: unexposed carriers had OR 3.34 (95% CI 1.00 to 11.09); exposed non-carriers had OR 16.00 (95% CI 5.45 to 46.98); exposed carriers had OR 28.87 (95% CI 9.95 to 83.78).
  • For SNP rs1508805, the minor allele was associated with lower odds in unexposed people (OR 0.19, 95% CI 0.04 to 0.87). Among exposed people, the OR was 5.22 for non-carriers and 10.33 for carriers.
  • Statistically significant positive additive interaction (by RERI and SI) was found for rs1508805, rs2501618, rs4701085, rs4290865, rs10519201 and rs7632718. After Bonferroni correction, the SI index remained significant for eight SNPs, but RERI was no longer significant for any SNP.
  • Statistically significant deviation from the multiplicative model was found for six SNPs. After Bonferroni correction, the V index remained significant for rs1508805 and rs4701085 (per Table III).
  • In the GMDR analysis, the model with asbestos exposure only had the highest cross-validation consistency (10/10), a testing balanced accuracy of 63.39% and OR 9.71. A four-factor model (exposure plus rs1508805, rs2501618 and rs5756444) had the highest testing balanced accuracy (64.45%), a cross-validation consistency of 5/10 and OR 6.64 (95% CI 3.60 to 11.30). The authors judged the exposure-only model to be the best one.
• The authors' conclusion: The authors concluded that their results give some suggestion that an individual's genetic background may modulate asbestos-related carcinogenesis of the pleura, but that asbestos remains the major risk factor for malignant pleural mesothelioma.
• Limitations the authors state:
  • Statistical power was limited.
  • Mesothelioma is rare and few cases were not exposed to asbestos, which may affect the estimated odds ratios and increase the variability of the interaction indexes.
  • Other SNPs with weaker effects, or rare variants that the genotyping platform could not assess, might also interact with asbestos exposure.
  • The Bonferroni correction is conservative and may produce false negative results.

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: Pleural Mesothelioma, Asbestos Exposure, Synergistic Effect.

Related studies

• Genetic variants associated with increased risk of malignant pleural mesothelioma: a genome-wide association study — G. Matullo, S. Guarrera, et al. (2013)
• The influence of gene-gene and gene-environment interactions on the risk of asbestosis — A. Franko, V. Dolžan, et al. (2013)
• 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)
• Germline mutations in DNA repair genes predispose asbestos-exposed patients to malignant pleural mesothelioma — M. Betti, E. Casalone, et al. (2017)
• A genome-wide association study for malignant mesothelioma risk — G. Cadby, S. Mukherjee, et al. (2013)
• Polymorphisms in DNA repair genes as risk factors for asbestos-related malignant mesothelioma in a general population study — I. Dianzani, L. Gibello, et al. (2006)

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