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.
Highlights
Malignant pleural mesothelioma (MPM) is a rare, aggressive tumor that generally causes death within 2 years
In order to identify genetic risk factors that might contribute to the development of MPM, we performed a genome-wide association study (GWAS) on 407 Italian MPM cases and 389 controls
Among the top SNPs identified in our Italian study sample, there were several genes previously reported to be involved in MPM or other cancer types, as well as chromosomal regions reported to be altered in MPM [20]
Summary
Malignant pleural mesothelioma (MPM) is a rare, aggressive tumor that generally causes death within 2 years. The only clearly established risk factors for MPM are asbestos exposure, and exposure to erionite, other mineral fibers and x-ray for medical purposes [1]. Persistent inflammation can induce chronic oxidative stress, genotoxic lesions, chromosomal aberrations and epigenetic alterations [2,3]. Asbestos fibers may interfere with chromosome segregation and mitosis [4]. In Western Europe, over 5,000 people with MPM die each year [8,9,10,11]. Considering the long median latency period between initial asbestos exposure and MPM diagnosis [12,13], MPM incidence is expected to peak around 2020 in Western countries [9,14,15]
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