Genetic Variants Associated with Increased Risk of Malignant Pleural Mesothelioma: A Genome-Wide Association Study

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.

Germline BAP1 Mutational Landscape of Asbestos-Exposed Malignant Mesothelioma Patients with Family History of Cancer

“…In a study of familial MM, clustering was not found to be due to similar exposures to asbestos, leading investigators to conclude that genetic factors must be involved (7). Thus, genetic susceptibility likely has a significant role in the etiology of MM (8, 9). …”

Targeted Next-Generation Sequencing of Cancer Genes in Advanced Stage Malignant Pleural Mesothelioma: A Retrospective Study

“…Third, another limitation of the our study is represented by the assessment of gene mutations only, whereas other types of genetic changes, such as amplification, 31 wide genetic losses, 8 or gene translocations, 32 are not detected by the chosen technology. First, there is a selection bias due to tissue availability because of asbestos workers' compensation cases usually filed.…”

Malignant pleural mesothelioma: history, controversy and future of a manmade epidemic

“…The GSTM1 protein is important for the detoxification of electrophilic compounds, including carcinogens, drugs, environmental toxins and products of oxidative stress, and its downregulation has been associated with several forms of cancer. More recently, the largest GWAS to date on pleural mesothelioma did not reveal any significant new information, other than indicating that genetic risk factors may play a role in the asbestos-associated mesothelioma [113].…”