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.

Figure 1. Manhattan plot of genotyped SNPs from logistic additive model.

A) all samples, B) exposed samples.

Figure 2. Regional association plots for 4 of the most consistent chromosome regions.

a. 3p24.2, b. 8q24.21, c. 14q11.2, d. 7p22.2. Consistency was based on haplotype, gene-, region- and pathway analysis. Each SNP is plotted with respect to its chromosomal location (x axis) and its log₁₀ transformed P value (y axis on the left) for associations with MPM. The tall blue spikes indicate the recombination rate (y axis on the right) at that region of the chromosome. The red-outlined diamond indicate the index SNP and other diamond indicate the genotyped SNPs, the squares indicate imputed SNPs using as reference 1000 Genomes Pilot 1 CEU population. LD values were calculated only on our control population.

Figure 3. Receiver Operating Curves (ROC) for the two multivariate models including asbestos exposure 1) without and 2) with the 10 most robust and significant genetic variants.

Figure 4. eQTL: PVT1 and MYC gene-expression levels in blood cells across rs78941347 genotypes.