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

• Published in: PloS one Vol. 8; no. 4; p. e61253
• Main Authors: Matullo, Giuseppe, Guarrera, Simonetta, Betti, Marta, Fiorito, Giovanni, Ferrante, Daniela, Voglino, Floriana, Cadby, Gemma, Di Gaetano, Cornelia, Rosa, Fabio, Russo, Alessia, Hirvonen, Ari, Casalone, Elisabetta, Tunesi, Sara, Padoan, Marina, Giordano, Mara, Aspesi, Anna, Casadio, Caterina, Ardissone, Francesco, Ruffini, Enrico, Betta, Pier Giacomo, Libener, Roberta, Guaschino, Roberto, Piccolini, Ezio, Neri, Monica, Musk, Arthur W B, de Klerk, Nicholas H, Hui, Jennie, Beilby, John, James, Alan L, Creaney, Jenette, Robinson, Bruce W, Mukherjee, Sutapa, Palmer, Lyle J, Mirabelli, Dario, Ugolini, Donatella, Bonassi, Stefano, Magnani, Corrado, Dianzani, Irma
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 23.04.2013; Public Library of Science (PLoS)
• Subjects: Aberration; Aged; Asbestos; Asbestos - adverse effects; Australia; Biology; Biomarkers; Cancer; Case-Control Studies; Confidence intervals; Deoxyribonucleic acid; Disease; DNA; DNA repair; Epidemiology; Exposure; Female; Genes; Genetic aspects; Genetic diversity; Genetic Loci; Genetic Markers; Genetic Predisposition to Disease; Genetic research; Genetic variance; Genetics; Genome-wide association studies; Genome-Wide Association Study; Genomes; Genomics; Haplotypes; Health sciences; Hospitals; Humans; Italy; Laboratories; Male; Medical research; Medical statistics; Medicine; Mesothelioma; Mesothelioma - etiology; Mesothelioma - genetics; Middle Aged; Multivariate analysis; Neoplasm Proteins - genetics; Occupational Exposure - adverse effects; Odds Ratio; Pathology; Pharmacology; Pleural Neoplasms - etiology; Pleural Neoplasms - genetics; Polymorphism, Single Nucleotide; Principal components analysis; Replication; Risk analysis; Risk Factors; Single-nucleotide polymorphism; Studies; Surgery; Thoracic surgery; Australia; Italy
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0061253

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.