title: 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.
authors.affiliation: Human Genetics Foundation, HuGeF, Turin, Italy. giuseppe.matullo@unito.it
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Matullo
authors.forename: Simonetta
authors.initials: S
authors.lastname: Guarrera
authors.forename: Marta
authors.initials: M
authors.lastname: Betti
authors.forename: Giovanni
authors.initials: G
authors.lastname: Fiorito
authors.forename: Daniela
authors.initials: D
authors.lastname: Ferrante
authors.forename: Floriana
authors.initials: F
authors.lastname: Voglino
authors.forename: Gemma
authors.initials: G
authors.lastname: Cadby
authors.forename: Cornelia
authors.initials: C
authors.lastname: Di Gaetano
authors.forename: Fabio
authors.initials: F
authors.lastname: Rosa
authors.forename: Alessia
authors.initials: A
authors.lastname: Russo
authors.forename: Ari
authors.initials: A
authors.lastname: Hirvonen
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Casalone
authors.forename: Sara
authors.initials: S
authors.lastname: Tunesi
authors.forename: Marina
authors.initials: M
authors.lastname: Padoan
authors.forename: Mara
authors.initials: M
authors.lastname: Giordano
authors.forename: Anna
authors.initials: A
authors.lastname: Aspesi
authors.forename: Caterina
authors.initials: C
authors.lastname: Casadio
authors.forename: Francesco
authors.initials: F
authors.lastname: Ardissone
authors.forename: Enrico
authors.initials: E
authors.lastname: Ruffini
authors.forename: Pier Giacomo
authors.initials: PG
authors.lastname: Betta
authors.forename: Roberta
authors.initials: R
authors.lastname: Libener
authors.forename: Roberto
authors.initials: R
authors.lastname: Guaschino
authors.forename: Ezio
authors.initials: E
authors.lastname: Piccolini
authors.forename: Monica
authors.initials: M
authors.lastname: Neri
authors.forename: Arthur W B
authors.initials: AW
authors.lastname: Musk
authors.forename: Nicholas H
authors.initials: NH
authors.lastname: de Klerk
authors.forename: Jennie
authors.initials: J
authors.lastname: Hui
authors.forename: John
authors.initials: J
authors.lastname: Beilby
authors.forename: Alan L
authors.initials: AL
authors.lastname: James
authors.forename: Jenette
authors.initials: J
authors.lastname: Creaney
authors.forename: Bruce W
authors.initials: BW
authors.lastname: Robinson
authors.forename: Sutapa
authors.initials: S
authors.lastname: Mukherjee
authors.forename: Lyle J
authors.initials: LJ
authors.lastname: Palmer
authors.forename: Dario
authors.initials: D
authors.lastname: Mirabelli
authors.forename: Donatella
authors.initials: D
authors.lastname: Ugolini
authors.forename: Stefano
authors.initials: S
authors.lastname: Bonassi
authors.forename: Corrado
authors.initials: C
authors.lastname: Magnani
authors.forename: Irma
authors.initials: I
authors.lastname: Dianzani
mesh_terms: D000368:Aged; D001194:Asbestos / Q000009:adverse effects*; D001315:Australia; D016022:Case-Control Studies; D005260:Female; D056426:Genetic Loci; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007558:Italy; D008297:Male; D008654:Mesothelioma / Q000209:etiology / Q000235:genetics*; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D016273:Occupational Exposure / Q000009:adverse effects*; D016017:Odds Ratio; D010997:Pleural Neoplasms / Q000209:etiology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
chemical_list: D005819:Genetic Markers; D009363:Neoplasm Proteins; D001194:Asbestos