TY - JOUR
T1 - Genetic Variants Associated with Increased Risk of Malignant Pleural Mesothelioma
T2 - A Genome-Wide Association Study
AU - Matullo, Giuseppe
AU - Guarrera, Simonetta
AU - Betti, Marta
AU - Fiorito, Giovanni
AU - Ferrante, Daniela
AU - Voglino, Floriana
AU - Cadby, Gemma
AU - Di Gaetano, Cornelia
AU - Rosa, Fabio
AU - Russo, Alessia
AU - Hirvonen, Ari
AU - Casalone, Elisabetta
AU - Tunesi, Sara
AU - Padoan, Marina
AU - Giordano, Mara
AU - Aspesi, Anna
AU - Casadio, Caterina
AU - Ardissone, Francesco
AU - Ruffini, Enrico
AU - Betta, Pier Giacomo
AU - Libener, Roberta
AU - Guaschino, Roberto
AU - Piccolini, Ezio
AU - Neri, Monica
AU - Musk, Arthur W.B.
AU - de Klerk, Nicholas H.
AU - Hui, Jennie
AU - Beilby, John
AU - James, Alan L.
AU - Creaney, Jenette
AU - Robinson, Bruce W.
AU - Mukherjee, Sutapa
AU - Palmer, Lyle J.
AU - Mirabelli, Dario
AU - Ugolini, Donatella
AU - Bonassi, Stefano
AU - Magnani, Corrado
AU - Dianzani, Irma
N1 - This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2013/4/23
Y1 - 2013/4/23
N2 - 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.
AB - 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.
KW - MPM
KW - genetic risk factors
KW - Multivariate analysis
UR - http://www.scopus.com/inward/record.url?scp=84876527407&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0061253
DO - 10.1371/journal.pone.0061253
M3 - Article
C2 - 23626673
AN - SCOPUS:84876527407
SN - 1932-6203
VL - 8
JO - PLoS One
JF - PLoS One
IS - 4
M1 - e61253
ER -