JOURNAL ARTICLE
MULTICENTER STUDY

Genetic associations of 115 polymorphisms with cancers of the upper aerodigestive tract across 10 European countries: the ARCAGE project

Cristina Canova, Mia Hashibe, Lorenzo Simonato, Mari Nelis, Andres Metspalu, Pagona Lagiou, Dimitrios Trichopoulos, Wolfgang Ahrens, Iris Pigeot, Franco Merletti, Lorenzo Richiardi, Renato Talamini, Luigi Barzan, Gary J Macfarlane, Tatiana V Macfarlane, Ivana Holcátová, Vladimir Bencko, Simone Benhamou, Christine Bouchardy, Kristina Kjaerheim, Ray Lowry, Antonio Agudo, Xavier Castellsagué, David I Conway, Patricia A McKinney, Ariana Znaor, Bernard E McCartan, Claire M Healy, Manuela Marron, Paul Brennan
Cancer Research 2009 April 1, 69 (7): 2956-65
19339270
Cancers of the upper aerodigestive tract (UADT) include malignant tumors of the oral cavity, pharynx, larynx, and esophagus and account for 6.4% of all new cancers in Europe. In the context of a multicenter case-control study conducted in 14 centers within 10 European countries and comprising 1,511 cases and 1,457 controls (ARCAGE study), 115 single nucleotide polymorphisms (SNP) from 62 a priori-selected genes were studied in relation to UADT cancer. We found 11 SNPs that were statistically associated with UADT cancers overall (5.75 expected). Considering the possibility of false-positive results, we focused on SNPs in CYP2A6, MDM2, tumor necrosis factor (TNF), and gene amplified in squamous cell carcinoma 1 (GASC1), for which low P values for trend (P trend<0.01) were observed in the main effects analyses of UADT cancer overall or by subsite. The rare variant of CYP2A6 -47A>C (rs28399433), a phase I metabolism gene, was associated with reduced UADT cancer risk (P trend=0.01). Three SNPs in the MDM2 gene, involved in cell cycle control, were associated with UADT cancer. MDM2 IVS5+1285A>G (rs3730536) showed a strong codominant effect (P trend=0.007). The rare variants of two SNPs in the TNF gene were associated with a decreased risk; for TNF IVS1+123G>A (rs1800610), the P trend was 0.007. Variants in two SNPs of GASC1 were found to be strongly associated with increased UADT cancer risk (for both, P trend=0.008). This study is the largest genetic epidemiologic study on UADT cancers in Europe. Our analysis points to potentially relevant genes in various pathways.

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