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Genetic Associations of 115 Polymorphisms with Cancers of the Upper Aerodigestive Tract across 10 European Countries: The ARCAGE Project

¹ Department of Environmental Medicine and Public Health, University of Padova, Padova, Italy; ² IARC, Lyon, France; ³ University of Tartu, Institute of Molecular and Cell Biology/Estonian Biocentre; ⁴ The Estonian Genome Project of the University of Tartu, Tartu, Estonia; ⁵ University of Athens School of Medicine, Athens, Greece; ⁶ Harvard School of Public Health, Boston, Massachusetts; ⁷ Bremen Institute for Prevention Research and Social Medicine, University of Bremen, Bremen, Germany; ⁸ Unit of Cancer Epidemiology, Center for Experimental Research and Medical Studies and University of Turin, Turin, Italy; ⁹ Aviano Cancer Centre, Aviano, Italy; ¹⁰ General Hospital of Pordenone, Pordenone, Italy; ¹¹ University of Aberdeen School of Medicine, Aberdeen, United Kingdom; ¹² Charles University in Prague, 1st Faculty of Medicine, Institute of Hygiene and Epidemiology, Prague, Czech Republic; ¹³ Institut National de la Santé et de la Recherche Médicale, U794, Paris, France; ¹⁴ Centre National de la Recherche Scientifique, FRE2939, Institut Gustave Roussy, Villejuif, France; ¹⁵ Cancer Registry, Geneva, Switzerland; ¹⁶ Cancer Registry of Norway, Oslo, Norway; ¹⁷ University of Newcastle Dental School, Newcastle, United Kingdom; ¹⁸ Institut Català d'Oncologia, Barcelona, Spain; ¹⁹ University of Glasgow Dental School, Glasgow, Scotland; ²⁰ Information Services Division, National Health Service, National Services Scotland, Edinburgh, Scotland; ²¹ University of Leeds, Leeds, United Kingdom; ²² Croatian National Cancer Registry, Croatian National Institute of Public Health, Zagreb, Croatia; and ²³ Trinity College School of Dental Science, Dublin, Ireland

Requests for reprints: Paul Brennan, International Agency for Research on Cancer, 150 cours Albert Thomas, 69008 Lyon, France. Phone: 33-4-72-73-8391; Fax: 33-4-72-73-83-42; E-mail: brennan{at}iarc.fr.

Key Words: upper aerodigestive cancer • single nucleotide polymorphisms • case-control study

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. [Cancer Res 2009;69(7):2956–65]