Sequence variants in DNA repair and cell cycle genes and the risk of upper aerodigestive tract cancers in Central Europe
Authors: Mia Hashibe, Janet Hall, Paolo Boffetta, David Zaridze, Neonila Szeszenia-Dabrowska, Dana Mates, Vladimir Janout, Eleonora Fabianova, Vladimir Bencko, Federico Canzian, Rayjean Hung, Paul Brennan
Journal: Cancer Research (2006)

2050   Introduction. Cancers of the upper aerodigestive tract (UADT), comprising the oral cavity, pharynx, larynx and esophagus, account for 5.2% of all cancer cases worldwide. The major risk factors, tobacco and alcohol can directly or indirectly generate DNA damage, which if unrepaired can give rise to mutations, unregulated cell growth and apoptosis induction. To clarify the role of DNA repair and cell cycle control proteins in UADT cancer susceptibility, we studied the risk in relation to 27 SNPs in 18 DNA repair enzymes (ERCC1, XPF, XPA, XPC, XPD, XPG, LIG1, OGG1, APEX, XRCC1, LIG3, PARP, MGMT, MLH1, MSH6, XRCC2, XRCC3, XRCC4) and 10 SNPs in 7 cell cycle control genes (CCND1, P16, P52, P72, P21, CHEK2, MDM2). Methods. A case-control study was conducted from 2000 to 2002 in 6 centers from 5 Central European countries: Romania, Poland, Russia, Slovakia and the Czech Republic. Patients diagnosed with squamous cell carcinoma of the UADT at designated hospitals were recruited (n=775: 156 oral, 109 pharynx, 315 larynx, 169 esophagus). Controls with a recent diagnosis of diseases unrelated to tobacco and alcohol were included (n=1014). Genomic DNA was extracted from blood samples and genotyping was performed by the Taqman assay. Odds ratios (OR) and 95% confidence intervals (CI) were estimated for the risks of UADT cancer overall and for the 4 specific sites (oral, pharynx, larynx, esophagus) for the 37 SNPs. For overall UADT cancer risk, we further stratified by age, smoking status, and alcohol drinking status. Results. Of the 444 potential associations explored, the risk estimates for 39 suggested an increase or decrease in cancer risk. For UADT cancer risk, associations were observed for the variant alleles of CHEK2 -200G>A (OR=1.43, 95%CI=1.06-1.92), CHEK2 I157T (OR=0.44, 95%CI=0.24-0.79), MGMT 171C>T (OR=2.24, 95%CI=1.16-4.34), OGG1 S326C (OR=2.00, 95%CI=1.10-3.63), XPA 23A>G (OR=0.73, 95%CI=0.52-1.03) and XPD D312N (OR=1.31, 95%CI=0.97-1.77). Several other sequence variants showed associations with specific cancers with no overall association with UADT cancer. For instance, the variant allele of ERCC1 8092C>A was associated with oral and esophageal cancers, the variant allele of XPC K929Q was inversely associated with oral cancer and the p53 intron 3 polymorphism increased the risk of esophageal cancer. Effect modification by tobacco was not apparent, but risk differences were suggested with alcohol drinking status for several sequence variants. Conclusion. This study, with the largest number of UADT cancer cases genotyped, identified 6 sequence variants of the 37 analyzed, that were associated with UADT cancer risk. While some of these associations are consistent with previous studies, we cannot rule out the possibility of false positive associations. As a next step, we plan to investigate our positive findings in another large-scale multicenter study on UADT cancers in South America.