Alcohol is an important risk factor for upper aerodigestive cancers and is principally metabolized by alcohol dehydrogenase (ADH) enzymes. We have investigated six ADH genetic variants in over 3,800 aerodigestive cancer cases and 5,200 controls from three individual studies. Gene variants rs1229984 (ADH1B) and rs1573496 (ADH7) were significantly protective against aerodigestive cancer in each individual study and overall (P ¼ 10 À10 and 10 À9 , respectively). These effects became more apparent with increasing alcohol consumption (P for trend ¼ 0.0002 and 0.065, respectively). Both gene effects were independent of each other, implying that multiple ADH genes may be involved in upper aerodigestive cancer etiology.The alcohol dehydrogenase (ADH) pathway includes seven distinct ADH genes, a key candidate gene group for aerodigestive cancers 1-3 .Studies of aerodigestive cancer in populations of European origin have focused on ADH1C with little evidence of any effect 4 . We previously reported an association for ADH1B R48H (rs1229984) in a central European (CE) population 5 and now consider the effect of this and five other ADH variants in an expanded study comprising 809 aerodigestive cancer cases and 2,586 controls from the CE study as well as a further 3,067 aerodigestive cancer cases and 2,692 controls from two other studies in Europe (ARCAGE study) and Latin America (LA study) (total of 3,876 cases and 5,278 controls). All three studies were coordinated by the International Agency for Research on Cancer (IARC) and followed a similar protocol (Supplementary Methods online). Of the 3,876 cases, 1,790 were cancers of the oral cavity or pharynx, 1,659 were cancers of the hypopharynx or larynx and 427 were cancers of the esophagus (Supplementary Table 1 online). Cases with a histology other than squamous cell were excluded.The HapMap Consortium has genotyped 163 SNPs in the vicinity of the ADH gene cluster with a minor allele frequency (MAF) of 4% or more in the CEPH Utah (CEU) population 6 . Inspection of the linkage disequilibrium (LD) pattern across this region indicates that ADH1A, ADH1B, ADH1C, ADH4, ADH5 and ADH6 are relatively highly correlated, whereas ADH7 showed little correlation with the remaining six ( Supplementary Fig. 1a online). From all verified missense SNPs in the seven ADH genes found in both the NCBI SNP and SNP500 databases 7 , we selected eight that had a MAF 4 4% in the CEU population. Three missense SNPs in ADH4 (rs1126671, rs1126673 and rs1042364) were in strong LD, and thus were genotyped by the highly correlated tagging SNP rs1984362 (r 2 4 0.89). In total, we genotyped six genetic variants (five missense SNPs and one tagging SNP) in all three studies (Table 1 and Supplementary Table 2 online).In the pooled analysis on all 3,876 cases and 5,278 controls, four variants reported a significant association (Supplementary Table 3 online). The most prominent was with rs1229984 (in ADH1B; OR for codominant model ¼ 0.59 (95% CI ¼ 0.50-0.69); P under codominant model ¼ 8 Â 10 À10 ). This variant w...

Genome-wide association studies (GWAS) have been successful in identifying common genetic variation involved in susceptibility to etiologically complex disease. We conducted a GWAS to identify common genetic variation involved in susceptibility to upper aero-digestive tract (UADT) cancers. Genome-wide genotyping was carried out using the Illumina HumanHap300 beadchips in 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls. The 19 top-ranked variants were investigated further in an additional 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies participating in the INHANCE consortium. Five common variants presented evidence for significant association in the combined analysis (p≤5×10−7). Two novel variants were identified, a 4q21 variant (rs1494961, p = 1×10−8) located near DNA repair related genes HEL308 and FAM175A (or Abraxas) and a 12q24 variant (rs4767364, p = 2×10−8) located in an extended linkage disequilibrium region that contains multiple genes including the aldehyde dehydrogenase 2 (ALDH2) gene. Three remaining variants are located in the ADH gene cluster and were identified previously in a candidate gene study involving some of these samples. The association between these three variants and UADT cancers was independently replicated in 5,092 UADT cancer cases and 6,794 controls non-overlapping samples presented here (rs1573496-ADH7, p = 5×10−8; rs1229984-ADH1B, p = 7×10−9; and rs698-ADH1C, p = 0.02). These results implicate two variants at 4q21 and 12q24 and further highlight three ADH variants in UADT cancer susceptibility.

Objective: To evaluate the association of oral health (OH), dental care (DC) and mouthwash with tumors of the upper-aerodigestive tract (UADT), and to which extend enzymes involved in the metabolism of alcohol modify the effect of alcohol-based mouthwashes.' Materials and Methods: Subjects were interviewed about OH and DC behaviors. Mouthwash use was analyzed in relation to alcohol dehydrogenase genes (ADH1B,ADH1C,ADH7) and one aldehyde dehydrogenase gene (ALDH2) known to be associated with head and neck cancers. Adjusted odds ratios (ORs) and 95%-confidence intervals [CI] were estimated with multiple logistic regression models. Results: ORs of low versus high scores of DC and OH were 2.36[CI=1. , respectively, for all UADT sites combined. The OR for use of mouthwash 3 or more times/day was 3.23[CI=1. 68-6.19]. The OR for the rare variant ADH7 coding for fast ethanol metabolism was lower in ) as compared to ) indicating effect modification (pheterogeneity=0.65) while no relevant differences were observed between users and non-users for the variant alleles of ADH1B, ADH1C or ALDH2. Conclusions: Poor OH and DC are independent risk factors for UADT. Whether mouthwash use may entail some risk through the alcohol content in most formulations on the market remains to be clarified. Materials and MethodsSubjects were interviewed about OH and DC behaviors. Mouthwash use was analyzed in relation to alcohol dehydrogenase genes (ADH1B,ADH1C,ADH7) and one aldehyde dehydrogenase gene (ALDH2) known to be associated with head and neck cancers.Adjusted odds ratios (ORs) and 95%-confidence intervals [CI] were estimated with multiple logistic regression models. Results ORs ConclusionsPoor OH and DC are independent risk factors for UADT. Whether mouthwash use may entail some risk through the alcohol content in most formulations on the market remains to be clarified. 5

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Self-reported PdD has acceptable validity and can be used for surveillance of PdD in large epidemiologic studies. However, there is a need for large, well-designed diagnostic studies.