Multiple ADH genes are associated with upper aerodigestive cancers

Abstract

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...

A variant allele of ADH1B and ALDH2, is associated with the risk of esophageal cancer

“…Two studies in Asian populations found a significantly higher risk of cancer of the upper aerodigestive tract (UADT), oral cavity or oropharynx and hypopharynx in moderate or heavy drinkers of alcohol carrying the ADH1B * 1/ * 1 (GG) genotype (21,22). Hashibe et al identified the variation of ADH1B rs1229984 as a risk factor for esophageal cancer in European and Latin American populations (23). Their results were consistent with the results of the present study and another investigation conducted by Tanaka et al in a Japanese population (11).…”

Alcohol dehydrogenase and aldehyde dehydrogenase gene polymorphisms, alcohol intake and the risk of colorectal cancer in the European Prospective Investigation into Cancer and Nutrition study

“…33 For alcohol-related cancers, an increased risk of upper aero-digestive tract cancers has been observed consistently in studies conducted in Europe 21,34 and in Japan. 35 For CRC, no clear explanation for the increased risk associated with the slow alcohol metabolizer rs1229984(G) (ADH1B) allele observed in Asian populations 15,16 has been provided.…”

Family history of cancer and the risk of laryngeal cancer: A case‐control study from Italy and Switzerland

“…7,[10][11][12][13] Familial aggregation may indicate that inheritable genetic factors play a role in laryngeal cancer risk, but may also reflect a tendency of relatives to have similar alcohol and tobacco habits. Genetic polymorphisms in genes involved in the metabolism of carcinogens have been associated to head and neck cancer risk, [14][15][16] although the data were limited for laryngeal cancer alone. A locus (15q25) including nicotinic acetylcholine receptor genes has been associated to lung cancer risk, but not to head and neck cancer.…”