Risk Of Upper Aerodigestive Tract Cancers Research Articles

The -308G/A Polymorphism of the Tumor Necrosis Factor-alpha Gene Is Associated with the Risk of Upper Aerodigestive Tract Cancer: A Meta-analysis

Tumor necrosis factor-alpha (TNF-α) has been proposed to contribute to the development of upper aerodigestive tract (UADT) cancer that is characterized by poor prognosis. The G-to-A nucleotide change at -308 of the TNF-α gene (-308G/A polymorphism) can increase the expression level of TNF-α and thus may affect the genetic susceptibility of UADT cancer. The association between the -308G/A polymorphism and UADT cancer has been widely studied, but the results published are quite controversial. To obtain a more precise conclusion, we performed a meta-analysis including 1,751 patients and 3,345 controls. The results indicated that the AA genotype of the -308G/A polymorphism had a 54%-increased risk of UADT cancer, compared with the G carriers (GG and GA genotypes) [odds ratio (OR) = 1.54, 95% confidence interval (CI): 1.07-2.21]. After stratified by ethnicity, the AA genotype was associated with increased risk of UADT cancers in South Asians (OR = 33.18 and 95% CI: 1.92-573.62 for AA vs. GA+GG) but not in Caucasians or East Asians. After stratified by tumor site, the -308G/A polymorphism was associated with increased risks of oropharynx cancer (OR = 2.68 and 95% CI: 1.34-5.35 for AA vs. GA+GG) but not associated with esophagus or larynx cancer. After stratified by histological type, the -308G/A polymorphism was associated with increased risks of squamous cell carcinoma (OR = 1.81 and 95% CI: 1.15-2.84 for AA vs. GA+GG) but not associated with adenocarcinoma. Our results indicate that the -308G/A polymorphism might contribute to an increased risk of UADT cancer susceptibility.

Time to First Cigarette and Upper Aerodigestive Tract Cancer Risk in Japan

Cigarette smoking is the major cause for upper aerodigestive tract (UADT) cancers. The time to first cigarette (TTFC) of the day is a distinct indicator of nicotine dependence, but scanty information is available on its possible relation with UADT cancers (oral, oropharyngeal, hypopharyngeal, laryngeal, nasopharyngeal, and esophageal cancers). This case-control study includes a total of 1,009 incident UADT cancer cases and 3,027 age- and sex-matched noncancer controls admitted to the Aichi Cancer Center (Nagoya, Japan) between 2001 and 2005. We estimated OR and 95% confidence intervals (CI) for TTFC using logistic regression models after adjustment for several potential confounders. TTFC was inversely related to the risk of UADT cancer, and this association was consistent across subtypes of head and neck cancer and esophageal cancer. For all UADT cancers considered among ever smokers and after accurate allowance for smoking quantity and duration, besides other relevant covariates, compared with TTFC more than 60 minutes, the adjusted ORs were 1.40 (95% CI: 0.93-2.11) for 31 to 60 minutes, 1.76 (95% CI: 1.20-2.58) for 6 to 30 minutes, and 2.43 (95% CI: 1.64-3.61) for within 5 minutes. No significant heterogeneity was found in strata of sex, age, alcohol consumption, fruit and vegetable intake, and occupation for overall and site-specific analysis. Nicotine dependence, as indicated by the TTFC, is associated with increased risk of UADT cancers and is therefore an independent marker of exposure to smoking. Our result indicates more detailed risk evaluation of UADT cancers that is enabled by the TTFC.

Tag single nucleotide polymorphisms of alcohol-metabolizing enzymes modify the risk of upper aerodigestive tract cancers: HapMap database analysis

Although alcohol is associated with higher upper aerodigestive tract (UADT) cancer risk, only a small fraction of alcoholics develop cancers. There is a lack of evidence proving the association of tag single nucleotide polymorphisms of alcohol-metabolizing enzymes with cancer risk. The aim of this study was to determine the association of these genetic polymorphisms with UADT cancer risk in a Chinese population. It was a hospital-based case-control candidate gene study. The databases of the International HapMap Project were searched for haplotype tag single nucleotide polymorphisms of the genes alcohol dehydrogenase (ADH)1B, ADH1C, and aldehyde dehydrogenase (ALDH)2. The genotyping was performed by the Sequenom MassARRAY system. Totally, 120 head and neck squamous cell carcinoma, 138 esophageal squamous cell carcinoma patients, and 276 age- and gender-matched subjects were enrolled between June 2008 and June 2010.Minor alleles of ADH1B (rs1229984) and ALDH2(rs671) were not only associated with the risk of UADT cancers (odds ratio [OR] [95% confidence interval, CI]: 3.53 [2.14-5.80] and 2.59 [1.79-3.75], respectively) but also potentiated the carcinogenic effects of alcohol (OR [95% CI]: 53.44 [25.21-113.29] and 70.08 [33.65-145.95], respectively). Similar effects were observed for head/neck and esophageal cancer subgroups. Multivariate logistic regression analysis identified four significant risk factors, including habitual use of cigarettes, alcohol, betel quid, and lower body mass index (P < 0.001). The haplotypes GAGC (OR 1.61, 95% CI 1.08-2.40, P = 0.018) and CCAATG (OR 1.69, 95% CI 1.24-2.30, P < 0.001) on chromosomes 4 and 12, respectively, were associated with higher cancer risk. These findings suggested that risk allele or haplotype carriers who consume alcohol and other carcinogens should be advised to undergo endoscopy screening. The information can be used to determine the degree of susceptibility of each subject and can be combined with other environmental factors, like carcinogen consumption, in the screening analysis.

Indoor air pollution from solid fuels and risk of upper aerodigestive tract cancers in Central and Eastern Europe

BackgroundIndoor air pollution from solid fuels is a potentially important risk factor for cancer, yet data on cancers from organs other than the lung are scarce. We investigated if indoor air pollution from coal and wood are risk factors for additional cancers, particularly that of the upper aerodigestive tract (oral cavity, larynx, pharynx and esophagus) in the high-risk areas of Central and Eastern Europe. MethodsWe used data from multi-center hospital-based case-control study of 1065 histologically confirmed upper aerodigestive tract cancer cases and 1346 controls. Standardized questionnaires were used to collect information on residential fuel use for cooking and heating. Using unconditional logistic regression, we calculated odds ratios (ORs) and 95% confidence intervals (95% CIs) for upper aerodigestive tract cancer risk after adjusting for potential confounders. ResultsLifelong wood use was associated with pharyngeal and esophageal (OR 4.05, 95% CI: 1.30–12.68 and OR 2.71, 95% CI: 1.21–6.10, respectively). We observed an exposure–response relationship between duration of wood use and risk of pharyngeal cancer among those who had never used coal (Ptrend=0.04), ruling out the possibility of residual confounding by coal. Similarly, we observed an increased risk of laryngeal cancers and head & neck cancers among those who always used coal, with a noted exposure–response relationship (Ptrend<0.01). ConclusionsOur results suggest a possible role of indoor air pollution from solid fuel use in head and neck carcinogenesis in the high risk area of Central and Eastern Europe.

Inverse association between yoghurt intake and upper aerodigestive tract cancer risk in a Japanese population

Although the combination of tobacco smoking and alcohol drinking account for approximately 80% of upper aerodigestive tract (UADT) cancer risk, the role of dietary factors, including dairy products, in the risk of these cancers remains controversial. We aimed to evaluate the association between dairy product intake and UADT cancer risk in a Japanese population. We conducted a case-control study in 959 patients with UADT cancer and 2877 sex- and age-matched noncancer control subjects who visited the Aichi Cancer Center in Nagoya, Japan. Data on lifestyle factors, including diet, were obtained by self-administered questionnaire. Associations were assessed by multivariate logistic regression models that considered potential confounders. We found a significant inverse association between yoghurt intake and UADT cancer risk with multivariate-adjusted odds ratios and 95% confidence intervals for <1 time/week, ≥ 1 time/week and <1 time/day, and ≥ 1 time/day consumption of yoghurt of 0.70 (95% confidence interval: 0.54-0.91), 0.67 (0.54-0.84), and 0.73 (0.55-0.95) relative to nonconsumers (P trend=0.005). When stratified by primary tumor site, this association was significant among patients with hypopharyngeal, laryngeal, and esophageal cancer. However, we saw no significant association between milk or butter intake and UADT cancer risk. In this study, we found that a high intake of yoghurt may lower the risk of developing UADT cancer in a Japanese population. Further investigation of this association is warranted.

Risk of upper aerodigestive tract cancer and type of alcoholic beverage: a European multicenter case–control study

The general relationship between cancers of the upper aerodigestive tract (UADT) and alcohol drinking is established. Nevertheless, it is uncertain whether different types of alcoholic beverages (wine, beer and liquor) carry different UADT cancer risks. Our study included 2,001 UADT cancer cases and 2,125 controls from 14 centres in 10 European countries. All cases were histologically or cytologically confirmed squamous cell carcinomas. Controls were frequency matched by sex, age and centre. Logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (95%CI) adjusted for age, sex, centre, education level, vegetable and fruit intake, tobacco smoking and alcohol drinking, where appropriate. Risk of beverage-specific alcohol consumption were calculated among 'pure drinker' who consumed one beverage type exclusively, among 'predominant drinkers' who consumed one beverage type to more than 66% and among 'mixed drinkers' who consumed more than one beverage type to similar proportions. Compared to never drinkers and adjusted for cumulative alcohol consumption, the OR and 95%CI for wine, beer and liquor drinking, respectively, were 1.24 (0.86, 1.78), 1.54 (1.05, 2.27) and 0.94 (0.53, 1.64) among 'pure drinkers' (p value for heterogeneity across beverage types=0.306), 1.05 (0.76,1.47), 1.25 (0.87,1.79) and 1.43 (0.95, 2.16) among 'predominant drinkers' (p value=0.456), and 1.09 (0.79, 1.50), 1.20 (0.88, 1.63) and 1.12 (0.82, 1.53) among 'mixed drinkers' (p value=0.889). Risk of UADT cancer increased with increasing consumption of all three alcohol beverage types. Our findings underscore the strong and comparable carcinogenic effect of ethanol in wine, beer and liquor on organs of the UADT.

Role of medical history and medication use in the aetiology of upper aerodigestive tract cancers in Europe: the ARCAGE study

The study aimed to investigate the role of medical history (skin warts, Candida albicans, herpetic lesions, heartburn, regurgitation) and medication use (for heartburn; for regurgitation; aspirin) in the aetiology of upper aerodigestive tract (UADT) cancer. A multicentre (10 European countries) case-control study [Alcohol-Related CAncers and GEnetic susceptibility (ARCAGE) project]. There were 1779 cases of UADT cancer and 1993 controls. History of warts or C. albicans infection was associated with a reduced risk [odds ratio (OR) 0.80, 95% confidence interval (CI) 0.68-0.94 and OR 0.73, 95% CI 0.60-0.89, respectively] but there was no association with herpetic lesions, heartburn, regurgitation or medication for related symptoms. Regurgitation was associated with an increased risk for cancer of the oesophagus (OR 1.47, 95% CI 0.98-2.21). Regular aspirin use was not associated with risk of UADT cancer overall but was associated with a reduced risk for cancer of oesophagus (OR 0.51, 95% CI 0.28-0.96), hypopharynx (OR 0.53, 95% CI 0.28-1.02) and larynx (OR 0.74, 95% CI 0.54-1.01). A history of some infections appears to be a marker for decreased risk of UADT cancer. The role of medical history and medication use varied by UADT subsites with aspirin use associated with a decreased risk of oesophageal cancer and suggestive of a decreased risk of hypopharyngeal and laryngeal cancers.

The neoplastic impact of tobacco‐free betel‐quid on the histological type and the anatomical site of aerodigestive tract cancers

Little is known about any consequences of swallowing tobacco-free betel-quid (TF-BQ) juice/remnants following chewing and its carcinogenic impact on the upper aerodigestive tract (UADT) to gastrointestinal tract (GIT). We investigated the neoplastic impact of TF-BQ on different anatomical locations along UADT and GIT, and differences according to their histological categories. We conducted a multicenter case-control study examining patients with 2,163 pathology-proven UADT and GIT cancers, comparing them with 2,250 control subjects. Generalized additive models, piecewise regression and polytomous logistic models were applied to identify possible dose-dependent structures and cancer risks. Contrary to nonsignificant GIT-adenocarcinoma risk (aOR=0.9), TF-BQ users experienced a 1.7- to 16.2-fold higher risk of UADT-squamous cell carcinomas than nonusers, with the peak risk discovered in oral neoplasms. We separately observed a curvilinear and linear TF-BQ dose-risk relationship in oral/pharyngeal/esophageal and laryngeal cancers. Chewers of betel inflorescence were generally at a greater UADT cancer risk. A higher first-piecewise increased risk of esophageal cancer was recognized among areca-fluid swallowers than among nonswallowers (continuous aOR=1.12 vs. 1.03). TF-BQ use accounted for 66.1-78.7% and 17.8-33.2% of the cases of oral/pharyngeal and esophageal/laryngeal cancers, respectively. However, a reduction from heavy TF-BQ consumption to low-to-moderate consumption only reduced 11.3-34.6% of etiologic fraction of oral/pharyngeal cancers. Alcohol supra-additively modified the risk of TF-BQ in determining the development of oral, pharyngeal and esophageal cancers. In conclusion, the interplay of TF-BQ and alcohol/tobacco use, combined with how chewing habit is practiced, influences carcinogenic consequences on anatomically diverse sites of UADT and GIT cancers, and histologically different types.

Alcohol Dehydrogenase‐1B Arg47His Polymorphism and Upper Aerodigestive Tract Cancer Risk: A Meta‐Analysis Including 24,252 Subjects

Cancers of the upper aerodigestive tract (UADT) include malignant tumors of the oral cavity, pharynx, larynx, and esophagus, account for approximately 4% of all new cancers in world. Alcohol drinking is an established risk factor for UADT cancers, and the rate of alcohol metabolism could significantly been influenced by genetic polymorphisms of alcohol dehydrogenase-1B (ADH1B) His47Arg (rs1229984). To evaluate whether combined evidence shows ADH1B His47Arg as a common genetic variant that influenced the risk of UADT cancers, we considered all available studies in a meta-analysis. Eighteen studies were combined representing data of 8,539 cases and 15,713 controls for meta-analysis. Stratified analyses were carried out to determine the gene-environment interaction between ADH1B His47Arg and alcohol drinking and gene-gene interaction between ADH1B His47Arg and aldehyde dehydrogenase-2 (ALDH2) Glu/Lys related to UADT cancer risk. Potential sources of heterogeneity between studies were explored; sensitivity analysis and publication bias was also evaluated. The ADH1B 47Arg allele was found to be associated with increased risk of UADT cancers, the pooled odds ratios (ORs) being 1.66 (95% CI: 1.54 to 1.79) and 3.47 (95% CI: 2.76 to 4.36) for the His/Arg and Arg/Arg genotypes compared with the His/His genotype, respectively. An 18.48-fold increase in OR (95% CI: 12.95 to 26.40) for UADT cancers among alcohol drinkers with Arg/Arg genotype was found, when compared among nondrinkers with the His/His genotype. Significant interaction between carriers with ADH1B 47Arg and ALDH2 487Lys allele related to risk for UADT cancers was more evident, compared with noncarriers (OR = 10.31, 95% CI: 5.45 to 18.85). ADH1B 47Arg allele is a common genetic variant that increased the risk of UADT cancers; furthermore, it modulates the susceptibility to UADT cancers coupled with alcohol drinking and interaction with the ALDH2 487Lys allele.

Occupation and risk of upper aerodigestive tract cancer: The ARCAGE study

We investigated the association between occupational history and upper aerodigestive tract (UADT) cancer risk in the ARCAGE European case-control study. The study included 1,851 patients with incident cancer of the oral cavity, oropharynx, hypopharynx, larynx or esophagus and 1,949 controls. We estimated odds ratios (OR) and 95% confidence intervals (CI) for ever employment in 283 occupations and 172 industries, adjusting for smoking and alcohol. Men (1,457 cases) and women (394 cases) were analyzed separately and we incorporated a semi-Bayes adjustment approach for multiple comparisons. Among men, we found increased risks for occupational categories previously reported to be associated with at least one type of UADT cancer, including painters (OR = 1.74, 95% CI: 1.01-3.00), bricklayers (1.58, 1.05-2.37), workers employed in the erection of roofs and frames (2.62, 1.08-6.36), reinforced concreters (3.46, 1.11-10.8), dockers (2.91, 1.05-8.05) and workers employed in the construction of roads (3.03, 1.23-7.46), general construction of buildings (1.44, 1.12-1.85) and cargo handling (2.60, 1.17-5.75). With the exception of the first three categories, risks both increased when restricting to long duration of employment and remained elevated after semi-Bayes adjustment. Increased risks were also found for loggers (3.56, 1.20-10.5) and cattle and dairy farming (3.60, 1.15-11.2). Among women, there was no clear evidence of increased risks of UADT cancer in association with occupations or industrial activities. This study provides evidence of an association between some occupational categories and UADT cancer risk among men. The most consistent findings, also supported by previous studies, were obtained for specific workers employed in the construction industry.

O4-4.6 Role of medical factors in the aetiology of upper aerodigestive tract cancers in Europe: the ARCAGE study

BackgroundCancer of the upper aerodigestive tract (UADT) (oral cavity, pharynx, larynx and oesophagus) is, globally, the fourth most common cancer and cause of cancer mortality. In addition to established risk...

Different interaction concepts to detect gene-environment interactions in the context of upper aero-digestive tract cancer

Introduction: Tobacco smoking and consumption of alcoholic beverages are established causes of cancers of the upper aero-digestive tract (UADT) and reduced intake of vegetables and fruits are likely causes. Little is known, however, about the role of gene-environment interactions (GEIs) respecting nutritional factors. Material and Methods: The study is embedded in the Alcohol-Related Cancers and Genetic Susceptibility in Europe (ARCAGE) study, a multi-centre case-control study conducted 2002–2005 in 10 European countries (Lagiou, 2009). Dietary habits were assessed using a semi-quantitative food frequency questionnaire. The analysis dataset included 1,395 controls and 1,379 cases. We used approximately 50% of the data for an exploratory screening procedure to generate a list of several potential gene-nutrition interactions. The remaining 50% build an independent dataset, which is used to estimate interaction effects between genes and nutrition variables. Logistic regression models are applied to estimate various interaction effects that are based on odds ratios (OR) like RERI (relative excess risk due to interaction), AP (attributable proportion due to interaction), the synergy index (S) and the multiplicative synergy index (SM). Interaction measures of combined gene-nutrition information will be compared with interaction effects of stratified data. Results: We observe inverse interaction effects between fruit consumption and MTHFR (folate metabolism). Homozygous minor allele carriers (AA genotype) show a significantly increased OR with less than daily fruit consumption (OR=3.8, CI=2.2–3.8) compared to non-carriers with more than daily fruit consumption. RERI=1.99 (CI=-0.1–4.0) indicates that the excess risk due to the exposure combination of the AA-genotype and „daily fruit consumption“ is 1.99 times higher compared to participants being exposed to neither of these two factors. The synergy index shows a significant synergistic departure from additivity (S=3.3, CI=1.2–8.9). Discussion: We demonstrate that different interaction measures lead to different interpretations of „interaction“. This will be discussed in the context of GEIs that could modify the risk of UADT cancers.

Putative EPHX1 Enzyme Activity Is Related with Risk of Lung and Upper Aerodigestive Tract Cancers: A Comprehensive Meta-Analysis

BackgroundEPHX1 is a key enzyme in metabolizing some exogenous carcinogens such as products of cigarette-smoking. Two functional polymorphisms in the EPHX1 gene, Tyr113His and His139Arg can alter the enzyme activity, suggesting their possible association with carcinogenesis risk, particularly of some tobacco-related cancers.Methodology/Principal FindingsA comprehensive systematic review and meta-analysis was performed of available studies on these two polymorphisms and cancer risk published up to November 2010, consisting of 84 studies (31144 cases and 42439 controls) for Tyr113His and 77 studies (28496 cases and 38506 controls) for His139Arg primarily focused on lung cancer, upper aerodigestive tract (UADT) cancers (including oral, pharynx, larynx and esophagus cancers), colorectal cancer or adenoma, bladder cancer and breast cancer. Results showed that Y113H low activity allele (H) was significantly associated with decreased risk of lung cancer (OR = 0.88, 95%CI = 0.80–0.96) and UADT cancers (OR = 0.86, 95%CI = 0.77–0.97) and H139R high activity allele (R) with increased risk of lung cancer (OR = 1.18, 95%CI = 1.04–1.33) but not of UADT cancers (OR = 1.05, 95%CI = 0.93–1.17). Pooled analysis of lung and UADT cancers revealed that low EPHX1 enzyme activity, predicted by the combination of Y113H and H139R showed decreased risk of these cancers (OR = 0.83, 95%CI = 0.75–0.93) whereas high EPHX1 activity increased risk of the cancers (OR = 1.20, 95%CI = 0.98–1.46). Furthermore, modest difference for the risk of lung and UADT cancers was found between cigarette smokers and nonsmokers both in single SNP analyses (low activity allele H: OR = 0.77/0.85 for smokers/nonsmokers; high activity allele R: OR = 1.20/1.09 for smokers/nonsmokers) and in combined double SNP analyses (putative low activity: OR = 0.73/0.88 for smokers/nonsmokers; putative high activity: OR = 1.02/0.93 for smokers/ nonsmokers).Conclusions/SignificancePutative low EPHX1 enzyme activity may have a potential protective effect on tobacco-related carcinogenesis of lung and UADT cancers, whereas putative high EPHX1 activity may have a harmful effect. Moreover, cigarette-smoking status may influence the association of EPHX1 enzyme activity and the related cancer risk.

The association between change in body mass index and upper aerodigestive tract cancers in the ARCAGE project: Multicenter case–control study

Previous studies reported an inverse relationship between body mass index (BMI) and upper aerodigestive tract (UADT) cancers. Examining change in BMI over time may clarify these previous observations. We used data from 2,048 cases and 2,173 hospital- and population-based controls from ten European countries (alcohol-related cancers and genetic susceptibility in Europe study) to investigate the relationship with BMI and adult change in BMI on UADT cancer risk. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for associations between BMI at three time intervals and BMI change on UADT cancer development, adjusting for center, age, sex, education, fruit and vegetable intake, smoking and alcohol consumption. We found an inverse relationship between UADT cancers and BMI at time of interview and 2 years before interview. No association was found with BMI at 30 years of age. Regarding BMI change between age 30 and 2 years before interview, BMI decrease (BMI change <-5%) vs. BMI stability (-5% ≤ BMI change <5%) showed no overall association with UADT cancers (OR = 1.15; 95% CI = 0.89, 1.49). An increase in BMI (BMI change ≥+5%) was inversely associated with UADT cancers (OR = 0.74; 95% CI = 0.62, 0.89). BMI gain remained inversely associated across all subsites except for esophageal cancer. When stratified by smoking or by drinking, association with BMI gain was detected only in drinkers and smokers. In conclusion, BMI gain is inversely associated with UADT cancers. These findings may be influenced by smoking and/or drinking behaviors and/or the development of preclinical UADT cancers and should be corroborated in studies of a prospective nature.

Inverse association between toothbrushing and upper aerodigestive tract cancer risk in a Japanese population

Oral hygiene is attracting increasing attention as a potential risk factor for cancers. To investigate the association between toothbrushing frequency and upper aerodigestive tract (UADT) cancer, the authors conducted a large-scale case-control study. A total of 856 UADT cancer case participants and 2696 age- and sex-matched control subjects without cancer were included. Edentulous or participants with unknown frequency of toothbrushing or number of remaining teeth were excluded. Associations were assessed by odds ratios and 95% confidence intervals in logistic regression models with adjustment for potential confounders. Compared with toothbrushing once per day, the adjusted odds ratio for brushing twice or more was 0.82 (95% confidence interval: 0.68, 0.99) whereas that for not brushing was 1.79 (0.79, 4.05). This association was observed especially in subjects who had a history of heavy smoking or drinking. The authors suggest that toothbrushing could have a protective effect for UADT cancer.

Past and current tendency for facial flushing after a small dose of alcohol is a marker for increased risk of upper aerodigestive tract cancer in Japanese drinkers

(Cancer Sci 2010; 101: 2497–2498)

Mediterranean diet and upper aerodigestive tract cancer: the Greek segment of the Alcohol-Related Cancers and Genetic Susceptibility in Europe study

Several dietary factors have been associated with the occurrence of cancers of the oral cavity and oropharynx, larynx and oesophagus, collectively called upper aerodigestive tract (UADT) cancers, but the evidence is considered as inconclusive. We hypothesised that the traditional Mediterranean dietary pattern may be more strongly inversely associated with UADT cancer risk than individual dietary components, and may explain the unexpectedly low incidence of these cancers in Greece. In the context of the European alcohol-related cancers and genetic susceptibility in Europe project, we have conducted a hospital-based case-control study in Athens, Greece, comparing 239 incident UADT cases and 194 hospital controls with admission diagnoses unrelated to tobacco, alcohol or diet. Adherence to Mediterranean diet was assessed through a widely used score, which ranges from 0 (minimal adherence) to 9 (maximal adherence) and increases with high consumption of plant foods and olive oil and low consumption of meat, dairy products and saturated lipids. Stricter adherence to the Mediterranean diet was associated with a substantial and significant decrease in UADT cancer risk (30% for a two-unit increase in score), whereas after mutual adjustment, no individual dietary component of this diet was significantly associated with this risk. Adherence to the traditional Mediterranean diet is associated with reduced risk of UADT cancers, and may explain the lower incidence of UADT cancers in Greece, in spite of the smoking and drinking habits of this population.

Impact of smoking on lung cancer risk is stronger in those with the homozygous aldehyde dehydrogenase 2 null allele in a Japanese population

The main lifestyle contributor to acetaldehyde exposure is the drinking of alcoholic beverages, but tobacco smoke also makes some contribution. Although acetaldehyde is associated with upper aerodigestive tract cancer risk, in accordance with genetically determined acetaldehyde metabolism, it is unclear whether lung cancer, a representative smoking-related cancer, is associated with acetaldehyde or genes impacting its metabolism. We conducted a case-control study to examine possible interaction between smoking and aldehyde dehydrogenase 2 (ALDH2) Glu504Lys polymorphism (rs671) on the risk of lung cancer in Japanese. Subjects were 718 lung cancer cases and 1416 non-cancer controls enrolled in the Hospital-based Epidemiologic Research Program at Aichi Cancer Center. Lifestyle factors, including smoking, were determined by self-administered questionnaire. We applied pack-years (PY; categorized into five levels: never, <15, <30, <45 and > or =45) as a marker of cumulative exposure to smoking. The impact of smoking, ALDH2 genotype, and their interaction on lung cancer risk were assessed by odds ratio (OR) and 95% confidence interval adjusted for potential confounders. Adjusted ORs for PY <15, <30, <45 and > or =45 relative to never smokers among those with Glu/Glu or Glu/Lys were 1.39, 1.80, 3.44 and 6.25, respectively (P-trend = 1.4 x 10(-30)). In contrast, ORs among Lys/Lys were 1.01, 10.2, 11.4 and 23.2, respectively (P-trend = 2.6 x 10(-7)). Interaction between ALDH2 genotype (Glu/Glu + Glu/Lys versus Lys/Lys) and cumulative smoking dose was statistically significant (P = 0.036) and was consistently observed in the analysis among never-drinkers (interaction P = 0.041). These results suggest that ALDH2 Lys/Lys, a null enzyme activity genotype, modifies the impact of smoking on the risk of lung cancer.

Alcohol, Tobacco and Genetic Susceptibility in Relation to Cancers of the Upper Aerodigestive Tract in Northern Italy

Each year in Italy there are approximately 14,000 new cases and 7,000 deaths from cancer of the upper aerodigestive tract, which includes malignant tumors originating from the oral cavity, pharynx, larynx and esophagus. Established etiological factors include tobacco consumption and heavy alcohol drinking. The study of single nucleotide polymorphisms in upper aerodigestive tract cancer etiology may help to identify high-risk subgroups and to better understand the pathways leading to the development of these cancers. Italian results on about 500 cases and 500 controls from a large case-control study (ARCAGE) conducted in 10 European countries are presented with the major objectives of updating results on the effects of alcohol and tobacco consumptions in northern Italy, investigating the role of genetic variation with regard to the metabolism of alcohol and carcinogens from tobacco smoke, and evaluating possible interactions of these single nucleotide polymorphisms with these carcinogens. The present study confirmed the importance of tobacco smoking and alcohol drinking as the main risk factors for upper aerodigestive tract cancers, indicating that about 68% of cancers among populations in northern Italy can be attributed to the combination of these risk factors. Significant associations between metabolizing phase I genes (CYP1A1 and CYP2A6), phase II genes (GSTA2) and upper aerodigestive tract cancers were found. A polymorphism of ADH1C has been associated with an increased risk of upper aerodigestive tract cancers, suggesting that the less rapid alcohol metabolizers are more susceptible to upper aerodigestive tract cancer risk. Our results suggest that the ADH1C allele modifies the carcinogenic dose response for alcohol in the upper aerodigestive tract, giving rise to a gene-environment interaction. The role of genes as possible modifiers of life-style risks seems the most reliable.

Active and Involuntary Tobacco Smoking and Upper Aerodigestive Tract Cancer Risks in a Multicenter Case-Control Study

Several important issues for the established association between tobacco smoking and upper aerodigestive tract (UADT) cancer risks include the associations with smoking by cancer subsite, by type of tobacco, and among never alcohol drinkers and the associations with involuntary smoking among nonsmokers. Our aim was to examine these specific issues in a large-scale case-control study in Europe. Analysis was done on 2,103 UADT squamous cell carcinoma cases and 2,221 controls in the Alcohol-Related Cancers and Genetic Susceptibility in Europe project, a multicenter case-control study in 10 European countries. Unconditional logistic regression was done to obtain odds ratios (OR) and 95% confidence intervals (95% CI). Compared with never tobacco smoking, current smoking was associated with UADT cancer risks (OR, 6.72; 95% CI, 5.45-8.30 for overall; OR, 5.83; 95% CI, 4.50-7.54 for oral cavity and oropharynx; OR, 12.19; 95% CI, 8.29-17.92 for hypopharynx and larynx; and OR, 4.17; 95% CI, 2.45-7.10 for esophagus). Among never drinkers, dose-response relationships with tobacco smoking pack-years were observed for hypopharyngeal and laryngeal cancers (P(trend) = 0.010) but not for oral cavity and oropharyngeal cancers (P(trend) = 0.282). Among never smokers, ever exposure to involuntary smoking was associated with an increased risk of UADT cancers (OR, 1.60; 95% CI, 1.04-2.46). Our results corroborate that tobacco smoking may play a stronger role in the development of hypopharyngeal and laryngeal cancers than that of oral cavity and oropharyngeal cancers among never drinkers and that involuntary smoking is an important risk factor for UADT cancers. Public health interventions to reduce involuntary smoking exposure could help reduce UADT cancer incidence.