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To investigate the potential role of vitamin or mineral supplementation on the risk of head and neck cancer (HNC), we analyzed individual-level pooled data from 12 case-control studies (7,002 HNC cases and 8,383 controls) participating in the International Head and Neck Cancer Epidemiology consortium. There were a total of 2,028 oral cavity cancer, 2,465 pharyngeal cancer, 874 unspecified oral/pharynx cancer, 1,329 laryngeal cancer and 306 overlapping HNC cases. Odds ratios (OR) and 95% confidence intervals (CIs) for self reported ever use of any vitamins, multivitamins, vitamin A, vitamin C, vitamin E, and calcium, beta-carotene, iron, selenium and zinc supplements were assessed. We further examined frequency, duration and cumulative exposure of each vitamin or mineral when possible and stratified by smoking and drinking status. All ORs were adjusted for age, sex, race/ethnicity, study center, education level, pack-years of smoking, frequency of alcohol drinking and fruit/vegetable intake. A decreased risk of HNC was observed with ever use of vitamin C (OR = 0.76, 95% CI = 0.59-0.96) and with ever use of calcium supplement (OR = 0.64, 95% CI = 0.42-0.97). The inverse association with HNC risk was also observed for 10 or more years of vitamin C use (OR = 0.72, 95% CI = 0.54-0.97) and more than 365 tablets of cumulative calcium intake (OR = 0.36, 95% CI = 0.16-0.83), but linear trends were not observed for the frequency or duration of any supplement intake. We did not observe any strong associations between vitamin or mineral supplement intake and the risk of HNC., (Copyright © 2011 UICC.)

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., (Copyright © 2011 UICC.)

Population-based studies have shown a concordance of breast cancer survival among first-degree relatives (FDRs), suggesting a heritable component. Reasons for such heritability remain to be elucidated. We aimed to determine whether association of breast cancer survival among FDRs is linked to shared patient and tumor characteristics or type of treatment. At the population-based Geneva Breast Cancer Registry, we identified 162 FDR pairs diagnosed with breast cancer. We categorized FDRs into poor, medium and good familial survival risk groups according to breast cancer-specific survival of their proband (mother or sister). We compared patient, tumor and treatment characteristics between categories and calculated standardized mortality ratios (SMRs) and adjusted disease-specific mortality for each group. Breast cancer patients in the poor familial survival risk group were more likely to be diagnosed at later stages than those in the good familial survival risk group. Similarly, they had higher SMRs than those in the medium and good survival risk groups (18.7, 95% confidence interval [CI]: 9.4-33.5 vs. 16.5, 95% CI: 7.5-31.3 and 9.4, 95% CI: 3.4-20.4, respectively). After adjustment for patient and tumor characteristics and type of treatment, women in the poor familial survival risk group were almost five times more likely to die of breast cancer than those in the good familial survival risk group (adjusted hazard ratio 4.8, 95% CI: 1.4-16.4). Our study shows that breast cancer prognosis clusters within families and suggests that the hereditary component is independent of patient and tumor characteristics and type of treatment., (Copyright © 2011 UICC.)

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., (Copyright © 2010 UICC.)

There is suggestive, but inconclusive, evidence that dietary factors may affect risk of cancers of the upper aerodigestive tract (UADT). In the context of the alcohol-related cancers and genetic susceptibility in Europe study, we have examined the association of dietary factors with UADT cancer risk. We have analyzed data from 2,304 patients with UADT cancer and 2,227 control subjects recruited in 14 centers in 10 European countries. Dietary data were collected through a semi-quantitative food frequency questionnaire that also assessed preferred temperature of hot beverages. Statistical analyses were conducted through multiple logistic regression controlling for potential confounding variables, including alcohol intake and smoking habits. Consumption of red meat (OR per increasing tertile = 1.14, 95% CI: 1.05-1.25), but not poultry, was significantly associated with increased UADT cancer risk and the association was somewhat stronger for esophageal cancer. Consumption of fruits (OR per increasing tertile = 0.68, 95% CI: 0.62-0.75) and vegetables (OR per increasing tertile = 0.73, 95% CI: 0.66-0.81) as well as of olive oil (OR for above versus below median = 0.78, 95% CI 0.67-0.90) and tea (OR for above versus below median = 0.83, 95% CI 0.69-0.98) were significantly associated with reduced risk of UADT cancer. There was no indication that an increase in tea or coffee temperature was associated with increased risk of UADT overall or cancer of the esophagus; in fact, the association was, if anything, inverse. In conclusion, the results of this large multicentric study indicate that diet plays an important role in the etiology of UADT cancer.

Cigarette smoking is the major risk factor for lung cancer, and together with alcohol for head and neck (H--N) cancer. These genotoxics produced DNA damage and particularly double-strand breaks (DSB) that are removed by various repair pathways. To understand the initiation of these cancers, we performed a genotype analysis to correlate some variants in specific genes in a case-control study of lung and H-N cancers. In a discovery phase, we sequenced DNA samples of 32 healthy Caucasians to describe genetic variants in 30 genes involved in the repair of DSB and in DNA damage response. 625 variants were detected on 29 out of the 30 genes successfully screened by sequencing exons, parts of introns and flanking regions. These included 470 non-exonic variants, from which 33 insertions/deletions, and 155 exonic alterations, corresponding to 59 non synonymous polymorphisms. 223 of these variants were not previously described. In total, 379 variants were successfully genotyped in a case-control study restricted to smokers including 151 lung cases, 251 H-N cases, and 172 controls. To account for multiple testing, we associated to each p-value a proportion of false positives (q-value). Haplotype-analysis suggested potential associations (p < 0.05) between lung cancer and 2 genes (RECQL4 and RAD52), which came with q-value of 8%, and between H-N cancer and 1 gene (DNA-PK) but with q-value of 56%. The 3 genes are key players for regulating the efficiency of DSB repair. Large-scale studies are needed to show if any of these 3 variants are truly associated with an increased risk of cancer., ((c) 2008 Wiley-Liss, Inc.)

Cigarette smoke can generate reactive oxygen species, which are capable of inducing double-strand breaks (DSBs) in DNA. Polymorphisms in XRCC2 and XRCC3 genes, involved in DSBs repair pathways, may alter an individual's susceptibility to smoking-related cancers. We investigated the effect of XRCC2 Arg(188)His and XRCC3 Thr(241)Met polymorphisms in cancer proneness in 121 oral/pharynx cancer cases, 129 larynx cancer cases and 172 noncancer controls, all Caucasian smokers. The XRCC2 His-allele was associated with a significantly increased risk of pharyngeal cancer (OR=2.9, 95% CI: 1.3-6.2). No significant associations were observed between the XRCC3 Thr(241)Met polymorphism and overall risk of developing UADT cancers. However, quite opposite to the expectations, a reduced risk of supraglottic cancer was found for carriers of the XRCC3 Met variant allele (OR=0.3, 95% CI: 0.2-0.7). These findings provide evidence for the view that polymorphisms in DNA repair genes may modify individual susceptibility to smoking-related cancers., ((c) 2004 Wiley-Liss, Inc.)

Polymorphisms in genes that encode for metabolic enzymes have been associated with variations in enzyme activity between individuals. Such variations could be associated with differences in individual exposure to carcinogens that are metabolized by these genes. In this study, we examine the association between polymorphisms in several metabolic genes and the consumption of tobacco in a large sample of healthy individuals. The database of the International Collaborative Study on Genetic Susceptibility to Environmental Carcinogens was used. All the individuals who were controls from the case-control studies included in the data set with information on smoking habits and on genetic polymorphisms were selected (n = 20938). Sufficient information was available on the following genes that are involved in the metabolism of tobacco smoke constituents: CYP1A1, GSTM1, GSTT1, NAT2 and GSTP1. None of the tested genes was clearly associated with smoking behavior. Information on smoking dose, available for a subset of subjects, showed no effect of metabolic gene polymorphisms on the amount of smoking. No association between polymorphisms in the genes studied and tobacco consumption was observed; therefore, no effect of these genes on smoking behavior should be expected., (Copyright 2004 Wiley-Liss, Inc.)

The interpretation of the evidence linking exposure to secondhand smoke with lung cancer is constrained by the imprecision of risk estimates. The objective of the study was to obtain precise and valid estimates of the risk of lung cancer in never smokers following exposure to secondhand smoke, including adjustment for potential confounders and exposure misclassification. Pooled analysis of data from 2 previously reported large case-control studies was used. Subjects included 1263 never smoking lung cancer patients and 2740 population and hospital controls recruited during 1985-1994 from 5 metropolitan areas in the United States, 11 areas in Germany, Italy, Sweden, United Kingdom, France, Spain and Portugal. Odds ratios (ORs) of lung cancer were calculated for ever exposure and duration of exposure to secondhand smoke from spouse, workplace and social sources. The OR for ever exposure to spousal smoking was 1.18 (95% CI = 1.01-1.37) and for long-term exposure was 1.23 (95% CI = 1.01-1.51). After exclusion of proxy interviews, the OR for ever exposure from the workplace was 1.16 (95% CI = 0.99-1.36) and for long-term exposure was 1.27 (95% CI = 1.03-1.57). Similar results were obtained for exposure from social settings and for exposure from combined sources. A dose-response relationship was present with increasing duration of exposure to secondhand smoke for all 3 sources, with an OR of 1.32 (95% CI = 1.10-1.79) for the long-term exposure from all sources. There was no evidence of confounding by employment in high-risk occupations, education or low vegetable intake. Sensitivity analysis for the effects of misclassification (both positive and negative) indicated that the observed risks are likely to underestimate the true risk. Clear dose-response relationships consistent with a causal association were observed between exposure to secondhand smoke from spousal, workplace and social sources and the development of lung cancer among never smokers., (Copyright 2003 Wiley-Liss, Inc.)

CYP1A1 is involved in the metabolism of benzopyrene, a suspected lung carcinogen; it is therefore conceivable that genetically determined variations in its activity modify individual susceptibility to lung cancer. The role of the CYP1A1 MspI polymorphism in lung cancer has been widely studied but has not been fully clarified. We have included 2,451 cases and 3,358 controls in a pooled analysis of 22 case-control studies on CYP1A1 and lung cancer risk. We found a clear association between the CYP1A1 homozygous MspI restriction fragment length polymorphism (RFLP) and lung cancer risk in Caucasians (age- and gender-adjusted odds ratio = 2.36; 95% confidence interval 1.16-4.81); other associations were weaker or not statistically significant. The association with the homozygous variant was equally strong for squamous cell carcinomas and adenocarcinomas among Caucasians. We analyzed the risk by duration of smoking: for Caucasian subjects with the MspI RFLP combined variants (homozygotes plus heterozygotes), the increase in the risk of lung cancer was steeper than among the individuals with the homozygous reference allele. Our analysis suggests that Caucasians with homozygous variant CYP1A1 polymorphism have a higher risk of lung cancer. The data were more consistent among Caucasians, with a strong association between the homozygous variant in both squamous cell carcinomas and adenocarcinomas, and a stronger association in men than in women. The analyses were more inconsistent and failed to reach statistical significance in Asians. This observation might be due to design specificities or unknown effect modifiers in the Asian studies., (Copyright 2003 Wiley-Liss, Inc.)

We present a new statistical model for the analysis of case-control or cohort studies examining a highly polymorphic candidate disease susceptibility gene. Many genotypes are possible for such a gene. Consequently, the average number of subjects having each genotype will be modest. If analyzed separately, the risks associated with most genotypes will be estimated imprecisely. Our Bayesian partition model clusters genotypes according to risk, only allowing partitions that satisfy a particular assumption about the joint effect of the two alleles making up a genotype. This assumption is genetically plausible, imposes structure on the set of genotype risks, and still leaves a highly flexible model. By Bayesian model averaging over partitions, the model becomes, in effect, a semiparametric model for genotype risk. It allows borrowing of strength, i.e., estimates of risk for one genotype are informed by the risk estimates of all the genotypes. We present the results of fitting the model to two datasets, one simulated and one genuine case-control study of the NAT1 gene and lung cancer, and compare it in a simulation study with a haplotype relative risk model. The partition model enables genotype risks to be estimated more accurately and the alleles to be ranked according to risk., (Copyright 2002 Wiley-Liss, Inc.)

Ten case-control studies have been carried out in 6 European countries to investigate the major risk factors for lung cancer. Carcinogenic effect from cigarette smoke was the most relevant interest in our study, which has included 7,609 cases of lung cancer and 10,431 controls, mainly population based. The results indicate elevated odds ratios (ORs; 23.9 among men and 8.7 among women) with attributable risks exceeding 90% for men and close to 60% for women. A large, and statistically significant, variability of the results across countries was detected after adjusting for the most common confounding variables, and after controlling, at least in part, for the instability of the ORs due to the small number of non-smokers in some of the study subsets. This pattern of lung cancer risk associated with cigarettes smoke, across different European regions, reflects inherent characteristics of the studies as well as differences in smoking habits, particularly calendar periods of starting, and it is likely to have been influenced by effect modifiers like indoor radon exposure, occupation, air pollution and dietary habits., (Copyright 2001 Wiley-Liss, Inc.)

The association between cigarette smoking and lung cancer risk in women was investigated within the framework of a case-control study in 9 centres from 6 European countries. Cases were 1,556 women up to 75 years of age with histologically confirmed primary lung cancer; 2, 450 controls with age distribution similar to cases were selected. The predominant cell type was adenocarcinoma (33.5%), with similar proportions for squamous-cell type (26.4%) and small-cell carcinoma (22.3%). Overall, smoking cigarettes at any time was associated with a 5-fold increase in lung cancer risk (odds ratio 5.21, 95% confidence interval 4.49-6.04); corresponding figures for current smoking habits were 8.94, 7.54-10.6. The association showed a dose-response relationship with duration of the habit and daily and cumulative lifetime smoking. A significant excess risk of 70% was associated with every 10 pack-years smoked. After 10 years of smoking cessation, the relative risk decreased to 20% compared to current smokers. The following characteristics were associated with a higher relative risk: inhalation of smoke, smoking non-filter cigarettes, smoking dark-type cigarettes and starting at young age. The association was observed for all major histological types, being the strongest for small-cell type carcinoma, followed by squamous-cell type and the lowest for adenocarcinoma. The proportion of lung-cancer cases in the population attributable to cigarette smoking ranged from 14% to 85%. We concluded that women share most features of the association between cigarette smoking and lung cancer observed in men., (Copyright 2000 Wiley-Liss, Inc.)

Alcohol is a recognized risk factor for upper aerodigestive tract (UAT) cancers, but the mechanism by which alcohol causes cancer remains obscure. Ethanol is oxidized to acetaldehyde (the suspected carcinogenic agent in alcohol) by alcohol dehydrogenases (ADHs) and cytochrome P-4502E1 (CYP2E1), both of which exhibit great inter-individual variability in activity. The hypothesis that these polymorphisms influence susceptibility to alcohol-related cancers remains poorly documented. We investigated whether ADH(3) and CYP2E1 DraI and RsaI genotypes modified the risk of UAT cancers among 121 oral cavity/pharyngeal cancer patients, 129 laryngeal cancer patients, and 172 controls, all French Caucasians. Cancer risks and gene-alcohol interactions were analyzed by unconditional logistic regression, accounting for potential confounders. ADH(3) genotype was not associated with UAT cancer. In contrast, a 2-fold risk of oral cavity/pharyngeal (OR = 2.0, 95% CI 1.0-3.9) and laryngeal (OR = 1.8, 95% CI 1.0-3.5) cancers was observed for carriers of the CYP2E1 DraI C variant allele compared with other individuals. The risk associated with the CYP2E1 RsaI c2 variant allele also increased for oral cavity/pharyngeal cancer (OR = 2.6, 95% CI 1.0-6. 6). The effects of ADH(3) or CYP2E1 genotype and alcohol or tobacco were independent. The highest risk of oral cavity/pharyngeal cancer was observed among the heaviest drinkers (>80 g/day) with the CYP2E1 DraI C allele (OR = 5.8, 95% CI 1.9-18.2) or the CYP2E1 RsaI c2 allele (OR = 7.2, 95% CI 1.4-38.2) compared with lighter drinkers with other genotypes. Our study suggests that CYP2E1 genotype modifies the risk of UAT cancers, but due to the low frequency of CYP2E1 variant alleles, large-scale studies are needed to confirm our findings., (Copyright 2000 Wiley-Liss, Inc.)

We conducted a case-control study of adenocarcinoma of the lung and exposure to environmental tobacco smoke (ETS) in 7 countries. We interviewed 70 cases of adenocarcinoma of the lung and 178 population or hospital controls. All subjects had smoked fewer than 400 cigarettes in their lifetimes. Ever exposure to ETS from the parents during childhood was associated with a decreased risk [odds ratio (OR) 0.6, 95% confidence interval (CI) 0.3-1.2], and there was a suggestion of a decreasing trend in risk with increasing duration of exposure. Ever exposure to ETS from the spouse was not associated with an increased risk (OR 1.0, 95% CI 0.5-1.8), while the OR of ever exposure to ETS at the workplace was 1.5 (95% CI 0.8-3.0). For both exposure sources, an increased risk was observed among the highly exposed, and the OR among those with the highest duration of exposure to ETS from the spouse or at the workplace was 1.8 (95% CI 0.5-6.2). A similar risk was estimated for current exposure to ETS from either source. Our results confirm previous reports of a weak effect of adult ETS exposure on risk of adenocarcinoma of the lung. Bias and confounding cannot be excluded as explanations for the apparent decrease in risk from childhood exposure., (Copyright 1999 Wiley-Liss, Inc.)

Several polymorphic glutathione S-transferase enzymes are involved in the detoxification of active metabolites of many potential carcinogens from tobacco smoke and may therefore be important in modulating susceptibility to smoking-related cancers. As part of a hospital-based case-control study performed in France among Caucasian smokers, we studied GSTM1, GSTM3, GSTP1 and GSTT1 gene polymorphisms in 121 patients with oral cavity and pharyngeal cancers and 172 hospital controls using peripheral blood DNA. An increase in risk was found among carriers of the GSTP1 (AG or GG) genotype (OR 1.6, 95% CI 1.0-2.8, p = 0.07) or the GSTT1 null genotype (OR 2.0, 95% CI 1.0-4.0, p = 0.05). The effect of these at-risk genotypes was most marked in subjects with a history of more than 30 years of smoking, among whom the respective ORs were 2.0 (95% CI 1.0-3.9) and 3.3 (95% CI 1.3-8.1), though the interaction tests between these genotypes and duration of smoking were not significant. In contrast, neither the GSTM1 null genotype nor the GSTM3 AA genotype was associated with oropharyngeal cancer risk (OR 0.9, 95% CI 0.5-1.5 and OR = 1.3, 95% CI 0.7-2.3, respectively). Our results thus suggest that GSTP1 and GSTT1 gene polymorphisms modulate susceptibility to smoking-related cancers of the oral cavity and pharynx.

A hospital-based case-control study of renal-cell carcinoma was conducted in France from 1987 to 1991. A total of 196 histologically confirmed cases (138 males and 58 females) and 347 controls (235 males and 112 females), matched for sex, age at interview, hospital and interviewer, were included. The risk of renal-cell carcinoma was not apparently increased with number of cigarettes per day, duration of smoking or early age at first cigarette smoking in males. No significant trend was found in the risks with increasing Quetelet index (QI) at the age of 20 in males. On the contrary, the risks increased significantly with an increasing QI prior to diagnosis. In females, the trends in risks were significant both for the relative weight at the age of 20 and prior to diagnosis. The consumption of regular or decaffeinated coffee, tea or alcoholic beverages was not associated with renal-cell carcinoma, in males or in females.

A case-control study of 1,529 histologically confirmed male lung cancer cases and 2,899 controls matched for sex, age, hospital of admission and interviewer was conducted in France between 1976 and 1980. The results presented concern the effects of smoking habits, especially cigar and pipe use, on the occurrence of lung cancer, in a total of 38 exclusive cigar smokers, 61 exclusive pipe smokers and 586 mixed tobacco smokers. Exclusive cigar or pipe use (RR = 5.6 and 1.6 respectively) has been shown less harmful than exclusive cigarette smoking (RR = 13.3), mixed cigar and cigarette smoking (RR = 8.5) and mixed pipe and cigarette smoking (RR = 8.0). Different inhalation practices were observed according to smoking habits: while among exclusive cigarette smokers 29.8% never inhaled the smoke, among exclusive cigar and exclusive pipe users these percentages were 89.5% and 86.9 respectively. No significant increase with greater exposure to cigar was found among mixed cigar and cigarette smokers after adjustment for exposure to cigarettes, defined by duration and daily consumption of cigarettes (RR = 1.20), and by type of cigarettes smoked--light or dark, filter or nonfilter (RR = 1.13). Similar results were observed among mixed pipe and cigarette smokers after adjustment for cigarette exposure (RR = 0.95 and 1.04).

A cohort study of 29 nurses who constantly handled cytostatic drugs, and 29 controls matched according to sex and age, was carried out between 1983 and 1986. Cytogenetic damage was assessed by sister chromatid exchanges (SCE) and chromosomal aberrations. No significant increase in mean number of SCE was found for nurses (7.37) as compared to matched controls (7.00), whereas a significant excess of SCE (p less than 0.001) was observed for smokers (8.23) as compared to non-smokers (6.75). The number of SCE was studied in relation to the amount and nature of cytostatics handled as well as to the duration of exposure. A significant association (p less than 0.05) was found between individual mean number of SCE and the total number of drugs handled after adjustment for confounding factors. In contrast, the number of SCE was not significantly related to the nature of drugs handled or to the duration of exposure. With regard to chromosomal damage, no significant difference was observed between nurses and controls in gap, break, dicentric and translocation frequencies.