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Objective: Manganese superoxide dismutase (MnSOD) is a mitochondrial enzyme that plays a key role in protecting the cell from oxidative damage. A polymorphism in the mitochondrial targeting sequence (a valine to alanine substitution), thought to alter transport of the enzyme into mitochondria, has been associated with increased risk for breast cancer with a more pronounced association among women with low intake of dietary antioxidants. We examined the role of MnSOD in the development of prostate cancer in a large, randomized cancer prevention trial of male smokers, the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. We hypothesized that MnSOD may be associated with prostate cancer and that long-term antioxidant supplementation (α-tocopherol 50 mg/day for five to eight years) could modify the effect on risk. Methods: Logistic regression was used to estimate these associations among 197 cases and 190 controls genotyped and matched for age, intervention group, and clinic. Results: Men homozygous for the MnSOD ala allele had a 70% increase in risk over men homozygous for the val allele (odds ratio, OR = 1.72, 95% confidence interval, CI = 0.96–3.08, p = 0.07). Supplementation with α-tocopherol had no impact on the MnSOD–prostate cancer association. Although there was no difference in the association with disease stage, men homozygous for MnSOD ala (compared to MnSOD val/val or val/ala) showed a three-fold risk increase for high-grade tumors (OR = 2.72, 95% CI: 1.15–6.40, p = 0.02). Conclusion: These data suggest an effect of the MnSOD ala/ala genotype on the development of prostate cancer. Our observation of a stronger association with high-grade tumors may have prognostic implications that should also be pursued.

Background: The objective of this investigation was to evaluate the association between toenail selenium concentration and lung cancer risk in male smokers. Methods: We conducted a nested case–control study within the Alpha–Tocopherol Beta–Carotene Cancer Prevention Study cohort. This substudy included 250 randomly selected incident lung cancer cases and 250 controls matched on age (up to ± 5 years), intervention group assignment, and date or randomization (±15 days). Odds ratios (ORs) and 95% confidence intervals (CIs) were determined using conditional logistic regression methods. Finland began fortification of argricultural fertilizers in the fall of 1984, increasing the dietary intake, plasma, and toenail selenium concentrations for the population. The present analyses were based on the calculated residual of toenail selenium after regressing it on date of randomization. The selenium residual and the interaction of the residual with date of randomization were included in models with smoking status and body mass index as covariates. Results: We observed a suggestion of a protective association for higher selenium status among men who entered the trial early (when the range of selenium values included very low levels). The OR for men with adjusted toenail selenium concentrations at the 75th percentile compared to those with the lowest selenium concentrations ranged between 0.20 (0.09–0.44) for men randomized earliest in the trail and 0.61 (0.27–1.41) for men randomized in the fifth year. Conclusions: These results suggest that low selenium status may be associated with increased risk for lung cancer.

Objectives: This study investigated the effects of alpha-tocopherol and beta-carotene supplementation on the incidence of gastric cancer. Methods: A total of 29,133 male smokers, aged 50–69 years, participated in a placebo-controlled prevention trial, the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study in southwestern Finland between 1985 and 1993. The men were randomly assigned to receive alpha-tocopherol (50 mg/day) or beta-carotene (20 mg/day) supplementation in a 2 × 2 factorial design. We identified 126 gastric cancer cases during the median follow-up of six years. Of these, 122 were adenocarcinomas: 75 of intestinal type, 30 of diffuse type, and 17 of mixed type. Results: There was no significant effect for either supplementation on the overall incidence of gastric cancer: relative risk (RR) 1.21, 95% confidence interval (CI) 0.85–1.74 for alpha-tocopherol, and RR 1.26, 95% CI 0.88–1.80 for beta-carotene. Subgroup analyses by histologic type suggested an increased risk for beta-carotene on intestinal type cancers, RR 1.59, 95% CI 0.99–2.56. There were no differences across anatomic locations (cardia/noncardia) in the effects of alpha-tocopherol or beta-carotene supplementation. Conclusions: Our study found no overall preventive effect of long-term supplementation with alpha-tocopherol or beta-carotene on gastric cancer in middle-aged male smokers.

Objective: To examine the association between several medical conditions, anthropometric measurements, occupational and leisure physical activity, and pancreatic cancer in a cohort of male Finnish smokers. Methods: We performed a cohort analysis of the 172 subjects who developed pancreatic cancer between 1985 and 1997 (median 10.2 years follow-up) among the 29,048 male smokers, 50–69 years old, who had complete baseline data and participated in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. Cox proportional hazards models were used to estimate multivariable adjusted hazard ratios (HR) and 95% confidence intervals (CI). Results: We observed positive associations between pancreatic cancer risk and self-reported history of diabetes mellitus (HR = 2.02, 95% CI 1.17–3.50) and bronchial asthma (HR = 2.16, 95% CI 1.17–3.98). Men having combined occupational and leisure activity greater than at sedentary levels had reduced risk for the cancer; for example those with moderate/heavy activity in both settings showed a HR of 0.42 (95% CI 0.22–0.83). There were no significant associations with other self-reported illnesses, total or HDL (high-density lipoprotein) cholesterol, height, weight, or body mass index. Conclusions: Our data suggest that diabetes mellitus and bronchial asthma predict the subsequent risk of developing pancreatic cancer in male smokers, and that greater physical activity may reduce the risk.

Objective: To study the associations between the intake of flavonols and flavones and the risk of cancer.

Objectives: Epidemiological studies have suggested a protective effect of vegetables and fruits on urinary tract cancer but the possible protective nutrients are unknown. We studied the effect of alpha-tocopherol (a form of vitamin E) and beta-carotene supplementation on urinary tract cancer in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. Methods: A total of 29,133 male smokers aged 50–69 years from southwestern Finland were randomly assigned to receive alpha-tocopherol (50 mg), beta-carotene (20 mg), both agents, or a placebo daily for 5–8 years (median 6.1 years). Incident urothelial cancers (bladder, ureter, and renal pelvis; n = 169) and renal cell cancers (n = 102) were identified through the nationwide cancer registry. The diagnoses were centrally confirmed by review of medical records and pathology specimens. The supplementation effects were estimated using a proportional hazards model. Results: Neither alpha-tocopherol nor beta-carotene affected the incidence of urothelial cancer, relative risk 1.1 (95% confidence interval (CI) 0.8–1.5) and 1.0 (95% CI 0.7–1.3), respectively, or the incidence of renal cell cancer, relative risk 1.1 (95% CI 0.7–1.6) and 0.8 (95% CI 0.6–1.3), respectively. Conclusion: Long-term supplementation with alpha-tocopherol and beta-carotene has no preventive effect on urinary tract cancers in middle-aged male smokers.

Background:Calcium, phosphorus, fructose, and animal protein are hypothesized to be associated with prostate cancer risk, potentially via their influence on 1,25-dihydroxyvitamin D3. We examined these nutrients and overall diet and prostate cancer risk in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study (ATBC Study). Materials and methods:The ATBC Study was a randomized 2 × 2 trial of alpha-tocopherol and beta-carotene on lung cancer incidence conducted among Finnish male smokers; 27,062 of the men completed a food-use questionnaire at baseline, and comprise the current study population. There were 184 incident clinical (stage 2–4) prostate cancer cases diagnosed between 1985 and 1993. We used Cox proportional hazards models to examine associations between dietary intakes and prostate cancer. Results:We did not observe significant independent associations for calcium and phosphorus and prostate cancer risk. However, men with lower calcium and higher phosphorus intake had a multivariate relative risk of 0.6 (95% CI 0.3–1.0) compared to men with lower intakes of both nutrients, adjusting for age, smoking, body mass index, total energy, education, and supplementation group. Of the other foods and nutrients examined, none was significantly associated with risk. Discussion:This study provides, at best, only weak evidence for the hypothesis that calcium and phosphorus are independently associated with prostate cancer risk, but suggests that there may be an interaction between these nutrients.

Objectives: We evaluated the association between alcohol intake and lung cancer in a trial-based cohort in Finland, the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC Study). Methods: During an average of 7.7 years of follow-up, 1059 lung cancer cases were diagnosed among the 27,111 male smokers with complete alcohol and dietary information. The relationship between alcohol and lung cancer was assessed in multivariate Cox regression models that adjusted for age, smoking, body mass index and intervention group. Results: Nondrinkers, 11% of the study population, were at increased lung cancer risk compared to drinkers (RR = 1.2, 95% CI: 1.0–1.4), possibly due to the inclusion of ex-drinkers who had stopped drinking for health reasons. Among drinkers only, we observed no association between lung cancer and total ethanol or specific beverage (beer, wine, spirits) intake. We found no significant effect modification by level of smoking, dietary micronutrients or trial intervention group; however, for men in the highest quartile of alcohol intake, we observed a slight increase in risk for lighter smokers (>1 pack/day) and reduced risk among the heaviest smokers (

Objectives: Based on previous epidemiological studies, high fat and meat consumption may increase and fiber, calcium, and vegetable consumption may decrease the risk of colorectal cancer. We sought to address these hypotheses in a male Finnish cohort.

The association between physical activity and prostate cancer was evaluated in the trial-based cohort of the Alpha-Tocopherol, Beta-Carotene (ATBC) Cancer Prevention Study (n = 29,133). During up to nine years of follow-up, 317 men developed incident prostate cancer. The relationship between occupational, leisure, and combined activity and prostate cancer was assessed in multivariate Cox regression models that adjusted for intervention group, benign prostatic hyperplasia, age, smoking, and urban residence. Compared with sedentary workers, relative risks (RR) and 95 percent confidence intervals (CI) for occupational walkers, walker/lifters, and heavy laborers were 0.6 (CI = 0.4-1.0), 0.8 (CI = 0.5-1.3), and 1.2 (CI = 0.7-2.0), respectively. Among working men, leisure activity (active cf sedentary) was associated inversely with risk (RR = 0.7, CI = 0.5-0.9). This inverse association for leisure activity was observed, with the exception of heavy laborers, for all occupational activity levels, and was strongest among walkers compared with men sedentary at work and leisure, and to a lesser degree among walker/lifters. These results are consistent with a protective effect of physical activity on prostate cancer.

Experimental and human epidemiologic data suggest a protective role for vitamin D in large bowel cancer. To investigate this association, we conducted a nested case-control study within a Finnish clinical trial cohort. Cases (n = 146) were participants diagnosed with primary adenocarcinoma of the large bowel. Controls were matched (2:1) to cases on age, date of baseline blood draw, and study clinic. Prediagnostic serum levels of the vitamin D metabolites, 25-hydroxyvitamin D (25-OH D), and 1,25-dihydroxyvitamin D (1,25-DIOH D) were used as primary exposure measures. The baseline geometric-mean serum level of 25-OH D was 11.6 percent lower in cases than in controls (12.2 cf 13.8 ug/l, P = 0.01) while serum levels of 1,25-DIOH D did not differ by case-control status. No association was seen between serum levels of 1,25-DIOH D and large bowel cancer risk. However, the estimated relative risk (RR) of large bowel cancer decreased with increasing level of serum 25-OH D and the association was more pronounced for rectal cancer (55 cases; RR by quartile = 1.00, 0.93, 0.77, 0.37; trend P = 0.06). Neither exclusion of early cases nor multivariate adjustment for potential confounders materially altered these estimates. There was no evidence of effect modification by level of 1,25-dihydroxyvitamin D or with other known risk-factors for large bowel cancer.