B.A.C. van Dijk

Vegetable and fruit consumption and risk of renal cell carcinoma: results from the Netherlands cohort study.

Vegetable and fruit consumption is generally inversely associated with various cancer types, including renal cell carcinoma (RCC). The Netherlands cohort study on diet and cancer (NLCS) consists of 120,852 men and women, aged 55–69 years, who filled out a self‐administered questionnaire that includes 150‐item food‐frequency questions and additional questions on lifestyle factors, at baseline in 1986. A case‐cohort approach was used. After 9.3 years of follow‐up, 275 microscopically confirmed incident cases were identified. Subjects with incomplete or inconsistent dietary data were excluded, leaving 260 RCC cases for analyses on fruit consumption and 249 RCC cases for analyses on vegetable consumption. Incidence rate ratios (RR) and corresponding 95% confidence intervals (CI) were estimated using Cox proportional hazard models. RRs for exposure variables are expressed per increment of 25 g/day and are adjusted for age, sex, smoking, body mass index and history of hypertension at baseline. The RRs for vegetable consumption were further adjusted for fruit consumption and vice versa. Total vegetable and fruit consumption (RR: 1.00; 95% CI 0.97–1.02), vegetable (RR: 1.00, 95% CI 0.96–1.06) and fruit consumption (RR: 1.00; 95% CI 0.97–1.03) were not associated with RCC risk. Also, no association existed for botanical subgroups of vegetables and fruit. For 30 individual vegetables and fruits, we observed one that significantly increased RR (mandarin consumption, RR: 1.76; 95% CI 1.28–2.42), which must be regarded cautiously because of multiple testing. These results suggest the absence of an association between vegetable and/or fruit consumption and RCC risk.

Hypertension, antihypertensives and mutations in the Von Hippel-Lindau gene in renal cell carcinoma: Results from the Netherlands Cohort Study

Objectives Hypertension and/or antihypertensive medication are reported to be risk factors of renal cell carcinoma (RCC). We investigated whether these risk factors are associated with von Hippel-Lindau gene (VHL) mutations in RCC. Methods The Netherlands Cohort Study on Diet and Cancer (NLCS) started in 1986 (n = 120 852 men and women) and uses the case–cohort methodology. After 11.3 years of follow-up, 337 RCC cases and 4774 subcohort members were available for analysis. DNA was isolated from paraffin-embedded tumour tissue for VHL analysis. Results Cohort members who reported hypertension or use of antihypertensive medication had a slightly (non-significant) increased risk of RCC: rate ratios (RR) 1.22 [95% confidence interval (CI), 0.94–1.58] and 1.14 (95% CI, 0.85–1.52), respectively. RRs were adjusted for sex, age, body mass index (BMI) and cigarette smoking. Of the 235 patients for whom tumour tissue specimens were collected, 187 had a clear-cell RCC, of whom 114 had a VHL mutation. History of hypertension was associated with a non-significantly increased risk of clear-cell RCC with VHL mutations: RR = 1.34 (95% CI, 0.87–2.07), and was not associated with the risk of clear-cell RCC without VHL mutations; RR = 0.88 (95% CI, 0.51–1.53). Use of diuretics was associated with clear-cell RCC without VHL mutations; RR = 2.11 (95% CI, 1.16–3.83). Conclusions In this study non-significantly increased risks for history of hypertension and use of antihypertensive medication with RCC were observed. The association with hypertension was stronger in RCC patients with VHL mutations, while there was a positive association of diuretics use and risk of RCC without VHL mutations.

Cigarette smoking, von Hippel-Lindau gene mutations and sporadic renal cell carcinoma.

We investigated whether smoking is associated with mutations in the Von Hippel–Lindau (VHL) gene in 337 cases of sporadic renal cell carcinoma (RCC) among 120 852 people followed for 11.3 years; the findings suggest that smoking causes RCC independently of VHL gene mutations.

Alcohol Dehydrogenase Type 3 (ADH3) and the Risk of Bladder Cancer

Objectives: The polymorphic enzyme alcohol dehydrogenase (ADH) catalyses the conversion of ethanol into the carcinogenic metabolite acetaldehyde which is partly excreted into the urine. Objectives of this pilot study are to determine whether this polymorphism may be related to bladder cancer and whether it modifies the relation between alcohol intake and bladder cancer. Methods: 120 bladder cancer patients and 133 convenience controls were recruited at the University Medical Centre Nijmegen. A self–administered questionnaire was used to assess alcohol intake and potential confounders. DNA was isolated from peripheral blood, and ADH3 genotype was determined using PCR/RFLP. People with the ADH3 genotype γ1γ1 were compared to people with other ADH3 genotypes. Above moderate drinkers (>14 glasses of alcohol per week) were compared to moderate drinkers. Odds ratios (ORs) and 95% confidence intervals were computed using logistic regression analyses. Results: After correction for sex, age and smoking, ORs for ADH3 genotype and alcohol intake were 2.10 (1.05–4.22) and 1.21 (0.60–2.44), respectively. Moderate drinkers with the ‘high–risk’ (γ1γ1) ADH3 genotype appeared to have a threefold higher risk of bladder cancer compared to moderate drinkers with a ‘low–risk’ (γ1γ2 or γ2γ2) genotype. Surprisingly, the ORs for above moderate drinkers with the low–risk genotype (1.95; 95% CI: 0.85–4.48) and with the high–risk genotype (2.18; 95% CI: 0.82–5.77) were almost similar, suggesting no interaction. Conclusions: ADH3 genotype is a possible risk factor for bladder cancer. Although moderate drinkers with the γ1γ1 genotype seem to have the highest risk, we did not get a clear indication that ADH3 genotype modifies the relationship between alcohol intake and bladder cancer.

Prostate cancer susceptibility genes on 8P21-23 in a Dutch population

Background:Prostate cancer is the most commonly diagnosed cancer in men in Europe and the United States. Numerous studies have indicated genetics to have a major role in the aetiology of this disease; as much as 42% of the risk may be explained by heritable factors. Genome-wide association studies have detected an association between prostate cancer and chromosome 8p21–23. In this study, we analysed eight microsatellite (MS) markers in that region in order to confirm previous results and narrow down the location of candidate prostate cancer genes.Methods:292 cases and 278 controls were selected from the Netherlands Cohort Study (NLCS). The following MSs were used in the analyses: D8S136, D8S1734, D8S1742, D8S261, D8S262, D8S351, D8S511 and D8S520. Associations were evaluated using a χ2 test and logistic regression. We checked for any effects on the association by tumour stage.Results:Associations that were found confirmed previous research that pointed to the 8p21–23 region. Two MSs: D8S136 (odds ratio (OR), 0.69; P=4.00 × 10−28), and D8S520 (OR, 0.80; P=3.37 × 10−11), were consistently and strongly related with prostate cancer. Genotype analysis showed an additive effect for D8S136 (P-trend=6.22 × 10−03) and D8S520 (P-trend=2.62 × 10−22), suggesting an increased risk for people with a short number of repeats on both alleles at those markers.Conclusions:This study provides strong evidence that the 8p21–23 region is likely to harbour prostate cancer genes.

Alcohol Consumption and Mutations or Promoter Hypermethylation of the von Hippel–Lindau Gene in Renal Cell Carcinoma

Alcohol consumption has been associated with a decreased risk for renal cell cancer in several studies. We investigated whether alcohol is associated with (epi)genetic changes of the von Hippel–Lindau (VHL) gene in renal cell cancer. The Netherlands Cohort Study (NLCS) on Diet and Cancer started in 1986 (n = 120,852) and uses the case-cohort method. After 11.3 years of follow-up, 314 renal cell cancer cases and 4,511 subcohort members were available for analysis. DNA was isolated from paraffin-embedded tumor tissue from 235 cases. VHL mutations were analyzed by sequencing, whereas VHL promoter methylation was analyzed using methylation-specific PCR. In multivariate analysis, hazard ratios of renal cell cancer for cohort members who consumed up to 5, 15, 30, and ≥30 g of alcohol per day were 0.72, 0.64, 0.81, and 0.69, respectively, compared with nondrinkers [95% confidence interval (95% CI) for the ≥30 category, 0.44-1.07; P for trend, 0.17]. Alcohol intake from beer, wine, and liquor was associated with decreased risks for renal cell cancer, although not statistically significant. Hazard ratios were not different for clear-cell renal cell cancer with and without VHL mutations, except for alcohol from beer, which was associated with an increased risk for clear-cell renal cell cancer without VHL mutations (hazard ratio for ≥5 g of alcohol from beer compared with nondrinkers, 2.74; 95% CI, 1.35-5.57). Alcohol was associated with a decreased risk for clear-cell renal cell cancer without VHL gene promoter methylation (hazard ratio for >15 g compared with nondrinkers, 0.58; 95% CI, 0.34-0.99). In this study, a not statistically significant inverse association was observed between alcohol and renal cell cancer. There was no statistical significant heterogeneity by VHL mutation or methylation status. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3543–50)