Description: Red meat intake has been linked to increased colorectal cancer (CRC) risk. Although the underlying mechanisms remain unclear, experimental studies suggest a role for dietary heme iron. Because heme iron was shown to promote specific mutations, it would be insightful to link heme iron data to CRC with mutations in key genes in an observational, population-based study. We investigated the association between dietary heme iron intake and risk of CRC with mutations in APC (adenomatous polyposis coli) and KRAS (Kirsten ras) and P53 overexpression in the Netherlands Cohort Study. After 7.3 years of follow-up, excluding the first 2.3 years due to incomplete coverage of the pathology registry and to avoid preclinical disease, adjusted hazard ratios (including adjustment for total meat) and 95% confidence intervals were calculated, using 4026 subcohort members (aged 55–69 years at baseline), 435 colon and 140 rectal cancer patients. When comparing the highest with the lowest tertile of intake, heme iron intake was associated with an increased risk of CRC harboring activating mutations in KRAS (hazard ratio = 1.71, 95% confidence interval: 1.15–2.57; P for trend = 0.03) and CRC without truncating mutations in APC (hazard ratio = 1.79, 95% confidence interval: 1.23–2.60; P for trend = 0.003). We observed a positive association between heme iron intake and the risk of CRC with activating G〉A mutations in KRAS ( P for trend = 0.01) and overall G〉A mutations in APC ( P for trend = 0.005). No associations were found with CRC harboring G〉T mutations in KRAS/APC . Heme iron intake was positively associated with the risk of P53 overexpressed tumors but not with tumors without P53 overexpression (Pheterogeneity = 0.12). Heme iron intake was associated with an increased risk of colorectal tumors harboring G〉A transitions in KRAS and APC and overexpression of P53. These novel findings suggest that alkylating rather than oxidative DNA-damaging mechanisms are involved in heme-induced colorectal carcinogenesis.

Description: Lower selenium levels have been associated with increased risk of prostate cancer (PCa), and genetic variation in the selenoprotein genes selenoprotein P ( SEPP1 ) and glutathione peroxidase 1 ( GPX1 ) is thought to modify this relationship. We investigated whether the association between toenail selenium levels and advanced PCa risk in the prospective Netherlands Cohort Study is modified by common genetic variation in SEPP1 and GPX1 . Toenail clippings were used to determine selenium levels and to isolate DNA for genotyping. This case–cohort study, which included 817 case subjects with advanced PCa and 1048 subcohort members, was analyzed with Cox regression models. All statistical tests were two-sided. Three genetic variants were associated with advanced (stage III/IV or IV) PCa risk: SEPP1 rs7579 (lower risk; P trend = .01), GPX1 rs17650792 (higher risk; P trend = .03), and GPX1 rs1800668 (lower risk; P trend = .005). Toenail selenium levels were inversely associated with advanced PCa risk, independently of common genetic variation in SEPP1 and GPX1 .

Description: Background The etiology of male breast cancer is poorly understood, partly because of its relative rarity. Although genetic factors are involved, less is known regarding the role of anthropometric and hormonally related risk factors. Methods In the Male Breast Cancer Pooling Project, a consortium of 11 case–control and 10 cohort investigations involving 2405 case patients (n = 1190 from case–control and n = 1215 from cohort studies) and 52013 control subjects, individual participant data were harmonized and pooled. Unconditional logistic regression generated study design–specific (case–control/cohort) odds ratios (ORs) and 95% confidence intervals (CIs), with exposure estimates combined using fixed effects meta-analysis. All statistical tests were two-sided. Results Risk was statistically significantly associated with weight (highest/lowest tertile: OR = 1.36; 95% CI = 1.18 to 1.57), height (OR = 1.18; 95% CI = 1.01 to 1.38), and body mass index (BMI; OR = 1.30; 95% CI = 1.12 to 1.51), with evidence that recent rather than distant BMI was the strongest predictor. Klinefelter syndrome (OR = 24.7; 95% CI = 8.94 to 68.4) and gynecomastia (OR = 9.78; 95% CI = 7.52 to 12.7) were also statistically significantly associated with risk, relations that were independent of BMI. Diabetes also emerged as an independent risk factor (OR = 1.19; 95% CI = 1.04 to 1.37). There were also suggestive relations with cryptorchidism (OR = 2.18; 95% CI = 0.96 to 4.94) and orchitis (OR = 1.43; 95% CI = 1.02 to 1.99). Although age at onset of puberty and histories of infertility were unrelated to risk, never having had children was statistically significantly related (OR = 1.29; 95% CI = 1.01 to 1.66). Among individuals diagnosed at older ages, a history of fractures was statistically significantly related (OR = 1.41; 95% CI = 1.07 to 1.86). Conclusions Consistent findings across case–control and cohort investigations, complemented by pooled analyses, indicated important roles for anthropometric and hormonal risk factors in the etiology of male breast cancer. Further investigation should focus on potential roles of endogenous hormones.

Description: Background: Breast cancer aetiology may differ by estrogen receptor (ER) status. Associations of alcohol and folate intakes with risk of breast cancer defined by ER status were examined in pooled analyses of the primary data from 20 cohorts. Methods: During a maximum of 6–18 years of follow-up of 1 089 273 women, 21 624 ER+ and 5113 ER– breast cancers were identified. Study-specific multivariable relative risks (RRs) were calculated using Cox proportional hazards regression models and then combined using a random-effects model. Results: Alcohol consumption was positively associated with risk of ER+ and ER– breast cancer. The pooled multivariable RRs (95% confidence intervals) comparing ≥ 30 g/d with 0 g/day of alcohol consumption were 1.35 (1.23-1.48) for ER+ and 1.28 (1.10-1.49) for ER– breast cancer ( P trend ≤ 0.001; P common-effects by ER status: 0.57). Associations were similar for alcohol intake from beer, wine and liquor. The associations with alcohol intake did not vary significantly by total (from foods and supplements) folate intake ( P interaction ≥ 0.26). Dietary (from foods only) and total folate intakes were not associated with risk of overall, ER+ and ER– breast cancer; pooled multivariable RRs ranged from 0.98 to 1.02 comparing extreme quintiles. Following-up US studies through only the period before mandatory folic acid fortification did not change the results. The alcohol and folate associations did not vary by tumour subtypes defined by progesterone receptor status. Conclusions: Alcohol consumption was positively associated with risk of both ER+ and ER– breast cancer, even among women with high folate intake. Folate intake was not associated with breast cancer risk.

Description: Background: Some observational studies suggest that a higher selenium status is associated with a lower risk of prostate cancer but have been generally too small to provide precise estimates of associations, particularly by disease stage and grade. Methods: Collaborating investigators from 15 prospective studies provided individual-participant records (from predominantly men of white European ancestry) on blood or toenail selenium concentrations and prostate cancer risk. Odds ratios of prostate cancer by selenium concentration were estimated using multivariable-adjusted conditional logistic regression. All statistical tests were two-sided. Results: Blood selenium was not associated with the risk of total prostate cancer (multivariable-adjusted odds ratio [OR] per 80 percentile increase = 1.01, 95% confidence interval [CI] = 0.83 to 1.23, based on 4527 case patients and 6021 control subjects). However, there was heterogeneity by disease aggressiveness (ie, advanced stage and/or prostate cancer death, P heterogeneity = .01), with high blood selenium associated with a lower risk of aggressive disease (OR = 0.43, 95% CI = 0.21 to 0.87) but not with nonaggressive disease. Nail selenium was inversely associated with total prostate cancer (OR = 0.29, 95% CI = 0.22 to 0.40, P trend 〈 .001, based on 1970 case patients and 2086 control subjects), including both nonaggressive (OR = 0.33, 95% CI = 0.22 to 0.50) and aggressive disease (OR = 0.18, 95% CI = 0.11 to 0.31, P heterogeneity = .08). Conclusions: Nail, but not blood, selenium concentration is inversely associated with risk of total prostate cancer, possibly because nails are a more reliable marker of long-term selenium exposure. Both blood and nail selenium concentrations are associated with a reduced risk of aggressive disease, which warrants further investigation.

Description: Background : Nut intake has been associated with lower mortality, but few studies have investigated causes of death other than cardiovascular disease, and dose-response relationships remain unclear. Methods : We investigated the relationship of nut (tree nut, peanut) and peanut butter intake with overall and cause-specific mortality. In the Netherlands Cohort Study, 120 852 men and women aged 55–69 years provided information on dietary and lifestyle habits in 1986. Mortality follow-up until 1996 consisted of linkage to Statistics Netherlands. Multivariate case-cohort analyses were based on 8823 deaths and 3202 subcohort members with complete data on nuts and potential confounders. We also conducted meta-analyses of our results with those published from other cohort studies. Results : Total nut intake was related to lower overall and cause-specific mortality (cancer, diabetes, cardiovascular, respiratory, neurodegenerative diseases, other causes) in men and women. When comparing those consuming 0.1–〈5, 5–〈10 and 10+ g nuts/day with non-consumers, multivariable hazard ratios for total mortality were 0.88, 0.74 and 0.77 [95% confidence interval (CI), 0.66–0.89], respectively ( P trend = 0.003). Cause-specific hazard ratios comparing 10+ vs 0 g/day varied from 0.56 for neurodegenerative to 0.83 for cardiovascular disease mortality. Restricted cubic splines showed nonlinear dose-response relationships with mortality. Peanuts and tree nuts were inversely related to mortality, whereas peanut butter was not. In meta-analyses, summary hazard ratios for highest vs lowest nut consumption were 0.85 for cancer, and 0.71 for respiratory mortality. Conclusions : Nut intake was related to lower overall and cause-specific mortality, with evidence for nonlinear dose-response relationships. Peanut butter was not related to mortality.

Description: Purpose: In this era of molecular diagnostics, prediction of clear-cell renal cell cancer (ccRCC) survival requires optimization, as current prognostic markers fail to determine individual patient outcome. Epigenetic events are promising molecular markers. Promoter CpG island methylation of cysteine dioxygenase type 1 ( CDO1 ), which was identified as prognostic marker for breast cancer, is studied as a potential marker for ccRCC survival. Experimental Design: We collected primary tissues of 365 ccRCC cases identified within the prospective Netherlands Cohort Study (NLCS). In this population-based series, CDO1 promoter methylation was observed in 124 of 324 (38.3%) patients with successful methylation-specific PCR analysis. Kaplan–Meier curves and Wilcoxon tests were used to evaluate 10-year ccRCC-specific survival. Cox regression analysis was used to obtain crude and multivariate HRs and 95% confidence intervals (CI). The relative prognostic value of multivariate models with and without CDO1 promoter methylation was compared using likelihood-ratio tests. Results: Patients with CDO1 promoter methylation have a significantly poorer survival than those without (Wilcoxon P = 0.006). Differences in survival were independent of other prognostic factors, including age and sex (HR, 1.66; 95% CI, 1.12–2.45) and TNM stage, tumor size, and Fuhrman grade (HR, 1.89; 95% CI, 1.25–2.85). Multivariate models performed better with than without CDO1 promoter methylation status (likelihood-ratio P = 0.003). Survival curves were validated in an independent series of 280 ccRCC cases from The Cancer Genome Atlas (TCGA; Wilcoxon P 〈 0.001). Conclusions: CDO1 promoter methylation may not substitute common prognostic makers to predict ccRCC survival, but offers additional, relevant prognostic information, indicating that it might be a novel molecular marker to determine ccRCC prognosis. Clin Cancer Res; 21(15); 3492–500. ©2015 AACR .

Description: Objective To prospectively study suspected occupational risk factors for amyotrophic lateral sclerosis (ALS). Methods For this case–cohort analysis within the prospective Netherlands Cohort Study, 58 279 men and 62 573 women aged 55–69 years at enrolment in 1986 were followed up for 17.3 years on ALS mortality. Information on occupational history and potential confounders were collected at baseline through a self-administered questionnaire and entered for a random subcohort (2092 men and 2074 women) and ALS deaths (76 men and 60 women). Occupational exposure to solvents, pesticides, metals, extremely low frequency magnetic fields (ELF-MFs) and electrical shocks was estimated by means of job exposure matrices (JEMs). Associations between ever/never occupationally exposed and cumulative exposure and ALS mortality were analysed by gender using Cox regression. Results Occupational exposure to ELF-MF showed a possible association with ALS mortality among men: HR for ever holding a job with high exposure versus background 2.19 (95% (CI): 1.02 to 4.73) and HR for the highest tertile of cumulative exposure versus background 1.93 (95% CI 1.05 to 3.55). Interpretation These results strengthen the evidence suggesting a positive association between ELF-MF exposure and ALS. We did not replicate earlier positive findings for other occupational exposures.

Description: Objectives Reliable retrospective exposure assessment continues to be a challenge in most population-based studies. Several methodologies exist for estimating exposures retrospectively, of which case-by-case expert assessment and job-exposure matrices (JEMs) are commonly used. This study evaluated the reliability of exposure estimates for selected carcinogens obtained through three JEMs by comparing the estimates with case-by-case expert assessment within the Netherlands Cohort Study (NLCS). Methods The NLCS includes 58 279 men aged 55–69 years at enrolment in 1986. For a subcohort of these men (n=1630), expert assessment is available for exposure to asbestos, polycyclic aromatic hydrocarbons (PAHs) and welding fumes. Reliability of the different JEMs (DOMJEM (asbestos, PAHs), FINJEM (asbestos, PAHs and welding fumes) and Asbestos JEM (asbestos) was determined by assessing the agreement between these JEMs and the expert assessment. Results Expert assessment revealed the lowest prevalence of exposure for all three exposures (asbestos 9.3%; PAHs 5.3%; welding fumes 11.7%). The DOMJEM showed the highest level of agreement with the expert assessment for asbestos and PAHs (s=0.29 and 0.42, respectively), closely followed by the FINJEM. For welding fumes, concordance between the expert assessment and FINJEM was high (=0.70). The Asbestos JEM showed poor agreement with the expert asbestos assessment (=0.10). Conclusions This study shows case-by-case expert assessment to result in the lowest prevalence of occupational exposure in the NLCS. Furthermore, the DOMJEM and FINJEM proved to be rather similar in agreement when compared with the expert assessment. The Asbestos JEM appeared to be less appropriate for use in the NLCS.