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Background The mTOR-PI3K-Akt pathway influences cell metabolism and (malignant) cell growth. We generated sex-specific polygenic risk scores capturing natural variation in 7 out of 10 top-ranked genes in this pathway. We studied the scores directly and in interaction with energy balance-related factors (body mass index (BMI), trouser/skirt size, height, physical activity, and early life energy restriction) in relation to colorectal cancer (CRC) risk in the Netherlands Cohort Study (NLCS) (n=120,852). The NLCS has a case-cohort design and 20.3 years of follow-up. Participants completed a baseline questionnaire on diet and cancer in 1986 when 55–69 years old. ~75% of the cohort returned toenail clippings used for DNA isolation and genotyping (n subcohort=3,793, n cases=3,464). To generate the scores, the dataset was split in two and risk alleles were defined and weighted based on sex-specific associations with CRC risk in the other dataset half, because there were no SNPs in the top-ranked genes associated with CRC risk in previous genome-wide association studies at a significance level p−5. Results Cox regression analyses showed positive associations between the sex-specific polygenic risk scores and colon but not rectal cancer risk in men and women, with hazard ratios for continuously modeled scores close to 1.10. There was no modifying effect observed of the scores on associations between the energy balance-related factors and CRC risk. However, BMI (in men), non-occupational physical activity (in women), and height (in men and women) were associated with the risk of CRC, in particular (proximal and distal) colon cancer, in the direction as expected in the lower tertiles of the sex-specific polygenic risk scores. Conclusions Current data suggest that the mTOR-PI3K-Akt pathway may be involved in colon cancer development. This study thereby sheds more light on colon cancer etiology through use of genetic variation in the mTOR-PI3K-Akt pathway.

There is limited prospective data on the relationship between consumption of vegetables and fruits and the risk of head-neck cancer (HNC) subtypes [i.e., oral cavity cancer (OCC), oro-/hypopharyngeal cancer (OHPC) and laryngeal cancer (LC)]. Therefore, we investigated these associations within the Netherlands Cohort Study, in which 120,852 participants completed a 150-item food frequency questionnaire at baseline in 1986. After 20.3 years of follow-up, 415 cases of HNC (131 OCC, 88 OHPC, three oral cavity/pharynx unspecified or overlapping and 193 LC) and 3,898 subcohort members were available for case-cohort analysis using Cox proportional hazards models. Total vegetable and fruit consumption was inversely associated with risk of HNC overall [multivariable-adjusted rate ratios for highest vs. lowest quartile: 0.61, 95% confidence interval (CI) 0.44-0.85, p trend 0.002] and all HNC subtypes, with the strongest associations for OCC. Total vegetable intake and total fruit intake were also associated with a decreased risk of HNC overall and HNC subtypes. No significant interaction was found between vegetable and fruit intake and alcohol consumption or cigarette smoking. In conclusion, in this large-scale cohort study, consumption of vegetables and fruits was associated with a decreased risk of HNC overall and all subtypes. Consumption of vegetables and fruits (or of specific groups of them) may protect against HNC and its subtypes. What's new? A diet rich in vegetables and fruits may decrease the risk of head and neck cancer (HNC) and HNC subtypes (oral cavity, oro-/hypopharyngeal and laryngeal cancer). However, prospective data are limited and the existing evidence has been largely based on case-control studies. In this large cohort study, the authors found that increased consumption of vegetables and fruits was indeed associated with a decreased risk of HNC overall and HNC subtypes. These results thus support the hypothesis that consumption of vegetables and fruits protects against HNC.

Acrylamide is a probable human carcinogen that was detected in several heat-treated foods, such as French fries and crisps, in 2002. Prospective studies are needed or) acrylamide and human cancer risk. We prospectively investigated the association between acrylamide and gastrointestinal cancer risk. In 1986, 120,852 men and women (aged 55-69 y) were included in the Netherlands Cohort Study on diet and cancer. At baseline, a random subcohort of 5000 participants was selected for a case-cohort approach. Acrylamide intake was assessed with a FFO at baseline and was based on acrylamide analyses in relevant Dutch foods. After 13.3 y of follow-up, 2190, 563, 349, and 216 cases of colorectal, gastric, pancreatic, and esophageal cancer, respectively, were available for analysis. The daily acrylamide intake of the subcohort was (mean +/- SD) 21.7 +/- 12.1 mu g. A 10-mu g/d increment of acrylamide intake was associated with multivariable-adjusted Cox proportional hazard rate ratios (HR) (95% Cl) of 1.00 (0.96-1.06), 1.02 (0.94-1.10), 1.06 (0.96-1.17), and 0.96 (0.85-1.09) for colorectal, gastric, pancreatic, and esophageal cancer, respectively. For former or never-smokers, the corresponding HR were 1.03 (0.94-1.12), 1.09 (0.98-1.22), 1.07 (0.93-1.24), and 0.92 (076-1.11). There were son-re significantly increased risks within subgroups stratified by obesity, nonoccupational physical activity, and age, factors that were a priori selected based on their capacity to modify cytochrome P4502E1 activity. Overall, acrylamide intake was not associated with colorectal, gastric, pancreatic, and esophageal cancer risk, but some subgroups deserve further attention. J. Nutr. 138: 2229-2236, 2008.

Objectives: The roles of retinol, vitamins C and E, and carotenoids as risk factors for prostate carcinoma are still questionable. We evaluated these in the Netherlands Cohort Study. Methods: The cohort study consisted of 58,279 men ages 55-69 years at baseline in 1986. After 6.3 years of follow-up, 642 incident prostate carcinoma cases were available for analysis. Intakes of retinol, vitamins C and E, and several carotenoids were measured by means of a 150-item semi-quantitative food-frequency questionnaire. Results: In multivariate analyses a positive association with prostate cancer risk was observed for intake of β-cryptoxanthin. Rate ratios (RRs) in increasing quintiles were 1.00 (ref), 0.94, 1.01, 1.16, 1.41; p-trend

The association between the consumption of onions and leeks (vegetables belonging to the Allium genus), garlic supplements, and the risk of lung carcinoma was investigated in a large-scale prospective cohort study on diet and cancer in the Netherlands. The Netherlands Cohort Study was started in 1986 among 120,852 men and women, ages 55-69 years, by collecting information on usual diet and important life-style characteristics. After 3.3 years of follow-up, 550 incident lung carcinoma cases were observed. Information on Allium vegetable consumption was available for 484 lung carcinoma cases and 3123 members of a randomly sampled subcohort. In stratified analysis, a lower lung carcinoma risk was observed in the highest onion intake category [rate ratio (RR) = 0.65; 95% confidence interval, 0.45-0.95] compared to the lowest consumption category. After including other, dietary and nondietary, determinants of lung carcinoma in the multivariable models and using pack years for past and current smoking, instead of using smoking status categorized as never, ex-, and current smoking, the rate ratio in the highest intake category increased to 0.80 and was no longer significantly different from unity (95% confidence interval, 0.52-1.24). Leek consumption was not associated with risk for lung carcinoma (RR = 1.08; 95% confidence interval 0.80-1.45 in the highest intake category, compared to the lowest). No statistically significant trends in the rate ratios associated with increasing consumption of these vegetables were detected for lung carcinoma or the four histological subtypes. A higher lung carcinoma risk was observed for those subjects who used exclusively garlic supplements (RR = 1.78; 95% confidence interval, 1.08-2.92), compared to those not taking dietary supplements. A lower lung carcinoma risk was seen for those using garlic supplements together with any other supplement (RR = 0.93; 95% confidence interval 0.46-1.86) compared to those using any other supplement. In conclusion, we found no evidence of a relation between the consumption of onions or leeks and the risk of lung carcinoma or any of the histological subtypes. Garlic supplement use seems not associated with a lower risk of lung carcinoma.

Introduction: Use of non-cigarette tobacco products such as cigars and pipe has been increasing, even though these products entail exposure to similar carcinogens to those in cigarettes. More research is needed to explore the risk of these products to guide cancer prevention efforts. Methods: To measure the association between cigars and/or pipe smoking, and cancer incidence in men, we performed meta-analyses of data from five prospective cohorts. Cox regression was used to evaluate the association between different aspects of cigars and pipe smoking and risk of each smoking-related cancer (head and neck, esophagus, lung, stomach, liver, pancreas, kidney, and bladder) for each study. Adjusted HRs were combined using random-effects models. Results: Cigars and/or pipe smokers were at increased risk for head and neck [HR, 1.51; 95% confidence interval (CI), 1.22–1.87], lung (HR, 2.04; 95% CI, 1.68–2.47), and liver cancers (HR, 1.56; 95% CI, 1.08–2.26). Ever-smokers of cigars and/or pipe had an increased risk of developing a smoking-related cancer when compared with never smokers of any tobacco product (overall HR, 1.07; 95% CI, 1.03–1.12). The risk for smoking-related cancers was also increased in mixed smokers who smoked cigars or pipe as well as cigarettes, even when they were smoking predominantly pipe or cigars. Discussion: This pooled analysis highlights the increased risk for smoking-related cancers, particularly for lung and head and neck cancers in exclusive and predominant smokers (former and current) of cigars and pipe. Tobacco prevention efforts should include these products in addition to cigarettes. Cancer Prev Res; 10(12); 704–9. ©2017 AACR.