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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.

Purpose: The evidence from the literature regarding the association of dietary factors and risk of prostate cancer is inconclusive. Methods: A nutrient-wide association study was conducted to systematically and comprehensively evaluate the associations between 92 foods or nutrients and risk of prostate cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC). Cox proportional hazard regression models adjusted for total energy intake, smoking status, body mass index, physical activity, diabetes and education were used to estimate hazard ratios and 95% confidence intervals for standardized dietary intakes. As in genome-wide association studies, correction for multiple comparisons was applied using the false discovery rate (FDR ' 5%) method and suggested results were replicated in an independent cohort, the Netherlands Cohort Study (NLCS). Results: A total of 5916 and 3842 incident cases of prostate cancer were diagnosed during a mean follow-up of 14 and 20 years in EPIC and NLCS, respectively. None of the dietary factors was associated with the risk of total prostate cancer in EPIC (minimum FDR-corrected P, 0.37). Null associations were also observed by disease stage, grade and fatality, except for positive associations observed for intake of dry cakes/biscuits with low-grade and butter with aggressive prostate cancer, respectively, out of which the intake of dry cakes/biscuits was replicated in the NLCS. Conclusions: Our findings provide little support for an association for the majority of the 92 examined dietary factors and risk of prostate cancer. The association of dry cakes/biscuits with low-grade prostate cancer warrants further replication given the scarcity in the literature. © 2019, The Author(s).

BACKGROUND: Oral contraceptives are known to reduce the incidence rate of endometrial cancer, but it is uncertain how long this effect lasts after use ceases, or whether it is modified by other factors.METHODS: Individual participant datasets were sought from principal investigators and provided centrally for 27 276 women with endometrial cancer (cases) and 115 743 without endometrial cancer (controls) from 36 epidemiological studies. The relative risks (RRs) of endometrial cancer associated with oral contraceptive use were estimated using logistic regression, stratified by study, age, parity, body-mass index, smoking, and use of menopausal hormone therapy.FINDINGS: The median age of cases was 63 years (IQR 57-68) and the median year of cancer diagnosis was 2001 (IQR 1994-2005). 9459 (35%) of 27 276 cases and 45 625 (39%) of 115 743 controls had ever used oral contraceptives, for median durations of 3·0 years (IQR 1-7) and 4·4 years (IQR 2-9), respectively. The longer that women had used oral contraceptives, the greater the reduction in risk of endometrial cancer; every 5 years of use was associated with a risk ratio of 0·76 (95% CI 0·73-0·78; p

Familial breast cancer: collaborative reanalysis of individual data from 52 epidemiological studies including 58,209 women with breast cancer and 101,986 women without the disease.Collaborative Group on Hormonal Factors in Breast Cancer.BACKGROUND: Women with a family history of breast cancer are at increased risk of the disease, but no study has been large enough to characterise reliably how, over women's lives, this risk is influenced by particular familial patterns of breast cancer. This report, on the relevance of breast cancer in first-degree relatives, is based on combined data from 52 epidemiological studies. METHODS: Individual data on breast cancer in first-degree relatives (mothers, sisters, and daughters) of 58209 women with breast cancer and of 101986 controls were collected, checked, and analysed centrally. Risk ratios for breast cancer were calculated by conditional logistic regression, stratified by study, age, menopausal status, number of sisters, parity, and age when the first child was born. Breast-cancer incidence and mortality rates for particular family histories were calculated by applying age-specific risk ratios to breast-cancer rates typical for more-developed countries. FINDINGS: Altogether 7496 (12.9%) women with breast cancer and 7438 (7.3%) controls reported that one or more first-degree relatives had a history of breast cancer: 12% of women with breast cancer had one affected relative and 1% had two or more. Risk ratios for breast cancer increased with increasing numbers of affected first-degree relatives: compared with women who had no affected relative, the ratios were 1.80 (99% CI 1.69-1.91), 2.93 (2.36-3.64), and 3.90 (2.03-7.49), respectively, for one, two, and three or more affected first-degree relatives (p

Hypertension is an established risk factor for renal cell cancer (RCC). The renin-angiotensin-aldosterone system (RAAS) regulates blood pressure and is closely linked to hypertension. RAAS additionally influences homeostasis of electrolytes (e.g. sodium and potassium) and fluid. We investigated single nucleotide polymorphisms (SNPs) in RAAS and their interactions with hypertension and intakes of sodium, potassium and fluid regarding RCC risk in the Netherlands Cohort Study (NLCS), which was initiated in 1986 and included 120,852 participants aged 55-69 years. Diet and lifestyle were assessed by questionnaires and toenail clippings were collected. Genotyping of toenail DNA was performed using the SEQUENOM(R) MassARRAY(R) platform for a literature-based selection of 13 candidate SNPs in seven key RAAS genes. After 20.3 years of follow-up, Cox regression analyses were conducted using a case-cohort approach including 3583 subcohort members and 503 RCC cases. Two SNPs in AGTR1 were associated with RCC risk. AGTR1_rs1492078 (AA vs GG) decreased RCC risk [hazard ratio (HR) (95% confidence interval (CI)): 0.70(0.49-1.00)], whereas AGTR1_rs5186 (CC vs AA) increased RCC risk [HR(95%CI): 1.49(1.08-2.05)]. Associations were stronger in participants with hypertension. The RCC risk for AGT_rs3889728 (AG+AA vs GG) was modified by hypertension (P-interaction=0.039). SNP-diet interactions were not significant, although HRs suggested interaction between SNPs in ACE and sodium intake. SNPs in AGTR1 and AGT influenced RCC susceptibility, and their effects were modified by hypertension. Sodium intake was differentially associated with RCC risk across genotypes of several SNPs, yet some analyses had probably inadequate power to show significant interaction. Results suggest that RAAS may be a candidate pathway in RCC etiology. (c) 2014 Wiley Periodicals, Inc.

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.

Metabolic gene polymorphisms have previously been suggested as risk factors for renal cell carcinoma (RCC). These polymorphisms are involved in activation or detoxification of carcinogens in cigarette smoke which is another RCC risk factor. We evaluated gene-environment interactions between CYP1A1, GSTmu1 and smoking in a large population-based RCC case group. The Netherlands Cohort Study on diet and cancer (NLCS) comprises 120,852 persons who completed a questionnaire on smoking and other risk factors at baseline. After 11.3 years of follow-up, 337 incident RCC cases were identified. DNA was collected for 245 cases. In a case-only analysis, interaction-odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using logistic regression. We observed a moderate, not statistically significant, interaction between current smoking and CYP1A1*2C (OR 1.42; 95% CI 0.70-2.89) and GSTmu1 null (OR 1.35; 95% CI 0.65-2.79). For current smokers with both a variant (heterozygous or homozygous) in CYP1A1 and GSTmu1 null, risk was also increased (OR 1.63; 95% CI 0.63-4.24). No interaction was observed between ever smokers, smoking duration (increments of 10 smoking years) or amount (increments of 5 cigarettes/day) and CYP1A or GSTmu1. Our results show a modest trend towards a statistically significant gene-environment interaction between CYP1A1, GSTmu1 and smoking in RCC. This could indicate that RCC risk among smokers might be more increased with the CYP1A1*2C genotype, GSTmu1 null, or both a CYP1A1 variant and GSTmu1 null.

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.

Objective: To explore a possible causal relationship between psychosocial work characteristics and mental health. Methods: Using longitudinal data from the Maastricht Cohort Study on "Fatigue at Work" (n =2332), the effects of changes in job demands and decision latitude on subsequent changes in need for recovery and prolonged fatigue were studied. Results: Increasing job demands are a significant predictor of a subsequent increase in need for recovery (beta = 0.063) and prolonged fatigue (P = 0.057). An increase in decision latitude predicted a subsequent decrease in need for recovery (beta = -0.078) and prolonged fatigue (beta = -0.063). After adjusting for changes in other work characteristics, the effects on changes in prolonged fatigue were no longer significant. Conclusion: These findings support a possible causal relationship between work characteristics and mental health and can be used for designing effective prevention and intervention strategies.

BACKGROUND: To the authors' knowledge, only a few prospective studies to date have investigated the correlation between vegetable and fruit consumption and the risk of ovarian carcinoma and their results have been inconclusive. METHODS: Vegetable and fruit intake was assessed in relation to ovarian carcinoma, among 62,573 postmenopausal women participating in The Netherlands Cohort Study on Diet and Cancer. Women reported on dietary habits and on other risk factors for cancer in a self-administered questionnaire in 1986. Follow-up of cancer was implemented by annual record linkage with The Netherlands Cancer Registry and a pathology register. After 11.3 years of follow-up, data regarding 252 incident invasive epithelial ovarian carcinoma cases and of 2216 subcohort members were available for case-cohort analyses. RESULTS: Multivariable-adjusted rate ratios (RR) of ovarian carcinoma for women in the highest compared with the lowest quintile of intake (RR(Q5 vs. Q1)) were 0.98 (95% confidence interval [95% CI], 0.61-1.58) for total vegetables and 1.11 (95% CI, 0.70-1.78) for total fruit. The RR(Q5 vs. Q1) values of ovarian carcinoma with intake of cooked vegetables, raw vegetables, brassicas, legumes, cooked leafy vegetables, and raw leafy vegetables were 1.35 (95% CI, 0.83-2.21), 0.75 (95% CI, 0.48-1.18), 1.42 (95% CI, 0.88-2.29), 0.93 (95% CI, 0.60-1.44), 1.05 (95% CI, 0.66-1.67), and 1.23 (95% CI, 0.75-2.02), respectively. With the exception of raw endive (multivariable-adjusted RR, 0.24; 95% CI, 0.07-0.78), none of the individual vegetable or fruit items showed a statistically significant association with ovarian carcinoma. CONCLUSIONS: The results of the current study did not support a significant association between vegetable or fruit consumption and ovarian carcinoma risk in a cohort of postmenopausal women. Cancer 2005. (c) 2005 American Cancer Society.

BACKGROUND: Pregnancy-related pelvic girdle and/or low back pain is a controversial syndrome because insight in etiology and prognosis is lacking. The controversy relates to factors eliciting pain and some prognostic factors such as the interpretation of pain at the symphysis. Recent research about treatment strategies also reflects those various opinions, in fact suggesting there is professional uncertainty about the optimal approach. Currently, physiotherapists often prescribe a pain-contingent treatment regime of relative rest and avoiding several day-to-day activities. Additionally, treatment more often includes an exercise program to guide rectification of the muscle imbalance and alignment of the pelvic girdle. Effectiveness of those interventions is not proven and the majority of the studies are methodologically flawed. Investigators draw particular attention to biomedical factors but there is growing evidence that important prognostic issues such as biopsychosocial factors appear to be even more important as point of action in a treatment program. METHODS/DESIGN: This pragmatic randomized controlled trial is designed to evaluate the effectiveness of a tailor-made treatment program with respect to biopsychosocial factors in primary care. The effect of the experimental intervention and usual care are evaluated as they are applied in primary health care. The trial is embedded in a cohort study that is designed as a longitudinal, prospective study, which studies prevalence, etiology, severity and prognosis during pregnancy until one year after delivery. The present paper focuses on choices regarding recruitment procedures, in-/exclusion criteria and the development of a well-timed intervention. DISCUSSION: This section briefly discusses the actions taken to minimize bias in the design, the proper time-window for the experimental intervention and the contrast between the experimental intervention and usual care.

Breast cancer and abortion: collaborative reanalysis of data from 53 epidemiological studies, including 83?000 women with breast cancer from 16 countries. Beral V, Bull D, Doll R, Peto R, Reeves G; Collaborative Group on Hormonal Factors in Breast Cancer. BACKGROUND: The Collaborative Group on Hormonal Factors in Breast Cancer has brought together the worldwide epidemiological evidence on the possible relation between breast cancer and previous spontaneous and induced abortions. METHODS: Data on individual women from 53 studies undertaken in 16 countries with liberal abortion laws were checked and analysed centrally. Relative risks of breast cancer--comparing the effects of having had a pregnancy that ended as an abortion with those of never having had that pregnancy--were calculated, stratified by study, age at diagnosis, parity, and age at first birth. Because the extent of under-reporting of past induced abortions might be influenced by whether or not women had been diagnosed with breast cancer, results of the studies--including a total of 44000 women with breast cancer--that used prospective information on abortion (ie, information that had been recorded before the diagnosis of breast cancer) were considered separately from results of the studies--including 39000 women with the disease--that used retrospective information (recorded after the diagnosis of breast cancer). FINDINGS: The overall relative risk of breast cancer, comparing women with a prospective record of having had one or more pregnancies that ended as a spontaneous abortion versus women with no such record, was 0.98 (95% CI 0.92-1.04, p=0.5). The corresponding relative risk for induced abortion was 0.93 (0.89-0.96, p=0.0002). Among women with a prospective record of having had a spontaneous or an induced abortion, the risk of breast cancer did not differ significantly according to the number or timing of either type of abortion. Published results on induced abortion from the few studies with prospectively recorded information that were not available for inclusion here are consistent with these findings. Overall results for induced abortion differed substantially between studies with prospective and those with retrospective information on abortion (test for heterogeneity between relative risks: chi2(1) =33.1, p