Measures of body fatness and height in early and mid-to-late adulthood and prostate cancer: risk and mortality in The Pooling Project of Prospective Studies of Diet and Cancer.

BACKGROUND: Advanced prostate cancer etiology is poorly understood. Few studies have examined associations of anthropometric factors (e.g. early adulthood obesity) with advanced prostate cancer risk. PATIENTS AND METHODS: We carried out pooled analyses to examine associations between body fatness, height, and prostate cancer risk. Among 830 772 men, 51 734 incident prostate cancer cases were identified, including 4762 advanced (T4/N1/M1 or prostate cancer deaths) cases, 2915 advanced restricted (same as advanced, but excluding localized cancers that resulted in death) cases, 9489 high-grade cases, and 3027 prostate cancer deaths. Cox proportional hazards models were used to calculate study-specific hazard ratios (HR) and 95% confidence intervals (CI); results were pooled using random effects models. RESULTS: No statistically significant associations were observed for body mass index (BMI) in early adulthood for advanced, advanced restricted, and high-grade prostate cancer, and prostate cancer mortality. Positive associations were shown for BMI at baseline with advanced prostate cancer (HR = 1.30, 95% CI = 0.95-1.78) and prostate cancer mortality (HR = 1.52, 95% CI = 1.12-2.07) comparing BMI ≥35.0 kg/m2 with 21-22.9 kg/m2. When considering early adulthood and baseline BMI together, a 27% higher prostate cancer mortality risk (95% CI = 9% to 49%) was observed for men with BMI <25.0 kg/m2 in early adulthood and BMI ≥30.0 kg/m2 at baseline compared with BMI <25.0 kg/m2 in early adulthood and BMI <30.0 kg/m2 at baseline. Baseline waist circumference, comparing ≥110 cm with <90 cm, and waist-to-hip ratio, comparing ≥1.00 with <0.90, were associated with significant 14%-16% increases in high-grade prostate cancer risk and suggestive or significant 20%-39% increases in prostate cancer mortality risk. Height was associated with suggestive or significant 33%-56% risks of advanced or advanced restricted prostate cancer and prostate cancer mortality, comparing ≥1.90 m with <1.65 m. CONCLUSION: Our findings suggest that height and total and central adiposity in mid-to-later adulthood, but not early adulthood adiposity, are associated with risk of advanced forms of prostate cancer. Thus, maintenance of healthy weight may help prevent advanced prostate cancer.

Longitudinal associations of light-intensity physical activity with quality of life, functioning and fatigue after colorectal cancer.

PURPOSE: Evidence from cross-sectional studies suggests that higher levels of light-intensity physical activity (LPA) are associated with better health-related quality of life (HRQoL) in colorectal cancer (CRC) survivors. However, these associations have not been investigated in longitudinal studies that provide the opportunity to analyse how within-individual changes in LPA affect HRQoL. We investigated longitudinal associations of LPA with HRQoL outcomes in CRC survivors, from 6 weeks to 2 years post-treatment. METHODS: Data were used of a prospective cohort study among 325 stage I-III CRC survivors (67% men, mean age: 67 years), recruited between 2012 and 2016. Validated questionnaires were used to assess hours/week of LPA (SQUASH) and HRQoL outcomes (EORTC QLQ-C30, Checklist Individual Strength) at 6 weeks, and 6, 12 and 24 months post-treatment. We applied linear mixed regression to analyse longitudinal confounder-adjusted associations of LPA with HRQoL. RESULTS: We observed statistically significant longitudinal associations between more LPA and better global quality of life and physical, role and social functioning, and less fatigue over time. Intra-individual analysis showed that within-person increases in LPA (per 8 h/week) were related to improved HRQoL, including better global quality of life (ß = 1.67, 95% CI 0.71; 2.63; total range scale: 0-100) and less fatigue (ß = - 1.22, 95% CI - 2.37; - 0.07; scale: 20-140). Stratified analyses indicated stronger associations among participants below the median of moderate-to-vigorous physical activity (MVPA) at diagnosis. CONCLUSION: Higher levels of LPA were longitudinally associated with better HRQoL and less fatigue in CRC survivors up to two years post-treatment. Further prospective studies using accelerometer data are necessary to inform development of interventions targeting LPA.

Coffee, tea, and caffeine intake and amyotrophic lateral sclerosis mortality in a pooled analysis of eight prospective cohort studies.

BACKGROUND AND PURPOSE: Caffeine is associated with a lower risk of some neurological diseases, but few prospective studies have investigated caffeine intake and risk of amyotrophic lateral sclerosis (ALS) mortality. We therefore determined associations between coffee, tea and caffeine intake, and risk of ALS mortality. METHODS: We conducted pooled analyses of eight international, prospective cohort studies, including 351 565 individuals (120 688 men and 230 877 women). We assessed coffee, tea and caffeine intake using validated food-frequency questionnaires administered at baseline. We used Cox regression to estimate study- and sex-specific risk ratios and 95% confidence intervals (CI) for ALS mortality, which were then pooled using a random-effects model. We conducted analyses using cohort-specific tertiles, absolute common cut-points and continuous measures of all exposures. RESULTS: During follow-up, 545 ALS deaths were documented. We did not observe statistically significant associations between coffee, tea or caffeine intake and risk of ALS mortality. The pooled multivariable risk ratio (MVRR) for ≥3 cups per day vs. >0 to <1 cup per day was 1.04 (95% CI, 0.74-1.47) for coffee and 1.17 (95% CI, 0.77-1.79) for tea. The pooled MVRR comparing the highest with the lowest tertile of caffeine intake (mg/day) was 0.99 (95% CI, 0.80-1.23). No statistically significant results were observed when exposures were modeled as tertiles or continuously. CONCLUSIONS: Our results do not support associations between coffee, tea or total caffeine intake and risk of ALS mortality.

Body size, physical activity, genetic variants in the insulin-like growth factor pathway and colorectal cancer risk.

Insulin-like growth factors (IGFs) have been associated with growth, body size, physical activity and colorectal cancer (CRC). We hypothesized that variants in IGF-related genes increase the CRC susceptibility associated with a larger body size and a lack of physical activity. We assessed this in The Netherlands Cohort Study. Participants (n = 120852) completed a baseline questionnaire on diet and cancer. ~75% returned toenail clippings. Using a case-cohort approach and 16.3 years of follow-up, toenail DNA from 3768 subcohort members and 2580 CRC cases was genotyped. We aggregated unfavorable alleles (potentially increasing CRC risk) for 18 single nucleotide polymorphisms in 8 genes into a sum score. The sum score (in tertiles) and an IGF1 19-CA repeat polymorphism (19/19, 19/non-19 and non-19/non-19 repeats) in combination with body size (mostly in tertiles) and (non-)occupational physical activity (>12, 8-12 and <8 kJ/min in the job and >90, >60-90, >30-60 and ≤30 min/day) were analyzed by Cox regression. Increasingly higher hazard ratios (HRs) for CRC were observed for a larger adult body mass index, larger trouser size and tallness in the presence of more unfavorable alleles in men. HRs (95% confidence intervals) for joint effects were 1.55 (1.06-2.25), 1.78 (1.29-2.46) and 1.48 (1.01-2.17), respectively. In women, variant repeat alleles halved CRC risk irrespective of body size and physical activity. Almost no interactions tested significant. To conclude, a larger body size was a CRC risk factor in men in the presence of an accumulation of unfavorable alleles in IGF-related genes, but interactions were generally nonsignificant.

The proportion of postmenopausal breast cancer cases in the Netherlands attributable to lifestyle-related risk factors.

We aimed to estimate the proportion of Dutch postmenopausal breast cancer cases in 2010 that is attributable to lifestyle-related risk factors. We calculated population attributable fractions (PAFs) of potentially modifiable risk factors for postmenopausal breast cancer in Dutch women aged >50 in 2010. First, age-specific PAFs were calculated for each risk factor, based on their relative risks for postmenopausal breast cancer (from meta-analyses) and age-specific prevalence in the population (from national surveys) around the year 2000, assuming a latency period of 10 years. To obtain the overall PAF, age-specific PAFs were summed in a weighted manner, using the age-specific breast cancer incidence rates (2010) as weights. 95 % confidence intervals for PAF estimates were derived by Monte Carlo simulations. Of Dutch women >40 years, in 2000, 51 % were overweight/obese, 55 % physically inactive (<5 days/week 30 min activity), 75 % regularly consumed alcohol, 42 % ever smoked cigarettes and 79 % had a low-fibre intake (<3.4 g/1000 kJ/day). These factors combined had a PAF of 25.7 % (95 % CI 24.2-27.2), corresponding to 2,665 Dutch postmenopausal breast cancer cases in 2010. PAFs were 8.8 % (95 % CI 6.3-11.3) for overweight/obesity, 6.6 % (95 % CI 5.2-8.0) for alcohol consumption, 5.5 % (95 % CI 4.0-7.0) for physical inactivity, 4.6 % (95 % CI 3.3-6.0) for smoking and 3.2 % (95 % CI 1.6-4.8) for low-fibre intake. Our findings imply that modifiable risk factors are jointly responsible for approximately one out of four Dutch postmenopausal breast cancer cases. This suggests that incidence rates can be lowered substantially by living a more healthy lifestyle.

Long-term dietary sodium, potassium and fluid intake; exploring potential novel risk factors for renal cell cancer in the Netherlands Cohort Study on diet and cancer.

BACKGROUND: As sodium, potassium and fluid intake are related to hypertension, an established risk factor for renal cell cancer (RCC), they may be independent risk factors for RCC. METHODS: The Netherlands Cohort Study (NLCS) with case-cohort design included 120,852 participants aged 55-69 years. At baseline, diet and lifestyle were assessed with questionnaires. After 17.3 years of follow-up, 485 RCC cases and 4438 subcohort members were available for analyses. RESULTS: Sodium intake increased RCC risk (P-trend=0.03), whereas fluid and potassium intake did not. For high sodium and low fluid intake, the RCC risk additionally increased (P-interaction=0.02). CONCLUSION: Sodium intake is a potential risk factor for RCC, particularly if fluid consumption is low.

Dairy products and pancreatic cancer risk: a pooled analysis of 14 cohort studies.

Pancreatic cancer has few early symptoms, is usually diagnosed at late stages, and has a high case-fatality rate. Identifying modifiable risk factors is crucial to reducing pancreatic cancer morbidity and mortality. Prior studies have suggested that specific foods and nutrients, such as dairy products and constituents, may play a role in pancreatic carcinogenesis. In this pooled analysis of the primary data from 14 prospective cohort studies, 2212 incident pancreatic cancer cases were identified during follow-up among 862 680 individuals. Adjusting for smoking habits, personal history of diabetes, alcohol intake, body mass index (BMI), and energy intake, multivariable study-specific hazard ratios (MVHR) and 95% confidence intervals (CIs) were calculated using the Cox proportional hazards models and then pooled using a random effects model. There was no association between total milk intake and pancreatic cancer risk (MVHR = 0.98, 95% CI = 0.82-1.18 comparing ≥500 with 1-69.9 g/day). Similarly, intakes of low-fat milk, whole milk, cheese, cottage cheese, yogurt, and ice-cream were not associated with pancreatic cancer risk. No statistically significant association was observed between dietary (MVHR = 0.96, 95% CI = 0.77-1.19) and total calcium (MVHR = 0.89, 95% CI = 0.71-1.12) intake and pancreatic cancer risk overall when comparing intakes ≥1300 with <500 mg/day. In addition, null associations were observed for dietary and total vitamin D intake and pancreatic cancer risk. Findings were consistent within sex, smoking status, and BMI strata or when the case definition was limited to pancreatic adenocarcinoma. Overall, these findings do not support the hypothesis that consumption of dairy foods, calcium, or vitamin D during adulthood is associated with pancreatic cancer risk.

Diabetes type II, other medical conditions and pancreatic cancer risk: a prospective study in The Netherlands.

BACKGROUND: To date, only a few risk factors for pancreatic cancer have been established. We examined prospectively relations between several medical conditions and pancreatic cancer incidence. METHODS: In 1986, 120 852 participants completed a baseline questionnaire on cancer risk factors, including several self-reported physician diagnosed medical conditions. At baseline, a random subcohort of 5000 participants was selected using a case-cohort approach for analysis. After 16.3 years of follow-up, 448 pancreatic cancer cases (63% microscopically confirmed) were available for analysis. RESULTS: Diabetes mellitus type II and hepatitis were positively associated with pancreatic cancer risk (multivariable-adjusted hazard ratio: 1.79; 95% confidence interval: 1.12-2.87 and hazard ratio: 1.37; 95% confidence interval: 1.04-1.81, respectively). Furthermore, a positive trend in risk with increasing years of diagnosis of diabetes (P=0.004) and of hepatitis (P=0.02) was observed. However, an inverse association was observed between hypertension and pancreatic cancer risk, this was found among microscopically confirmed cases only (hazard ratio: 0.66; 95% confidence interval: 0.49-0.90), while years since diagnosis of hypertension significantly decreased cancer risk (P for trend=0.02). CONCLUSION: In this prospective study, a positive association was observed between self-reported physician diagnosed diabetes mellitus type II and hepatitis and pancreatic cancer risk, whereas an inverse association was observed with hypertension.

The etiology of uterine sarcomas: a pooled analysis of the epidemiology of endometrial cancer consortium.

BACKGROUND: Uterine sarcomas are characterised by early age at diagnosis, poor prognosis, and higher incidence among Black compared with White women, but their aetiology is poorly understood. Therefore, we performed a pooled analysis of data collected in the Epidemiology of Endometrial Cancer Consortium. We also examined risk factor associations for malignant mixed mullerian tumours (MMMTs) and endometrioid endometrial carcinomas (EECs) for comparison purposes. METHODS: We pooled data on 229 uterine sarcomas, 244 MMMTs, 7623 EEC cases, and 28,829 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) for risk factors associated with uterine sarcoma, MMMT, and EEC were estimated with polytomous logistic regression. We also examined associations between epidemiological factors and histological subtypes of uterine sarcoma. RESULTS: Significant risk factors for uterine sarcoma included obesity (body mass index (BMI)≥30 vs BMI<25 kg m(-2) (OR: 1.73, 95% CI: 1.22-2.46), P-trend=0.008) and history of diabetes (OR: 2.33, 95% CI: 1.41-3.83). Older age at menarche was inversely associated with uterine sarcoma risk (≥15 years vs <11 years (OR: 0.70, 95% CI: 0.34-1.44), P-trend: 0.04). BMI was significantly, but less strongly related to uterine sarcomas compared with EECs (OR: 3.03, 95% CI: 2.82-3.26) or MMMTs (OR: 2.25, 95% CI: 1.60-3.15, P-heterogeneity=0.01). CONCLUSION: In the largest aetiological study of uterine sarcomas, associations between menstrual, hormonal, and anthropometric risk factors and uterine sarcoma were similar to those identified for EEC. Further exploration of factors that might explain patterns of age- and race-specific incidence rates for uterine sarcoma are needed.

A novel classification of colorectal tumors based on microsatellite instability, the CpG island methylator phenotype and chromosomal instability: implications for prognosis.

BACKGROUND: We studied the overlap between the major (epi)genomic events microsatellite instability (MSI), the CpG island methylator phenotype (CIMP) and chromosomal instability (CIN) in colorectal cancer (CRC), and whether specific (epi)genotypes were associated with CRC-related deaths. PATIENTS AND METHODS: Molecular analyses using tumor DNA were successful in 509 CRC cases identified within the Netherlands Cohort Study in the period 1989-1993. Follow-up for the vital status until May 2005 was 100%. RESULTS: MSI (12.6%), CIMP-only (5.3%), CIMP + CIN (13.4%), CIN-only (58.2%) and triple-negative tumors (10.6%) differed significantly regarding tumor localization, differentiation grade, initial adjuvant therapy (AT) use and genetic characteristics (P ≤ 0.03). CIMP-only, CIMP + CIN and triple-negative tumors, compared with CIN-only tumors, were significantly associated with a 3.67, 2.44 and 3.78-fold risk of CRC-related deaths after 2-year follow-up (95% confidence intervals, CIs, 1.70-7.91, 1.35-4.41 and 1.97-7.25, respectively), but not after late follow-up. MSI tumors were borderline significantly associated with a 0.40-fold risk of CRC-related deaths after late follow-up (95% CI 0.15-1.03). CONCLUSION(S): This is the first study to show that specific (epi)genotypes may hold a differential prognostic value that may vary over time. Although no specific treatment data were available, an explanation for the differential findings over time might be that (epi)genotypes modify therapy response.

Genetic susceptibility to sporadic ovarian cancer: a systematic review.

Ovarian cancer is a highly lethal disease. Many researchers have, therefore, attempted to identify high risk populations. In this perspective, numerous genetic association studies have been performed to discover common ovarian cancer susceptibility variants. Accordingly, there is an increasing need to synthesize the evidence in order to identify true associations. A comprehensive and systematic assessment of all available data on genetic susceptibility to sporadic ovarian cancer was carried out. The evidence of statistically significant findings was evaluated based on the number of positive replications, the ratio of positive and negative studies, and the false-positive report probability (FPRP). The authors reviewed three genome-wide association studies (GWAS) and 147 candidate gene studies, published from 1990 to October 2010, including around 1100 genetic variants in more than 200 candidate genes and 20 intergenic regions. Genetic variants with the strongest evidence for an association with ovarian cancer include the rs2854344 in the RB1 gene and SNPs on chromosomes 9p22.2, 8q24, 2q31, and 19p13. Promising genetic pathways for ovarian cancer include the cell cycle, DNA repair, sex steroid hormone and oncogenic pathway. Concluding, this review shows that many genetic association studies have been performed, but only a few genetic variants show strong evidence for an association with ovarian cancer. More research is needed to elucidate causal genetic variants, taking into consideration gene-gene and gene-environment interactions, combined effects of common and rare variants, and differences between histological subtypes of this cancer.

Red and processed meat consumption and the risk of esophageal and gastric cancer subtypes in The Netherlands Cohort Study.

BACKGROUND: Prospective data on red and processed meat in relation to risk of subtypes of esophageal and gastric cancer are scarce. We present analyses of association between red and processed meat and the risk of esophageal and gastric cancer subtypes within The Netherlands Cohort Study on Diet and Cancer. DESIGN: 120 852 individuals aged 55-69 years were recruited in 1986, and meat intake was assessed using a 150-item food frequency questionnaire. After 16.3 years of follow-up, 107 esophageal squamous cell carcinomas, 145 esophageal adenocarcinomas, 163 gastric cardia adenocarcinomas, 489 gastric non-cardia adenocarcinomas, and 3923 subcohort members were included in a case-cohort analysis. RESULTS: Processed as well as red meat intake was positively associated with esophageal squamous cell carcinoma in men. Hazard ratios for highest versus lowest quintile of processed and red meat were 3.47 [95% confidence intervals (CI): 1.21-9.94; P for trend: 0.04] and 2.66 (95% CI: 0.94-7.48; P for trend: 0.06), respectively. No association was seen for adenocarcinomas or gastric cancer subtypes or for any of the four subtypes among women. CONCLUSION: Our findings suggest that red and processed meat consumption is associated with increased risk of esophageal squamous cell carcinoma in men but not with cancers of other esophageal and gastric subtypes.

Prediction of long-term sickness absence among employees with depressive complaints.

INTRODUCTION: To study the properties of a screening instrument in predicting long-term sickness absence among employees with depressive complaints. METHODS: Employees at high risk of future sickness absence were selected by the screening instrument Balansmeter (BM). Depressive complaints were assessed with the depression scale of the Hospital Anxiety and Depression Scale. The total study population consisted of 7,401 employees. Sickness absence was assessed objectively and analyzed at 12 and 18 months of follow-up using company registers on certified sick leave. RESULTS: The relative risk (RR) for long-term sickness absence, for employees at high risk versus not at high risk, was 3.26 (95% CI 2.54-4.22) in men and 2.55 (1.98-3.35) in women, when the BM was applied in the total study population. The RR of long-term sickness absence of employees with depressive complaints compared with employees without depressive complaints was 3.13 (2.41-4.09) in men and 2.45 (2.00-3.00) in women. The RR of long-term sickness absence for the BM applied in employees with depressive complaints was 5.23 in men and 3.87 in women. When the BM with a cut-off point with a higher sensitivity was applied in employees with depressive complaints, the RR for long-term sickness absence was 4.88 in men and 3.80 in women. CONCLUSIONS: The screening instrument Balansmeter is able to predict long-term sickness absence within employees with depressive complaints. The total prediction of long-term sickness absence proved better in employees with depressive complaints compared with employees of a general working population.

Artificial intelligence for detection of microsatellite instability in colorectal cancer-a multicentric analysis of a pre-screening tool for clinical application.

BACKGROUND: Microsatellite instability (MSI)/mismatch repair deficiency (dMMR) is a key genetic feature which should be tested in every patient with colorectal cancer (CRC) according to medical guidelines. Artificial intelligence (AI) methods can detect MSI/dMMR directly in routine pathology slides, but the test performance has not been systematically investigated with predefined test thresholds. METHOD: We trained and validated AI-based MSI/dMMR detectors and evaluated predefined performance metrics using nine patient cohorts of 8343 patients across different countries and ethnicities. RESULTS: Classifiers achieved clinical-grade performance, yielding an area under the receiver operating curve (AUROC) of up to 0.96 without using any manual annotations. Subsequently, we show that the AI system can be applied as a rule-out test: by using cohort-specific thresholds, on average 52.73% of tumors in each surgical cohort [total number of MSI/dMMR = 1020, microsatellite stable (MSS)/ proficient mismatch repair (pMMR) = 7323 patients] could be identified as MSS/pMMR with a fixed sensitivity at 95%. In an additional cohort of N = 1530 (MSI/dMMR = 211, MSS/pMMR = 1319) endoscopy biopsy samples, the system achieved an AUROC of 0.89, and the cohort-specific threshold ruled out 44.12% of tumors with a fixed sensitivity at 95%. As a more robust alternative to cohort-specific thresholds, we showed that with a fixed threshold of 0.25 for all the cohorts, we can rule-out 25.51% in surgical specimens and 6.10% in biopsies. INTERPRETATION: When applied in a clinical setting, this means that the AI system can rule out MSI/dMMR in a quarter (with global thresholds) or half of all CRC patients (with local fine-tuning), thereby reducing cost and turnaround time for molecular profiling.

Fatty acids in breast milk and development of atopic eczema and allergic sensitisation in infancy.

BACKGROUND: One of the explanations for the increasing prevalence of atopic diseases is a relative low perinatal supply of n-3 fatty acids. However, this does not explain the protective effects of whole-fat dairy products or high levels of transfatty acids in breast milk, observed in some studies. We evaluated the role of perinatal supply of fatty acids in the early development of atopic eczema and allergic sensitisation. METHODS: Fatty acids, including n-3 long-chain polyunsaturated fatty acids (LCPs) as well as ruminant fatty acids (rumenic acid, cis-9,trans-11-C18:2 conjugated linoleic acid; and vaccenic acid, trans-11-C18:1), were determined in breast milk sampled at 1 month postpartum from 310 mother-infant pairs in the KOALA Birth Cohort Study, the Netherlands. Children were followed for atopic outcomes until 2 years of age. RESULTS: Higher concentrations of n-3 LCPs as well as ruminant fatty acids were associated with lower risk of (1) parent-reported eczema, (2) atopic dermatitis (UK Working Party criteria), and (3) sensitisation at age 1 year (as revealed by specific serum IgE levels to cow's milk, hen's egg and/or peanut). In multivariable logistic regression analysis, the inverse associations between ruminant fatty acid concentrations in breast milk and atopic outcomes were found to be independent from n-3 LCPs. CONCLUSIONS: The results confirm a protective role of preformed n-3 LCPs in the development of atopic disease. Moreover, this is the first study in humans confirming results from animal studies of protective effects of ruminant fatty acids against the development of atopic manifestations.

Alcohol consumption, cigarette smoking and risk of subtypes of oesophageal and gastric cancer: a prospective cohort study.

OBJECTIVE: Alcohol consumption and cigarette smoking may be differentially associated with oesophageal squamous cell carcinoma (OSCC), oesophageal adenocarcinoma (OAC), gastric cardia adenocarcinoma (GCA) and gastric non-cardia adenocarcinoma (GNCA). However, because this was based on retrospective studies, these hypotheses were examined in a prospective cohort. METHODS: The prospective Netherlands Cohort Study consists of 120 852 participants who completed a baseline questionnaire on diet and other cancer risk factors in 1986. After 16.3 years of follow-up, 107 OSCC, 145 OAC, 164 GCA and 491 GNCA cases were available for analysis using Cox proportional hazards models and the case-cohort approach. RESULTS: The multivariable adjusted incidence rate ratio (RR) for OSCC was 4.61 (95% CI 2.24 to 9.50) for > or = 30 g ethanol/day compared with abstainers (p trend <0.001), while no associations with alcohol were found for OAC, GCA or GNCA. Compared with never smokers, current smokers had RRs varying from 1.60 for GCA to 2.63 for OSCC, and were statistically significant or borderline statistically significant. Frequency, duration and pack-years of smoking were independently associated with risk of all four cancers. A positive interaction was found between alcohol consumption and smoking status regarding OSCC risk. The RR for current smokers who consumed >15 g/day of ethanol was 8.05 (95% CI 3.89 to 16.60; p interaction = 0.65), when compared with never smokers who consumed <5 g/day of ethanol. CONCLUSIONS: This prospective study found alcohol consumption to be associated with increased risk of only OSCC. Cigarette smoking was associated with risk of all four cancers.

Development of a prognostic risk model for clear cell renal cell carcinoma by systematic evaluation of DNA methylation markers.

BACKGROUND: Current risk models for renal cell carcinoma (RCC) based on clinicopathological factors are sub-optimal in accurately identifying high-risk patients. Here, we perform a head-to-head comparison of previously published DNA methylation markers and propose a potential prognostic model for clear cell RCC (ccRCC). PATIENTS AND METHODS: Promoter methylation of PCDH8, BNC1, SCUBE3, GREM1, LAD1, NEFH, RASSF1A, GATA5, SFRP1, CDO1, and NEURL was determined by nested methylation-specific PCR. To identify clinically relevant methylated regions, The Cancer Genome Atlas (TCGA) was used to guide primer design. Formalin-fixed paraffin-embedded (FFPE) tissue samples from 336 non-metastatic ccRCC patients from the prospective Netherlands Cohort Study (NLCS) were used to develop a Cox proportional hazards model using stepwise backward elimination and bootstrapping to correct for optimism. For validation purposes, FFPE ccRCC tissue of 64 patients from the University Hospitals Leuven and a series of 232 cases from The Cancer Genome Atlas (TCGA) were used. RESULTS: Methylation of GREM1, GATA5, LAD1, NEFH, NEURL, and SFRP1 was associated with poor ccRCC-specific survival, independent of age, sex, tumor size, TNM stage or tumor grade. Moreover, the association between GREM1, NEFH, and NEURL methylation and outcome was shown to be dependent on the genomic region. A prognostic biomarker model containing GREM1, GATA5, LAD1, NEFH and NEURL methylation in combination with clinicopathological characteristics, performed better compared to the model with clinicopathological characteristics only (clinical model), in both the NLCS and the validation population with a c-statistic of 0.71 versus 0.65 and a c-statistic of 0.95 versus 0.86 consecutively. However, the biomarker model had limited added prognostic value in the TCGA series with a c-statistic of 0.76 versus 0.75 for the clinical model. CONCLUSION: In this study we performed a head-to-head comparison of potential prognostic methylation markers for ccRCC using a novel approach to guide primers design which utilizes the optimal location for measuring DNA methylation. Using this approach, we identified five methylation markers that potentially show prognostic value in addition to currently known clinicopathological factors.

Reproductive and hormonal factors in association with ovarian cancer in the Netherlands cohort study.

Parity, oral contraceptive use, and hysterectomy are known to protect against ovarian cancer, whereas the effect of other reproductive factors remains unclear. The authors investigated the association between several reproductive and hormonal factors and the risk of epithelial invasive ovarian cancer among postmenopausal women participating in the Netherlands Cohort Study on Diet and Cancer. Information on reproductive history and exogenous hormone use was obtained through a self-administered questionnaire at baseline in 1986. After 16.3 years of follow-up, 375 cases and 2,331 subcohort members were available for case-cohort analysis. Ovarian cancer risk was reduced for parous women, with increasing parity, and for hysterectomized women. Moreover, the authors found evidence that oral contraceptive use is protective against ovarian cancer, even when initiated at an older age. In addition, a reduced risk was observed for each year reduction in age at natural menopause and per year reduction in total menstrual life span. A small increased risk was observed with prolonged time to pregnancy, but no difference was found between ever-married nulliparous women and never-married nulliparous women. Moreover, no associations were observed for age at first birth, age at menarche, age at first and last use of oral contraceptives, and use of hormone replacement therapy.

MGMT and MLH1 promoter methylation versus APC, KRAS and BRAF gene mutations in colorectal cancer: indications for distinct pathways and sequence of events.

BACKGROUND: To study how caretaker gene silencing relates to gatekeeper mutations in colorectal cancer (CRC), we investigated whether O6-methylguanine DNA methyltransferase (MGMT) and Human Mut-L Homologue 1 (MLH1) promoter hypermethylation are associated with APC, KRAS and BRAF mutations among 734 CRC patients. METHODS: We compared MGMT hypermethylation with G:C > A:T mutations in APC and KRAS and with the occurrence of such mutations in CpG or non-CpG dinucleotides in APC. We also compared MLH1 hypermethylation with truncating APC mutations and activating KRAS and BRAF mutations. RESULTS: Only 10% of the tumors showed both MGMT and MLH1 hypermethylation. MGMT hypermethylation occurred more frequently in tumors with G:C > A:T KRAS mutations (55%) compared with those without these mutations (38%, P < 0.001). No such difference was observed for G:C > A:T mutations in APC, regardless of whether mutations occurred in CpG or non-CpG dinucleotides. MLH1 hypermethylation was less common in tumors with APC mutations (P = 0.006) or KRAS mutations (P = 0.001), but was positively associated with BRAF mutations (P < 0.001). CONCLUSIONS: MGMT hypermethylation is associated with G:C > A:T mutations in KRAS, but not in APC, suggesting that MGMT hypermethylation may succeed APC mutations but precedes KRAS mutations in colorectal carcinogenesis. MLH1-hypermethylated tumors harbor fewer APC and KRAS mutations and more BRAF mutations, suggesting that they develop distinctly from an MGMT methylator pathway.