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

A systematic SNP selection approach to identify mechanisms underlying disease aetiology: Linking height to post-menopausal breast and colorectal cancer risk

Data from GWAS suggest that SNPs associated with complex diseases or traits tend to co-segregate in regions of low recombination, harbouring functionally linked gene clusters. This phenomenon allows for selecting a limited number of SNPs from GWAS repositories for large-scale studies investigating shared mechanisms between diseases. For example, we were interested in shared mechanisms between adult-attained height and post-menopausal breast cancer (BC) and colorectal cancer (CRC) risk, because height is a risk factor for these cancers, though likely not a causal factor. Using SNPs from public GWAS repositories at p-values < 1 × 10-5 and a genomic sliding window of 1 mega base pair, we identified SNP clusters including at least one SNP associated with height and one SNP associated with either post-menopausal BC or CRC risk (or both). SNPs were annotated to genes using HapMap and GRAIL and analysed for significantly overrepresented pathways using ConsensuspathDB. Twelve clusters including 56 SNPs annotated to 26 genes were prioritised because these included at least one height- and one BC risk- or CRC risk-associated SNP annotated to the same gene. Annotated genes were involved in Indian hedgehog signalling (p-value = 7.78 × 10-7) and several cancer site-specific pathways. This systematic approach identified a limited number of clustered SNPs, which pinpoint potential shared mechanisms linking together the complex phenotypes height, post-menopausal BC and CRC

A meta-analysis of observational studies identifies predictors of sickness absence

Objective: About one in every three employees seen by their occupational physician is absent from work because of psychosocial health complaints. To implement preventive measures, it is necessary to identify predictors for this type of sickness absence. Study Design and Setting: A meta-analysis was carried out to quantify the association between predictive factors and psychosocial sickness absence and to assess clinical outcomes and heterogeneity. Eligible for inclusion were prospective studies that examined this association and provided sufficient information to estimate summary odds ratios (SORs). Results: Twenty prospective studies were included. Significant SORs for sick leave >3 days were found for being unmarried, 1.37 (95% confidence interval [CI] = 1.15-1.64), experiencing psychosomatic complaints, 1.79 (95% CI = 1.54-2.07), using medication, 3.13 (95% CI = 1.71-5.72), having a burnout, 2.34 (95% CI = 1.59-3.45), suffering from psychological problems, 1.97 (95% CI = 1.37-2.85), having low job control, 1.28 (95% CI = 1.23-1.33), having low decision latitude, 1.33 (95% CI = 1.16-1.56), and experiencing no fairness at work, 1.30 (95% CI = 1.18-1.45). Conclusion: This study shows that predictors of sickness absence can be identified in a homogeneous manner. The results provide leads to public health interventions to successfully improve psychosocial health and to reduce sickness absence

Comparison of expert and job-exposure matrix-based retrospective exposure assessment of occupational carcinogens in the Netherlands Cohort Study

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 55e69 years at enrolment in 1986. For a subcohort of these men (n¼1630), 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 (ks¼0.29 and 0.42, respectively), closely followed by the FINJEM. For welding fumes, concordance between the expert assessment and FINJEM was high (k¼0.70). The Asbestos JEM showed poor agreement with the expert asbestos assessment (k¼0.10). 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

Promoter methylation of CDO1 identifies clear-cell renal cell cancer patients with poor survival outcome

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.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

The CpG island methylator phenotype: What's in a name?

Although the CpG island methylator phenotype (CIMP) was first identified and has been most extensively studied in colorectal cancer, the term "CIMP" has been repeatedly used over the past decade to describe CpG island promoter methylation in other tumor types, including bladder, breast, endometrial, gastric, glioblastoma (gliomas), hepatocellular, lung, ovarian, pancreatic, renal cell, and prostate cancers, as well as for leukemia, melanoma, duodenal adenocarninomas, adrenocortical carcinomas, and neuroblastomas. CIMP has been reported to be useful for predicting prognosis and response to treatment in a variety of tumor types, but it remains unclear whether or not CIMP is a universal phenomenon across human neoplasia or if there should be cancer-specific definitions of the phenotype. Recently, it was shown that somatic isocitrate dehydrogenase-1 (IDH1) mutations, frequently observed in gliomas, establish CIMP in primary human astrocytes by remodeling the methylome. Interestingly, somatic IDH1 and IDH2 mutations, and loss-of-function mutations in ten-eleven translocation (TET) methylcytosine dioxygenase-2 (TET2) associated with a hypermethylation phenotype, are also found in multiple enchondromas of patients with Ollier disease and Mafucci syndrome, and leukemia, respectively. These data provide the first clues for the elucidation of a molecular basis for CIMP. Although CIMP appears as a phenomenon that occurs in various cancer types, the definition is poorly defined and differs for each tumor. The current perspective discusses the use of the term CIMP in cancer, its significance in clinical practice, and future directions that may aid in identifying the true cause and definition of CIMP in different forms of human neoplasia