BackgroundWe examined the association between kidney stones and renal cell carcinoma (RCC) and upper tract urothelial carcinoma (UTUC) risk in the Netherlands Cohort Study on diet and cancer.MethodsIn total, 120,852 participants aged 55–69 completed a self-administered questionnaire on diet, medical conditions and other risk factors for cancer at baseline (1986). After 20.3 years of cancer follow-up 4352 subcohort members, 544 RCC cases and 140 UTUC cases were eligible for case-cohort analysis. Hazard ratios (HR) and 95% confidence intervals (CIs) were estimated by multivariable-adjusted proportional hazards models.ResultsKidney stones were associated with an increased RCC risk (HR: 1.39, 95% CI 1.05–1.84), vs. no kidney stones. Kidney stones were associated with an increased risk of papillary RCC (HR: 3.08, 95% CI 1.55–6.11), but not clear-cell RCC (HR: 1.14, 95% CI 0.79–1.65). UTUC risk was increased for participants with kidney stones (HR: 1.66, 95% CI 1.03–2.68). No heterogeneity of associations was found for UTUC in the ureter and renal pelvis. An early kidney stone diagnosis (≤40 years) was associated with an increased RCC and UTUC risk, compared to later diagnosis.ConclusionKidney stones were associated with increased papillary RCC risk, but not clear-cell RCC risk. No heterogeneity was found for UTUC subtypes.

The gut microbiota represents a complex and diverse ecosystem with a profound impact on human health, promoting immune maturation, and host metabolism as well as colonization resistance. Important members that have often been disregarded are the methanogenic archaea. Methanogenic archaea reduce hydrogen levels via the production of methane, thereby stimulating food fermentation by saccharolytic bacteria. On the other hand, colonization by archaea has been suggested to promote a number of gastrointestinal and metabolic diseases such as colorectal cancer, inflammatory bowel disease, and obesity. Archaea have been shown to be absent during infancy while omnipresent in school-aged children, suggesting that colonization may result from environmental exposure during childhood. The factors that determine the acquisition of methanogenic archaea, however, have remained undefined. Therefore, we aimed to explore determinants associated with the acquisition of the two main gastrointestinal archaeal species, Methanobrevibacter smithii and Methanosphaera stadtmanae, in children. Within the context of the KOALA Birth Cohort Study, fecal samples from 472 children aged 6-10 years were analyzed for the abundance of M. smithii and M. stadtmanae using qPCR. Environmental factors such as diet, lifestyle, hygiene, child rearing, and medication were recorded by repeated questionnaires. The relationship between these determinants and the presence and abundance of archaea was analyzed by logistic and linear regression respectively. Three hundred and sixty-nine out of the 472 children (78.2%) were colonized by M. smithii, and 39 out of the 472 children (8.3%) by M. stadtmanae. The consumption of organic yogurt (odds ratio: 4.25, CI95: 1.51; 11.95) and the consumption of organic milk (odds ratio: 5.58, CI95: 1.83; 17.01) were positively associated with the presence of M. smithii. We subsequently screened raw milk, processed milk, and yogurt samples for methanogens. We identified milk products as possible source for M. smithii, but not M. stadtmanae. In conclusion, M. smithii seems present in milk products and their consumption may determine archaeal gut colonization van de Pol et al. Archaeal Gut Colonization in Children in children. For the first time, a large variety of determinants have been explored in association with gut colonization by methanogenic archaea. Although more information is needed to confirm and unravel the mechanisms in detail, it provides new insights on microbial colonization processes in early life.

In this study, we investigate the influence of the seven genes (VHL, PBRM1, SETD2, BAP1, KDM5C, MTOR and TP53) most frequently mutated in clear cell renal cell cancer (ccRCC) on cancer-specific survival (CSS) in the prospective Netherlands Cohort Study on diet and cancer. DNA isolated from routinely archived formalin-fixed paraffin-embedded tumour blocks from 252 incident ccRCC cases was available for targeted next generation sequencing. Based on the sequencing quality and the completeness of information on clinical characteristics and follow-up, we could use 110 cases for survival analysis. The association with CSS for each mutated gene in these cases was tested using multivariable Cox proportional hazards models to estimate hazards ratios (HR) and confidence intervals (CIs), and we observed mutations in one or more of the seven genes in 64 out of 110 cases (58%). In the multivariable-adjusted analyses, mutations in VHL and PBRM1 were associated with better CSS (HRs (95% CI) 0.34 (0.13‒0.89) and 0.17 (0.04–0.66), respectively), although these results were not statistically significant after multiple testing correction. No association was observed for the other five genes, which may be attributable to limited power.

We investigated the relationship between germline single nucleotide polymorphisms (Snps) in Von Hippel-Lindau (VHL) and Hypoxia-inducible factor 1-alpha (HIF1A), and their gene-environment and gene-gene interactions, and clear-cell Rcc (ccRcc) risk. furthermore, we assessed the relationship between VHL Snps and VHL promoter methylation. three VHL polymorphisms and one HIF1A polymorphism were genotyped in the Netherlands Cohort Study. In 1986, 120,852 participants aged 55-69 completed a self-administered questionnaire on diet and lifestyle and toenail clippings were collected. Toenail DNA was genotyped using the Sequenom MassARRAY platform. After 20.3 years, 3004 subcohort members and 406 RCC cases, of which 263 ccRCC cases, were eligible for multivariate case-cohort analyses. VHL_rs779805 was associated with RCC (Hazard Ratio (HR) 1.53; 95% Confidence Interval (CI) 1.07-2.17) and ccRCC risk (HR 1.88; 95% CI 1.25-2.81). No associations were found for other SNPs. Potential gene-environment interactions were found between alcohol consumption and selected SNPs. However, none remained statistically significant after multiple comparison correction. no gene-gene interactions were observed between VHL and HIF1A. VHL promoter methylation was not associated with VHL Snps. VHL SNPs may increase (cc)RCC susceptibility. No associations were found between gene-environment and gene-gene interactions and (cc)Rcc risk and between VHL promoter methylation and VHL Snps. Genetic and epigenetic alterations in the Von Hippel-Lindau (VHL) gene are important drivers of carcinogenesis in clear-cell renal cell carcinoma (ccRCC) 1. For sporadic ccRCC, biallelic inactivation of VHL because of rare, but highly penetrant, somatic mutations is relatively common 2,3. Previous studies have estimated that 50-82% of patients with sporadic ccRCC have a mutation in the VHL gene 4-8. The VHL gene encodes the VHL tumor suppressor protein (pVHL). Inactivation of pVHL leads to the unchecked accumulation of hypoxia-inducible factor 1 alpha (HIF1A), which facilitates oxygen delivery, adaptation to oxygen deprivation and angiogenesis 1,9. Therefore, genetic or epigenetic alterations in VHL and HIF1A may lead to enhanced cell survival and carcinogenesis. In contrast to the rare, but highly penetrant, sequence alterations leading to VHL loss, some germline Single Nucleotide Polymorphisms (SNPs) are highly frequent, but have a low penetrance. In general, SNPs account for many different phenotypes as they may alter disease susceptibility by affecting the gene's function 10. Genome-wide

At present, mostly case-control and retrospective studies have investigated the association between etiologic risk factors and the development of histologic subtypes of renal cell carcinoma (RCC). Therefore, we assessed the heterogeneity between body mass index (BMI), cigarette smoking, alcohol consumption and hypertension across clear-cell RCC (ccRCC) and papillary RCC (pRCC) risk in the prospective Netherlands Cohort Study on diet and cancer. In 1986, 120 852 participants aged 55 to 69 completed a self-administered questionnaire on diet and other risk factors for cancer. Participants were followed up for cancer through record linkage. Tumor histology was assessed through centralized revision by two experienced uropathologists. After 20.3 years of follow-up, 384 histologically verified RCC cases, including 315 ccRCC and 46 pRCC cases and 4144 subcohort members were eligible for case-cohort analysis. Hazard ratios and 95% confidence intervals were estimated by multivariableadjusted proportional hazards models. Overall, BMI was associated positively with ccRCC risk, but inversely with pRCC risk. Cigarette smoking was associated with an increased ccRCC, but a decreased pRCC risk. Alcohol consumption was inversely associated with both ccRCC and pRCC risk. Hypertension was associated with an increased risk of both ccRCC and pRCC. Statistically significant etiologic heterogeneity was observed for BMI, BMI change since age 20, and smoking duration in current smokers across ccRCC and pRCC risk. In conclusion, we observed potential heterogeneity for BMI, BMI change and smoking duration across ccRCC and pRCC risk. K E Y W O R D S heterogeneity, prospective cohort study, renal cell carcinoma, risk factors, tumor histology 1 | BACKGROUND Kidney cancer consists primarily of adenocarcinomas that arise in the renal parenchyma, commonly referred to as renal cell carcinomas (RCC). 1 RCC is comprised of various entities defined by a distinct tumor histology, chromosomal alterations and molecular pathways. 2 Abbreviations: BMI, body mass index (kg/m 2); CBS, Statistics Netherlands; ccRCC, clear-cell renal cell carcinoma; CI, confidence interval; FFPE tissue, formalin-fixed paraffin-embedded