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Background: High numbers of lymphocytes in tumor tissue, including T regulatory cells (Treg), have been associated with better colorectal cancer survival. Tregs, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and therefore variants in genes related to Treg differentiation and function could be associated with colorectal cancer prognosis. Methods: In a prospective German cohort of 3,593 colorectal cancer patients, we assessed the association of 771 single-nucleotide polymorphisms (SNP) in 58 Treg-related genes with overall and colorectal cancer–specific survival using Cox regression models. Effect modification by microsatellite instability (MSI) status was also investigated because tumors with MSI show greater lymphocytic infiltration and have been associated with better prognosis. Replication of significant results was attempted in 2,047 colorectal cancer patients of the International Survival Analysis in Colorectal Cancer Consortium (ISACC). Results: A significant association of the TGFBR3 SNP rs7524066 with more favorable colorectal cancer–specific survival [hazard ratio (HR) per minor allele: 0.83; 95% confidence interval (CI), 0.74–0.94; P value: 0.0033] was replicated in ISACC (HR: 0.82; 95% CI, 0.68–0.98; P value: 0.03). Suggestive evidence for association was found with two IL7 SNPs, rs16906568 and rs7845577. Thirteen SNPs with differential associations with overall survival according to MSI in the discovery analysis were not confirmed. Conclusions: Common genetic variation in the Treg pathway implicating genes such as TGFBR3 and IL7 was shown to be associated with prognosis of colorectal cancer patients. Impact: The implicated genes warrant further investigation.

The human proteome is a crucial intermediate between complex diseases and their genetic and environmental components, and an important source of drug development targets and biomarkers. Here, we comprehensively assess the genetic architecture of 257 circulating protein biomarkers of cardiometabolic relevance through high-depth (22.5×) whole-genome sequencing (WGS) in 1328 individuals. We discover 131 independent sequence variant associations (P, The human proteome represents a crucial link between complex disease and genetic/environmental factors. Here, the authors investigate 257 cardiometabolic-relevant protein biomarkers in whole genome sequencing data from 1328 individuals, revealing the genetic architecture underlying biomarker variation.

Background: Low serum 25-hydroxyvitamin D [25(OH)D] concentrations in patients with colorectal cancer have been consistently associated with higher mortality in observational studies. It is unclear whether low 25(OH)D levels directly influence colorectal cancer mortality. To minimize bias, we use genetic variants associated with vitamin D levels to evaluate the association with overall and colorectal cancer–specific survival. Methods: Six genetic variants have been robustly identified to be associated with 25(OH)D levels in genome-wide association studies. On the basis of data from the International Survival Analysis in Colorectal Cancer Consortium, the individual genetic variants and a weighted genetic risk score were tested for association with overall and colorectal cancer–specific survival using Cox proportional hazards models in 7,657 patients with stage I to IV colorectal cancer, of whom 2,438 died from any cause and 1,648 died from colorectal cancer. Results: The 25(OH)D decreasing allele of SNP rs2282679 (GC gene, encodes group-specific component/vitamin D–binding protein) was associated with poorer colorectal cancer–specific survival, although not significant after multiple-testing correction. None of the other five SNPs showed an association. The genetic risk score showed nonsignificant associations with increased overall [HR = 1.54; confidence interval (CI), 0.86–2.78] and colorectal cancer–specific mortality (HR = 1.76; 95% CI, 0.86–3.58). A significant increased risk of overall mortality was observed in women (HR = 3.26; 95% CI, 1.45–7.33; Pheterogeneity = 0.01) and normal-weight individuals (HR = 4.14; 95% CI, 1.50–11.43, Pheterogeneity = 0.02). Conclusions: Our results provided little evidence for an association of genetic predisposition of lower vitamin D levels with increased overall or colorectal cancer–specific survival, although power might have been an issue. Impact: Further studies are warranted to investigate the association in specific subgroups.

Large genome-wide association studies (GWAS) have identified loci that are associated with complex traits and diseases, but index variants are often not causal and reside in non-coding regions of the genome. To gain a better understanding of the relevant biological mechanisms, in termediate traits such as gene expression and protein levels are increasingly being investigated because these are likely mediators between genetic variants and disease outcome. Genetic variants associated with intermediate traits, termed molecular quantitative trait loci (molQTLs), car then be used as instrumental variables in a Mendelian randomization (MR) approach to identify the causal features and mechanisms of complex traits. Challenges such as pleiotropy and the non-specificity of molQTLs remain, and further approaches and methods need to be developed.

Aim: Use of menopausal hormone therapy (MHT) has been associated with a reduced risk for colorectal cancer, but mechanisms underlying this relationship are not well understood. In the colon, MHT appears to act through estrogen receptor β (ERβ) which may influence DNA methylation by binding to DNA. Using genome-wide methylation profiling data, we aimed to identify genes that may be differentially methylated according to MHT use. Materials & methods: DNA methylation was measured using Illumina HumanMethylation450k arrays in two independent tumor sample sets of colorectal cancer patients. Differential methylation was determined using R/limma. Results: In the discovery analysis, two CpG sites showed differential DNA methylation according to MHT use, both were not replicated. In stratified analyses, 342 CpG sites were associated with current MHT use only in ERβ-positive tumors. Conclusion: The suggestive findings of differential methylation according to current MHT use in ERβ-positive tumors warrant further investigation.

BACKGROUND: Substantial evidence supports an association between use of menopausal hormone therapy and decreased colorectal cancer (CRC) risk, indicating a role of exogenous sex hormones in CRC development. However, findings on endogenous oestrogen exposure and CRC are inconsistent. METHODS: We used a Mendelian randomisation approach to test for a causal effect of age at menarche and age at menopause as surrogates for endogenous oestrogen exposure on CRC risk. Weighted genetic risk scores based on 358 single-nucleotide polymorphisms associated with age at menarche and 51 single-nucleotide polymorphisms associated with age at menopause were used to estimate the association with CRC risk using logistic regression in 12,944 women diagnosed with CRC and 10,741 women without CRC from three consortia. Sensitivity analyses were conducted to address pleiotropy and possible confounding by body mass index. RESULTS: Genetic risk scores for age at menarche (odds ratio per year 0.98, 95% confidence interval: 0.95-1.02) and age at menopause (odds ratio 0.98, 95% confidence interval: 0.94-1.01) were not significantly associated with CRC risk. The sensitivity analyses yielded similar results. CONCLUSIONS: Our study does not support a causal relationship between genetic risk scores for age at menarche and age at menopause and CRC risk.

The human proteome is a crucial intermediate between complex diseases and their genetic and environmental components, and an important source of drug development targets and biomarkers. Here, we conduct high-depth (22.5x) whole-genome sequencing (WGS) in 1,328 individuals to fully assess the genetic architecture of 257 circulating protein biomarkers of cardiometabolic relevance. We discover 132 independent sequence variant associations ( P

Involvement of sex hormones in colorectal cancer (CRC) development has been linked to oestrogen receptor β (ERβ). Expression of ERβ is found reduced in tumour tissue and inversely related to mortality. However, mechanisms are not well understood. Our study aimed to detect differentially methylated genes associated with ERβ expression, which could point to mechanisms by which ERβ could influence risk and prognosis of CRC. Epigenome-wide DNA methylation profiling was performed using Illumina HumanMethylation450k BeadChip arrays in two independent tumour sample sets of CRC patients recruited in 2003–2010 by the German DACHS study (discovery cohort n = 917, replication cohort n = 907). ERβ expression was measured using immunohistochemistry and scored as negative, moderate and high. Differentially methylated CpG sites and genomic regions were determined using limma in the R-package RnBeads. For the comparison of tumours with moderate/high ERβ versus negative expression, differentially methylated CpG sites were identified but not confirmed by replication. Comparing tumours of high with tumours of negative ERβ expression revealed 2,904 differentially methylated CpG sites of which 403 were replicated (FDR adjusted p-value