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Systematic meta-analyses, field synopsis and global assessment of the evidence of genetic association studies in colorectal cancer.
Montazeri, Z, Li, X, Nyiraneza, C, Ma, X, Timofeeva, M, Svinti, V, Meng, X, He, Y, Bo, Y, Morgan, S, et al
Gut. 2020;(8):1460-1471
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Abstract
OBJECTIVE To provide an understanding of the role of common genetic variations in colorectal cancer (CRC) risk, we report an updated field synopsis and comprehensive assessment of evidence to catalogue all genetic markers for CRC (CRCgene2). DESIGN We included 869 publications after parallel literature review and extracted data for 1063 polymorphisms in 303 different genes. Meta-analyses were performed for 308 single nucleotide polymorphisms (SNPs) in 158 different genes with at least three independent studies available for analysis. Scottish, Canadian and Spanish data from genome-wide association studies (GWASs) were incorporated for the meta-analyses of 132 SNPs. To assess and classify the credibility of the associations, we applied the Venice criteria and Bayesian False-Discovery Probability (BFDP). Genetic associations classified as 'positive' and 'less-credible positive' were further validated in three large GWAS consortia conducted in populations of European origin. RESULTS We initially identified 18 independent variants at 16 loci that were classified as 'positive' polymorphisms for their highly credible associations with CRC risk and 59 variants at 49 loci that were classified as 'less-credible positive' SNPs; 72.2% of the 'positive' SNPs were successfully replicated in three large GWASs and the ones that were not replicated were downgraded to 'less-credible' positive (reducing the 'positive' variants to 14 at 11 loci). For the remaining 231 variants, which were previously reported, our meta-analyses found no evidence to support their associations with CRC risk. CONCLUSION The CRCgene2 database provides an updated list of genetic variants related to CRC risk by using harmonised methods to assess their credibility.
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Gene-environment interactions and colorectal cancer risk: An umbrella review of systematic reviews and meta-analyses of observational studies.
Yang, T, Li, X, Montazeri, Z, Little, J, Farrington, SM, Ioannidis, JPA, Dunlop, MG, Campbell, H, Timofeeva, M, Theodoratou, E
International journal of cancer. 2019;(9):2315-2329
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Abstract
The cause of colorectal cancer (CRC) is multifactorial, involving both genetic variants and environmental risk factors. We systematically searched the MEDLINE, EMBASE, China National Knowledge Infrastructure (CNKI) and Wanfang databases from inception to December 2016, to identify systematic reviews and meta-analyses of observational studies that investigated gene-environment (G×E) interactions in CRC risk. Then, we critically evaluated the cumulative evidence for the G×E interactions using an extension of the Human Genome Epidemiology Network's Venice criteria. Overall, 15 articles reporting systematic reviews of observational studies on 89 G×E interactions, 20 articles reporting meta-analyses of candidate gene- or single-nucleotide polymorphism-based studies on 521 G×E interactions, and 8 articles reporting 33 genome-wide G×E interaction analyses were identified. On the basis of prior and observed scores, only the interaction between rs6983267 (8q24) and aspirin use was found to have a moderate overall credibility score as well as main genetic and environmental effects. Though 5 other interactions were also found to have moderate evidence, these interaction effects were tenuous due to the lack of main genetic effects and/or environmental effects. We did not find highly convincing evidence for any interactions, but several associations were found to have moderate strength of evidence. Our conclusions are based on application of the Venice criteria which were designed to provide a conservative assessment of G×E interactions and thus do not include an evaluation of biological plausibility of an observed joint effect.
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A Complex Role for Calcium Signaling in Colorectal Cancer Development and Progression.
Wang, W, Yu, S, Huang, S, Deng, R, Ding, Y, Wu, Y, Li, X, Wang, A, Wang, S, Chen, W, et al
Molecular cancer research : MCR. 2019;(11):2145-2153
Abstract
Clinical data suggest that many malignant cancers are associated with hypercalcemia. Hypercalcemia can facilitate the proliferation and metastasis of gastric and colon tumors, and has been considered a hallmark of end-stage disease. However, it has also been reported that dietary calcium or vitamin D supplementation could reduce the risk of many types of cancers. In particular, the intestines can absorb considerable amounts of calcium via Ca2+-permeable ion channels, and hypercalcemia is common in patients with colorectal cancer. Thus, this review considers the role of calcium signaling in the context of colorectal cancer and summarizes the functions of specific regulators of cellular calcium levels in the proliferation, invasion, metastasis, cell death, and drug resistance of colorectal cancer cells. The data reveal that even a slight upregulation of intracellular Ca2+ signaling can facilitate the onset and progression of colorectal cancer, while continuous Ca2+ influx and Ca2+ overload may cause tumor cell death. This dual function of Ca2+ signaling adds nuance to the debate over the hallmarks of colorectal cancer, and may even provide new directions and strategies for clinical interventions.
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Exploring causality in the association between circulating 25-hydroxyvitamin D and colorectal cancer risk: a large Mendelian randomisation study.
He, Y, Timofeeva, M, Farrington, SM, Vaughan-Shaw, P, Svinti, V, Walker, M, Zgaga, L, Meng, X, Li, X, Spiliopoulou, A, et al
BMC medicine. 2018;(1):142
Abstract
BACKGROUND Whilst observational studies establish that lower plasma 25-hydroxyvitamin D (25-OHD) levels are associated with higher risk of colorectal cancer (CRC), establishing causality has proven challenging. Since vitamin D is modifiable, these observations have substantial clinical and public health implications. Indeed, many health agencies already recommend supplemental vitamin D. Here, we explore causality in a large Mendelian randomisation (MR) study using an improved genetic instrument for circulating 25-OHD. METHODS We developed a weighted genetic score for circulating 25-OHD using six genetic variants that we recently reported to be associated with circulating 25-OHD in a large genome-wide association study (GWAS) meta-analysis. Using this score as instrumental variable in MR analyses, we sought to determine whether circulating 25-OHD is causally linked with CRC risk. We conducted MR analysis using individual-level data from 10,725 CRC cases and 30,794 controls (Scotland, UK Biobank and Croatia). We then applied estimates from meta-analysis of 11 GWAS of CRC risk (18,967 cases; 48,168 controls) in a summary statistics MR approach. RESULTS The new genetic score for 25-OHD was strongly associated with measured plasma 25-OHD levels in 2821 healthy Scottish controls (P = 1.47 × 10- 11), improving upon previous genetic instruments (F-statistic 46.0 vs. 13.0). However, individual-level MR revealed no association between 25-OHD score and CRC risk (OR 1.03/unit log-transformed circulating 25-OHD, 95% CI 0.51-2.07, P = 0.93). Similarly, we found no evidence for a causal relationship between 25-OHD and CRC risk using summary statistics MR analysis (OR 0.91, 95% CI 0.69-1.19, P = 0.48). CONCLUSIONS Despite the scale of this study and employing an improved score capturing more of the genetic contribution to circulating 25-OHD, we found no evidence for a causal relationship between circulating 25-OHD and CRC risk. Although the magnitude of effect for vitamin D suggested by observational studies can confidently be excluded, smaller effects sizes and non-linear relationships remain plausible. Circulating vitamin D may be a CRC biomarker, but a causal effect on CRC risk remains unproven.
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Enhanced instructions improve the quality of bowel preparation for colonoscopy: a meta-analysis of randomized controlled trials.
Guo, X, Yang, Z, Zhao, L, Leung, F, Luo, H, Kang, X, Li, X, Jia, H, Yang, S, Tao, Q, et al
Gastrointestinal endoscopy. 2017;(1):90-97.e6
Abstract
BACKGROUND AND AIMS The success of a colonoscopy is highly dependent on the quality of bowel preparation (BP). Many patients have poor BP due to non-compliance with regular instructions. Reports concerning the effects of enhanced instructions on BP quality are inconsistent. The aim of this meta-analysis was to compare BP quality between patients receiving enhanced instructions in addition to regular instructions and those who received regular instructions only. METHODS MEDLINE, EMBASE, Web of Science, and the Cochrane Library were searched to identify relevant studies published for August 2015. The quality of BP (adequate/inadequate), adenoma detection rate, polyp detection rate, willingness to repeat preparation, and adverse events were estimated by using odds ratios (OR) and 95% confidence intervals (CI) with random effects models. RESULTS Eight randomized controlled trials (n = 3795) were included. Patients who received enhanced instructions showed significantly better BP quality than those receiving only regular instructions (OR, 2.35; 95% CI, 1.65-3.35; P < .001). Subgroup analysis showed that the beneficial effects of enhanced instructions on BP quality were consistent among patients receiving different purgative types, administration methods, or diet restriction (all P < .05). Patients in the enhanced instructions group showed more willingness to repeat the preparation (OR, 1.91; 95% CI, 1.20-3.04; P = .006). CONCLUSIONS Enhanced instructions significantly improved the quality of BP and willingness to repeat the preparation in patients undergoing colonoscopy. Factors related to patient instructions appear to be as important as the preparation method itself in improving BP quality.