| 1. |
- Tsilidis, Konstantinos K., et al.
(författare)
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Genetically predicted circulating concentrations of micronutrients and risk of colorectal cancer among individuals of European descent : a Mendelian randomization study
- 2021
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Ingår i: American Journal of Clinical Nutrition. - : Oxford University Press. - 0002-9165 .- 1938-3207. ; 113:6, s. 1490-1502
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The literature on associations of circulating concentrations of minerals and vitamins with risk of colorectal cancer is limited and inconsistent. Evidence from randomized controlled trials (RCTs) to support the efficacy of dietary modification or nutrient supplementation for colorectal cancer prevention is also limited.OBJECTIVES: To complement observational and RCT findings, we investigated associations of genetically predicted concentrations of 11 micronutrients (β-carotene, calcium, copper, folate, iron, magnesium, phosphorus, selenium, vitamin B-6, vitamin B-12, and zinc) with colorectal cancer risk using Mendelian randomization (MR). METHODS: Two-sample MR was conducted using 58,221 individuals with colorectal cancer and 67,694 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry. Inverse variance-weighted MR analyses were performed with sensitivity analyses to assess the impact of potential violations of MR assumptions.RESULTS: Nominally significant associations were noted for genetically predicted iron concentration and higher risk of colon cancer [ORs per SD (ORSD): 1.08; 95% CI: 1.00, 1.17; P value = 0.05] and similarly for proximal colon cancer, and for vitamin B-12 concentration and higher risk of colorectal cancer (ORSD: 1.12; 95% CI: 1.03, 1.21; P value = 0.01) and similarly for colon cancer. A nominally significant association was also noted for genetically predicted selenium concentration and lower risk of colon cancer (ORSD: 0.98; 95% CI: 0.96, 1.00; P value = 0.05) and similarly for distal colon cancer. These associations were robust to sensitivity analyses. Nominally significant inverse associations were observed for zinc and risk of colorectal and distal colon cancers, but sensitivity analyses could not be performed. None of these findings survived correction for multiple testing. Genetically predicted concentrations of β-carotene, calcium, copper, folate, magnesium, phosphorus, and vitamin B-6 were not associated with disease risk.CONCLUSIONS: These results suggest possible causal associations of circulating iron and vitamin B-12 (positively) and selenium (inversely) with risk of colon cancer.
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| 2. |
- Assi, Nada, et al.
(författare)
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Are Metabolic Signatures Mediating the Relationship between Lifestyle Factors and Hepatocellular Carcinoma Risk? Results from a Nested Case–Control Study in EPIC
- 2018
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - 1055-9965 .- 1538-7755. ; 27:5, s. 531-540
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Tidskriftsartikel (refereegranskat)abstract
- Background: The "meeting-in-the-middle" (MITM) is a principle to identify exposure biomarkers that are also predictors of disease. The MITM statistical framework was applied in a nested case-control study of hepatocellular carcinoma (HCC) within European Prospective Investigation into Cancer and Nutrition (EPIC), where healthy lifestyle index (HLI) variables were related to targeted serum metabolites.Methods: Lifestyle and targeted metabolomic data were available from 147 incident HCC cases and 147 matched controls. Partial least squares analysis related 7 lifestyle variables from a modified HLI to a set of 132 serum-measured metabolites and a liver function score. Mediation analysis evaluated whether metabolic profiles mediated the relationship between each lifestyle exposure and HCC risk.Results: Exposure-related metabolic signatures were identified. Particularly, the body mass index (BMI)-associated metabolic component was positively related to glutamic acid, tyrosine, PC aaC38:3, and liver function score and negatively to lysoPC aC17:0 and aC18:2. The lifetime alcohol-specific signature had negative loadings on sphingomyelins (SM C16:1, C18:1, SM(OH) C14:1, C16:1 and C22:2). Both exposures were associated with increased HCC with total effects (TE) = 1.23 (95% confidence interval = 0.93-1.62) and 1.40 (1.14-1.72), respectively, for BMI and alcohol consumption. Both metabolic signatures mediated the association between BMI and lifetime alcohol consumption and HCC with natural indirect effects, respectively, equal to 1.56 (1.24-1.96) and 1.09 (1.03-1.15), accounting for a proportion mediated of 100% and 24%.Conclusions: In a refined MITM framework, relevant metabolic signatures were identified as mediators in the relationship between lifestyle exposures and HCC risk.Impact: The understanding of the biological basis for the relationship between modifiable exposures and cancer would pave avenues for clinical and public health interventions on metabolic mediators.
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| 3. |
- Murphy, Neil, et al.
(författare)
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Circulating Levels of Insulin-like Growth Factor 1 and Insulin-like Growth Factor Binding Protein 3 Associate With Risk of Colorectal Cancer Based on Serologic and Mendelian Randomization Analyses
- 2020
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Ingår i: Gastroenterology. - : Elsevier BV. - 0016-5085 .- 1528-0012. ; 158:5, s. 1300-1312.e20
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Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: Human studies examining associations between circulating levels of insulin-like growth factor 1 (IGF1) and insulin-like growth factor binding protein 3 (IGFBP3) and colorectal cancer risk have reported inconsistent results. We conducted complementary serologic and Mendelian randomization (MR) analyses to determine whether alterations in circulating levels of IGF1 or IGFBP3 are associated with colorectal cancer development.Methods: Serum levels of IGF1 were measured in blood samples collected from 397,380 participants from the UK Biobank, from 2006 through 2010. Incident cancer cases and cancer cases recorded first in death certificates were identified through linkage to national cancer and death registries. Complete follow-up was available through March 31, 2016. For the MR analyses, we identified genetic variants associated with circulating levels of IGF1 and IGFBP3. The association of these genetic variants with colorectal cancer was examined with 2-sample MR methods using genome-wide association study consortia data (52,865 cases with colorectal cancer and 46,287 individuals without [controls])Results: After a median follow-up period of 7.1 years, 2665 cases of colorectal cancer were recorded. In a multivariable-adjusted model, circulating level of IGF1 associated with colorectal cancer risk (hazard ratio per 1 standard deviation increment of IGF1, 1.11; 95% confidence interval [CI] 1.05–1.17). Similar associations were found by sex, follow-up time, and tumor subsite. In the MR analyses, a 1 standard deviation increment in IGF1 level, predicted based on genetic factors, was associated with a higher risk of colorectal cancer risk (odds ratio 1.08; 95% CI 1.03–1.12; P = 3.3 × 10–4). Level of IGFBP3, predicted based on genetic factors, was associated with colorectal cancer risk (odds ratio per 1 standard deviation increment, 1.12; 95% CI 1.06–1.18; P = 4.2 × 10–5). Colorectal cancer risk was associated with only 1 variant in the IGFBP3 gene region (rs11977526), which also associated with anthropometric traits and circulating level of IGF2.Conclusions: In an analysis of blood samples from almost 400,000 participants in the UK Biobank, we found an association between circulating level of IGF1 and colorectal cancer. Using genetic data from 52,865 cases with colorectal cancer and 46,287 controls, a higher level of IGF1, determined by genetic factors, was associated with colorectal cancer. Further studies are needed to determine how this signaling pathway might contribute to colorectal carcinogenesis.
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| 4. |
- Johansson, Mattias, et al.
(författare)
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Circulating Biomarkers of One-Carbon Metabolism in Relation to Renal Cell Carcinoma Incidence and Survival
- 2014
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 106:12
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Tidskriftsartikel (refereegranskat)abstract
- Background: The etiology of renal cell carcinoma (RCC) is only partially understood, but a metabolic component appears likely. We investigated biomarkers of one-carbon metabolism and RCC onset and survival. Methods: The European Prospective Investigation into Cancer and Nutrition (EPIC) recruited 385 747 participants with blood samples between 1992 and 2000, and this analysis included 556 RCC case-control pairs. A subsequent replication study included 144 case-control pairs nested within the Melbourne Collaborative Cohort Study (MCCS). Plasma concentrations of vitamin B2, vitamin B6, folate, vitamin B12, methionine and homocysteine were measured in prediagnostic samples and evaluated with respect to RCC risk using conditional and unconditional logistic regression models, and to all-cause mortality in RCC cases using Cox regression models. All statistical tests were two-sided. Results: EPIC participants with higher plasma concentrations of vitamin B6 had lower risk of RCC, the odds ratio comparing the 4th and 1st quartiles (OR4vs1) being 0.40 95% confidence interval [CI] = 0.28 to 0.57, P-trend < .001. We found similar results after adjusting for potential confounders (adjusted P-trend < .001). In survival analysis, the hazard ratio for all-cause mortality in RCC cases when comparing the 4th and 1st quartiles (HR4vs1) of vitamin B6 was 0.57 (95% CI = 0.37 to 0.87, P-trend < .001). Subsequent replication of these associations within the MCCS yielded very similar results for both RCC risk (OR4vs1 = 0.47, 95% CI = 0.23 to 0.99, P-trend = .07) and all-cause mortality (HR4vs1 = 0.56, 95% CI = 0.27 to 1.17, P-trend = .02). No association was evident for the other measured biomarkers. Conclusion: Study participants with higher circulating concentrations of vitamin B6 had lower risk of RCC and improved survival following diagnosis in two independent cohorts.
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| 5. |
- Key, Timothy J., et al.
(författare)
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Carotenoids, retinol, tocopherols, and prostate cancer risk : pooled analysis of 15 studies
- 2015
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Ingår i: American Journal of Clinical Nutrition. - : Elsevier BV. - 0002-9165 .- 1938-3207. ; 102:5, s. 1142-1157
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Tidskriftsartikel (refereegranskat)abstract
- Background: Individual studies have suggested that circulating carotenoids, retinol, or tocopherols may be associated with prostate cancer risk, but the studies have not been large enough to provide precise estimates of associations, particularly by stage and grade of disease. Objective: The objective of this study was to conduct a pooled analysis of the associations of the concentrations of 7 carotenoids, retinol, alpha-tocopherol, and gamma-tocopherol with risk of prostate cancer and to describe whether any associations differ by stage or grade of the disease or other factors. Design: Principal investigators of prospective studies provided individual participant data for prostate cancer cases and controls. Risk by study-specific fifths of each biomarker was estimated by using multivariable-adjusted conditional logistic regression in matched case-control sets. Results: Data were available for up to 11,239 cases (including 1654 advanced stage and 1741 aggressive) and 18,541 controls from 15 studies. Lycopene was not associated with overall risk of prostate cancer, but there was statistically significant heterogeneity by stage of disease, and the OR for aggressive disease for the highest compared with the lowest fifth of lycopene was 0.65 (95% CI: 0.46, 0.91; P-trend = 0.032). No other carotenoid was significantly associated with overall risk of prostate cancer or with risk of advanced-stage or aggressive disease. For retinol, the OR for the highest compared with the lowest fifth was 1.13 (95% CI: 1.04, 1.22; P-trend = 0.015). For alpha-tocopherol, the OR for the highest compared with the lowest fifth was 0.86 (95% CI: 0.78, 0.94; P-trend < 0.001), with significant heterogeneity by stage of disease; the OR for aggressive prostate cancer was 0.74 (95% CI: 0.59, 0.92; P-trend = 0.001). gamma-Tocopherol was not associated with risk. Conclusions: Overall prostate cancer risk was positively associated with retinol and inversely associated with alpha-tocopherol, and risk of aggressive prostate cancer was inversely associated with lycopene and alpha-tocopherol. Whether these associations reflect causal relations is unclear.
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| 6. |
- Kliemann, Nathalie, et al.
(författare)
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Metabolic signatures of greater body size and their associations with risk of colorectal and endometrial cancers in the European Prospective Investigation into Cancer and Nutrition
- 2021
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Ingår i: BMC Medicine. - : BioMed Central. - 1741-7015. ; 19:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: The mechanisms underlying the obesity-cancer relationship are incompletely understood. This study aimed to characterise metabolic signatures of greater body size and to investigate their association with two obesity-related malignancies, endometrial and colorectal cancers, and with weight loss within the context of an intervention study.Methods: Targeted mass spectrometry metabolomics data from 4326 participants enrolled in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort and 17 individuals from a single-arm pilot weight loss intervention (Intercept) were used in this analysis. Metabolic signatures of body size were first determined in discovery (N = 3029) and replication (N = 1297) sets among EPIC participants by testing the associations between 129 metabolites and body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR) using linear regression models followed by partial least squares analyses. Conditional logistic regression models assessed the associations between the metabolic signatures with endometrial (N = 635 cases and 648 controls) and colorectal (N = 423 cases and 423 controls) cancer risk using nested case-control studies in EPIC. Pearson correlation between changes in the metabolic signatures and weight loss was tested among Intercept participants.Results: After adjustment for multiple comparisons, greater BMI, WC, and WHR were associated with higher levels of valine, isoleucine, glutamate, PC aa C38:3, and PC aa C38:4 and with lower levels of asparagine, glutamine, glycine, serine, lysoPC C17:0, lysoPC C18:1, lysoPC C18:2, PC aa C42:0, PC ae C34:3, PC ae C40:5, and PC ae C42:5. The metabolic signature of BMI (OR1-sd 1.50, 95% CI 1.30–1.74), WC (OR1-sd 1.46, 95% CI 1.27–1.69), and WHR (OR1-sd 1.54, 95% CI 1.33–1.79) were each associated with endometrial cancer risk. Risk of colorectal cancer was positively associated with the metabolic signature of WHR (OR1-sd: 1.26, 95% CI 1.07–1.49). In the Intercept study, a positive correlation was observed between weight loss and changes in the metabolic signatures of BMI (r = 0.5, 95% CI 0.06–0.94, p = 0.03), WC (r = 0.5, 95% CI 0.05–0.94, p = 0.03), and WHR (r = 0.6, 95% CI 0.32–0.87, p = 0.01).Conclusions: Obesity is associated with a distinct metabolic signature comprising changes in levels of specific amino acids and lipids which is positively associated with both colorectal and endometrial cancer and is potentially reversible following weight loss.
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| 7. |
- Merritt, Melissa A., et al.
(författare)
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Investigation of Dietary Factors and Endometrial Cancer Risk Using a Nutrient-wide Association Study Approach in the EPIC and Nurses' Health Study (NHS) and NHSII
- 2015
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - 1055-9965 .- 1538-7755. ; 24:2, s. 466-471
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Tidskriftsartikel (refereegranskat)abstract
- Data on the role of dietary factors in endometrial cancer development are limited and inconsistent. We applied a "nutrient-wide association study" approach to systematically evaluate dietary risk associations for endometrial cancer while controlling for multiple hypothesis tests using the false discovery rate (FDR) and validating the results in an independent cohort. We evaluated endometrial cancer risk associations for dietary intake of 84 foods and nutrients based on dietary questionnaires in three prospective studies, the European Prospective Investigation into Cancer and Nutrition (EPIC; N = 1,303 cases) followed by validation of nine foods/nutrients (FDR <= 0.10) in the Nurses' Health Studies (NHS/NHSII; N = 1,531 cases). Cox regression models were used to estimate HRs and 95% confidence intervals (CI). In multivariate adjusted comparisons of the extreme categories of intake at baseline, coffee was inversely associated with endometrial cancer risk (EPIC, median intake 750 g/day vs. 8.6; HR, 0.81; 95% CI, 0.68-0.97, P-trend = 0.09; NHS/NHSII, median intake 1067 g/day vs. none; HR, 0.82; 95% CI, 0.70-0.96, P-trend = 0.04). Eight other dietary factors that were associated with endometrial cancer risk in the EPIC study (total fat, monounsaturated fat, carbohydrates, phosphorus, butter, yogurt, cheese, and potatoes) were not confirmed in the NHS/NHSII. Our findings suggest that coffee intake may be inversely associated with endometrial cancer risk. Further data are needed to confirm these findings and to examine the mechanisms linking coffee intake to endometrial cancer risk to develop improved prevention strategies. (C)2015 AACR.
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| 8. |
- Murphy, Neil, et al.
(författare)
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A Nested Case-Control Study of Metabolically Defined Body Size Phenotypes and Risk of Colorectal Cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC)
- 2016
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Ingår i: PLoS Medicine. - : Public Library of Science (PLoS). - 1549-1277 .- 1549-1676. ; 13:4
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Tidskriftsartikel (refereegranskat)abstract
- Background Obesity is positively associated with colorectal cancer. Recently, body size subtypes categorised by the prevalence of hyperinsulinaemia have been defined, and metabolically healthy overweight/obese individuals (without hyperinsulinaemia) have been suggested to be at lower risk of cardiovascular disease than their metabolically unhealthy (hyperinsulinaemic) overweight/obese counterparts. Whether similarly variable relationships exist for metabolically defined body size phenotypes and colorectal cancer risk is unknown.Methods and Findings The association of metabolically defined body size phenotypes with colorectal cancer was investigated in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Metabolic health/body size phenotypes were defined according to hyperinsulinaemia status using serum concentrations of C-peptide, a marker of insulin secretion. A total of 737 incident colorectal cancer cases and 737 matched controls were divided into tertiles based on the distribution of C-peptide concentration amongst the control population, and participants were classified as metabolically healthy if below the first tertile of C-peptide and metabolically unhealthy if above the first tertile. These metabolic health definitions were then combined with body mass index (BMI) measurements to create four metabolic health/body size phenotype categories: (1) metabolically healthy/normal weight (BMI < 25 kg/m(2)), (2) metabolically healthy/overweight (BMI >= 25 kg/m2), (3) metabolically unhealthy/normal weight (BMI < 25 kg/m2), and (4) metabolically unhealthy/overweight (BMI >= 25 kg/m2). Additionally, in separate models, waist circumference measurements (using the International Diabetes Federation cut-points [>= 80 cm for women and >= 94 cm for men]) were used (instead of BMI) to create the four metabolic health/body size phenotype categories. Statistical tests used in the analysis were all two-sided, and a p-value of <0.05 was considered statistically significant. In multivariable-adjusted conditional logistic regression models with BMI used to define adiposity, compared with metabolically healthy/normal weight individuals, we observed a higher colorectal cancer risk among metabolically unhealthy/normal weight (odds ratio [OR] = 1.59, 95% CI 1.10-2.28) and metabolically unhealthy/overweight (OR = 1.40, 95% CI 1.01-1.94) participants, but not among metabolically healthy/overweight individuals (OR = 0.96, 95% CI 0.65-1.42). Among the overweight individuals, lower colorectal cancer risk was observed for metabolically healthy/overweight individuals compared with metabolically unhealthy/overweight individuals (OR = 0.69, 95% CI 0.49-0.96). These associations were generally consistent when waist circumference was used as the measure of adiposity. To our knowledge, there is no universally accepted clinical definition for using C-peptide level as an indication of hyperinsulinaemia. Therefore, a possible limitation of our analysis was that the classification of individuals as being hyperinsulinaemic-based on their C-peptide level-was arbitrary. However, when we used quartiles or the median of C-peptide, instead of tertiles, as the cut-point of hyperinsulinaemia, a similar pattern of associations was observed.Conclusions These results support the idea that individuals with the metabolically healthy/overweight phenotype (with normal insulin levels) are at lower colorectal cancer risk than those with hyperinsulinaemia. The combination of anthropometric measures with metabolic parameters, such as C-peptide, may be useful for defining strata of the population at greater risk of colorectal cancer.
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| 9. |
- Naudin, Sabine, et al.
(författare)
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Healthy lifestyle and the risk of pancreatic cancer in the EPIC study
- 2020
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Ingår i: European Journal of Epidemiology. - : Springer Science and Business Media LLC. - 0393-2990 .- 1573-7284. ; 35:10, s. 975-986
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Tidskriftsartikel (refereegranskat)abstract
- Pancreatic cancer (PC) is a highly fatal cancer with currently limited opportunities for early detection and effective treatment. Modifiable factors may offer pathways for primary prevention. In this study, the association between the Healthy Lifestyle Index (HLI) and PC risk was examined. Within the European Prospective Investigation into Cancer and Nutrition cohort, 1113 incident PC (57% women) were diagnosed from 400,577 participants followed-up for 15 years (median). HLI scores combined smoking, alcohol intake, dietary exposure, physical activity and, in turn, overall and central adiposity using BMI (HLIBMI) and waist-to-hip ratio (WHR, HLIWHR), respectively. High values of HLI indicate adherence to healthy behaviors. Cox proportional hazard models with age as primary time variable were used to estimate PC hazard ratios (HR) and 95% confidence intervals (CI). Sensitivity analyses were performed by excluding, in turn, each factor from the HLI score. Population attributable fractions (PAF) were estimated assuming participants’ shift to healthier lifestyles. The HRs for a one-standard deviation increment of HLIBMI and HLIWHR were 0.84 (95% CI: 0.79, 0.89; ptrend = 4.3e−09) and 0.77 (0.72, 0.82; ptrend = 1.7e−15), respectively. Exclusions of smoking from HLIWHR resulted in HRs of 0.88 (0.82, 0.94; ptrend = 4.9e−04). The overall PAF estimate was 19% (95% CI: 11%, 26%), and 14% (6%, 21%) when smoking was removed from the score. Adherence to a healthy lifestyle was inversely associated with PC risk, beyond the beneficial role of smoking avoidance. Public health measures targeting compliance with healthy lifestyles may have an impact on PC incidence.
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| 10. |
- Papadimitriou, Nikos, et al.
(författare)
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Physical activity and risks of breast and colorectal cancer : a Mendelian randomisation analysis
- 2020
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Physical activity has been associated with lower risks of breast and colorectal cancer in epidemiological studies; however, it is unknown if these associations are causal or confounded. In two-sample Mendelian randomisation analyses, using summary genetic data from the UK Biobank and GWA consortia, we found that a one standard deviation increment in average acceleration was associated with lower risks of breast cancer (odds ratio [OR]: 0.51, 95% confidence interval [CI]: 0.27 to 0.98, P-value=0.04) and colorectal cancer (OR: 0.66, 95% CI: 0.48 to 0.90, P-value=0.01). We found similar magnitude inverse associations for estrogen positive (ER+ve) breast cancer and for colon cancer. Our results support a potentially causal relationship between higher physical activity levels and lower risks of breast cancer and colorectal cancer. Based on these data, the promotion of physical activity is probably an effective strategy in the primary prevention of these commonly diagnosed cancers. Physical activity has been linked to lower risks of colorectal and breast cancer. Here, the authors present a Mendelian randomisation analysis supporting a potentially causal relationship between higher physical activity levels and lower risks of breast cancer and colorectal cancer.
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