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His M, Gunter MJ, Keski-Rahkonen P, et al., 2023, Application of Metabolomics to Epidemiologic Studies of Breast Cancer: New Perspectives for Etiology and Prevention., J Clin Oncol
PURPOSE: To provide an overview on how the application of metabolomics (high-throughput characterization of metabolites from cells, organs, tissues, or biofluids) to population-based studies may inform our understanding of breast cancer etiology. METHODS: We evaluated studies that applied metabolomic analyses to prediagnostic blood samples from prospective epidemiologic studies to identify circulating metabolites associated with breast cancer risk, overall and by breast cancer subtype and menopausal status. We provide some important considerations for the application and interpretation of metabolomics approaches in this context. RESULTS: Overall, specific lipids and amino acids were indicated as the most common metabolite classes associated with breast cancer development. However, comparison of results across studies is challenging because of heterogeneity in laboratory techniques, analytical methods, sample size, and applied statistical methods. CONCLUSION: Metabolomics is being increasingly applied to population-based studies for the identification of new etiologic hypotheses and/or mechanisms related to breast cancer development. Despite its success in applications to epidemiology, studies of larger sample size with detailed information on menopausal status, breast cancer subtypes, and repeated biologic samples collected over time are needed to improve comparison of results between studies and enhance validation of results, allowing potential clinical translation of findings.
Bull CJ, Hazelwood E, Bell JA, et al., 2023, Identifying metabolic features of colorectal cancer liability using Mendelian randomization., medRxiv
BACKGROUND: Recognizing the early signs of cancer risk is vital for informing prevention, early detection, and survival. METHODS: To investigate whether changes in circulating metabolites characterise the early stages of colorectal cancer (CRC) development, we examined associations between a genetic risk score (GRS) associated with CRC liability (72 single nucleotide polymorphisms) and 231 circulating metabolites measured by nuclear magnetic resonance spectroscopy in the Avon Longitudinal Study of Parents and Children (N=6,221). Linear regression models were applied to examine associations between genetic liability to colorectal cancer and circulating metabolites measured in the same individuals at age 8, 16, 18 and 25 years. RESULTS: The GRS for CRC was associated with up to 28% of the circulating metabolites at FDR-P<0.05 across all time points, particularly with higher fatty acids and very-low- and low-density lipoprotein subclass lipids. Two-sample reverse Mendelian randomization (MR) analyses investigating CRC liability (52,775 cases, 45,940 controls) and metabolites measured in a random subset of UK Biobank participants (N=118,466, median age 58y) revealed broadly consistent effect estimates with the GRS analysis. In conventional (forward) MR analyses, genetically predicted polyunsaturated fatty acid concentrations were most strongly associated with higher CRC risk. CONCLUSIONS: These analyses suggest that higher genetic liability to CRC can cause early alterations in systemic metabolism, and suggest that fatty acids may play an important role in CRC development. FUNDING: This work was supported by the Elizabeth Blackwell Institute for Health Research, University of Bristol, the Wellcome Trust, the Medical Research Council, Diabetes UK, the University of Bristol NIHR Biomedical Research Centre, and Cancer Research UK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This work used
Stein MJ, Baurecht H, Sedlmeier AM, et al., 2023, Association between circadian physical activity patterns and mortality in the UK Biobank., Int J Behav Nutr Phys Act, Vol: 20
BACKGROUND: The benefit of physical activity (PA) for increasing longevity is well-established, however, the impact of diurnal timing of PA on mortality remains poorly understood. We aimed to derive circadian PA patterns and investigate their associations with all-cause mortality. METHODS: We used 24 h PA time series from 96,351 UK Biobank participants aged between 42 and 79 years at accelerometry in 2013-2015. Functional principal component analysis (fPCA) was applied to obtain circadian PA patterns. Using multivariable Cox proportional hazard models, we related the loading scores of these fPCs to estimate risk of mortality. RESULTS: During 6.9 years of follow-up, 2,850 deaths occurred. Four distinct fPCs accounted for 96% of the variation of the accelerometry data. Using a loading score of zero (i.e., average overall PA during the day) as the reference, a fPC1 score of + 2 (high overall PA) was inversely associated with mortality (Hazard ratio, HR = 0.91; 95% CI: 0.84-0.99), whereas a score of -2 (low overall PA) was associated with higher mortality (1.69; 95% CI: 1.57-1.81; p for non-linearity < 0.001). Significant inverse linear associations with mortality were observed for engaging in midday PA instead of early and late PA (fPC3) (HR for a 1-unit increase 0.88; 95% CI: 0.83-0.93). In contrast, midday and nocturnal PA instead of early and evening PA (fPC4) were positively associated with mortality (HR for a 1-unit increase 1.16; 95% CI: 1.08-1.25). CONCLUSION: Our results suggest that it is less important during which daytime hours one is active but rather, to engage in some level of elevated PA for longevity.
Dimou N, Kim AE, Flanagan O, et al., 2023, Probing the diabetes and colorectal cancer relationship using gene - environment interaction analyses, Annual Meeting of the American-Association-for-Cancer-Research (AACR), Publisher: SPRINGERNATURE, Pages: 511-520, ISSN: 0007-0920
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Pham TT, Nimptsch K, Papadimitriou N, et al., 2023, Genetically determined circulating resistin concentrations and risk of colorectal cancer: a two-sample Mendelian randomization study, JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY, ISSN: 0171-5216
Constantinescu A-E, Bull CJ, Jones N, et al., 2023, Circulating white blood cell traits and colorectal cancer risk: A Mendelian randomisation study, INTERNATIONAL JOURNAL OF CANCER, ISSN: 0020-7136
Aglago EK, Kim A, Lin Y, et al., 2023, A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk, CANCER RESEARCH, Vol: 83, Pages: 2572-2583, ISSN: 0008-5472
Aglago EK, Kim A, Lin Y, et al., 2023, Supplementary Data from A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk
<jats:p><p>supplementary materials</p></jats:p>
Aglago EK, Kim A, Lin Y, et al., 2023, Table 2 from A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk
<jats:p><p>Summary of G × BMI analyses using 1DF, two-step, and 3DF analyses.</p></jats:p>
Aglago EK, Kim A, Lin Y, et al., 2023, Table 2 from A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk
<jats:p><p>Summary of G × BMI analyses using 1DF, two-step, and 3DF analyses.</p></jats:p>
Aglago EK, Kim A, Lin Y, et al., 2023, Table 1 from A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk
<jats:p><p>Selected characteristics of the participants.</p></jats:p>
Aglago EK, Kim A, Lin Y, et al., 2023, Supplementary Data from A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk
<jats:p><p>supplementary materials</p></jats:p>
Aglago EK, Kim A, Lin Y, et al., 2023, Data from A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk
<jats:p><div>Abstract<p>Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Gene-environment interactions (G × E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G × E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G × E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G × E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant G×BMI interaction located within the Formin 1/Gremlin 1 (<i>FMN1/GREM1</i>) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the <i>FMN1/GREM1</i> gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer.</p>Significance:<p>This gene-environment interaction analysis revealed a genetic locus in FMN1/GREM1 that interacts with body mass index in colorectal
Aglago EK, Kim A, Lin Y, et al., 2023, Table 1 from A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk
<jats:p><p>Selected characteristics of the participants.</p></jats:p>
Aglago EK, Kim A, Lin Y, et al., 2023, Data from A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk
<jats:p><div>Abstract<p>Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Gene-environment interactions (G × E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G × E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G × E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G × E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant G×BMI interaction located within the Formin 1/Gremlin 1 (<i>FMN1/GREM1</i>) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the <i>FMN1/GREM1</i> gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer.</p>Significance:<p>This gene-environment interaction analysis revealed a genetic locus in FMN1/GREM1 that interacts with body mass index in colorectal
Yarmolinsky J, Bouras E, Constantinescu A, et al., 2023, Genetically proxied glucose-lowering drug target perturbation and risk of cancer: a Mendelian randomisation analysis, DIABETOLOGIA, Vol: 66, Pages: 1481-1500, ISSN: 0012-186X
Clasen JL, Mabunda R, Heath AK, et al., 2023, Reproductive and hormonal factors and risk of renal cell carcinoma among women in the European Prospective Investigation into Cancer and Nutrition, Cancer Medicine, Vol: 12, Pages: 15588-15600, ISSN: 2045-7634
BackgroundRenal cell carcinoma (RCC) is twice as common among men compared with women, and hormonal factors have been suggested to partially explain this difference. There is currently little evidence on the roles of reproductive and hormonal risk factors in RCC aetiology.Materials & MethodsWe investigated associations of age at menarche and age at menopause, pregnancy-related factors, hysterectomy and ovariectomy and exogenous hormone use with RCC risk among 298,042 women in the European Prospective Investigation into Cancer and Nutrition (EPIC) study.ResultsDuring 15 years of follow-up, 438 RCC cases were identified. Parous women had higher rates of RCC compared with nulliparous women (HR = 1.71, 95% CI 1.18, 2.46), and women who were older at age of first pregnancy had lower rates of RCC (30 years + vs. <20 years HR = 0.53, 95% CI 0.34, 0.82). Additionally, we identified a positive association for hysterectomy (HR = 1.43 95% CI 1.09, 1.86) and bilateral ovariectomy (HR = 1.67, 95% CI 1.13, 2.47), but not unilateral ovariectomy (HR = 0.99, 95% CI 0.61, 1.62) with RCC risk. No clear associations were found for age at menarche, age at menopause or exogenous hormone use.ConclusionOur results suggest that parity and reproductive organ surgeries may play a role in RCC aetiology.
Kenkhuis M-F, Klingestijn M, Fanshawe A-M, et al., 2023, Longitudinal associations of sedentary behavior and physical activity with body composition in colorectal cancer survivors up to 2 years post treatment, JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY, Vol: 149, Pages: 4063-4075, ISSN: 0171-5216
Watling CZ, Kelly RK, Murphy N, et al., 2023, Data from Prospective Analysis Reveals Associations between Carbohydrate Intakes, Genetic Predictors of Short-Chain Fatty Acid Synthesis, and Colorectal Cancer Risk
<jats:p><div>Abstract<p>Whole grain and fiber intakes may decrease the risk of colorectal cancer. The interplay between host genetic factors, colonization of specific bacteria, production of short-chain fatty acids (SCFA), and intake of whole grains and fiber could alter the protective role of carbohydrates against colorectal cancer. Here, we assessed intakes of types and sources of carbohydrates in 114,217 UK Biobank participants with detailed dietary data (2–5 24-hour dietary assessments), and a host polygenic score (PGS) was applied to categorize participants as high or low for intraluminal microbial SCFA production, namely, butyrate and propionate. Multivariable Cox proportional hazards models were used to determine the associations of carbohydrates and SCFA with colorectal cancer incidence. During a median follow-up of 9.4 years, 1,193 participants were diagnosed with colorectal cancer. Risk was inversely associated with intakes of non-free sugar and whole grain fiber. Evidence of heterogeneity was observed by the butyrate PGS; consuming higher amounts of whole grain starch was only associated with a lower risk of colorectal cancer in those with predicted high SCFA production. Similarly, in additional analyses utilizing the larger UK Biobank cohort (<i>N</i> = 343,621) with less detailed dietary assessment, only individuals with a high genetically predicted butyrate production had a lower risk of colorectal cancer per 5 g/day intake of bread and cereal fiber. This study suggests that colorectal cancer risk varies by intake of carbohydrate types and sources, and the impact of whole grain intake may be modified by SCFA production.</p>Significance:<p>Prospective population-level analyses provide evidence supporting the importance of butyrate production in reduction of colorectal cancer risk by whole grain consumption.</p></div></jats:p>
Watling CZ, Kelly RK, Murphy N, et al., 2023, Figure 4 from Prospective Analysis Reveals Associations between Carbohydrate Intakes, Genetic Predictors of Short-Chain Fatty Acid Synthesis, and Colorectal Cancer Risk
<jats:p><p>Multivariable-adjusted hazard ratios (95% CI) for intake of fiber from breads and cereals from the touchscreen questionnaire and colorectal cancer risk by genetically predicted host short-chain fatty acid production for butyrate (<b>A</b>) and propionate (<i>n</i> = 343,621; <b>B</b>). Models stratified for sex and age at recruitment, and further adjusted for region, first 10 principal components, height, physical activity, Townsend deprivation index, education, employment, smoking, alcohol consumption measured at recruitment, diabetes status, nonsteroidal anti-inflammatory drug use, body mass index, processed and red meat intake, and female-specific covariates: menopausal hormone therapy use and menopausal status. Analyses are restricted to white British participants. χ<sup>2</sup> and <i>P</i> value represents improvement of fit obtained from likelihood ratio tests for including an interaction term between butyrate or propionate polygenic score and fiber from breads and cereals (modeled as a 5 gram/day increment) into the model. g/day, grams per day; <i>N</i>, number of participants; Q, quintile; ref, reference group.</p></jats:p>
Watling CZ, Kelly RK, Murphy N, et al., 2023, Figure 4 from Prospective Analysis Reveals Associations between Carbohydrate Intakes, Genetic Predictors of Short-Chain Fatty Acid Synthesis, and Colorectal Cancer Risk
<jats:p><p>Multivariable-adjusted hazard ratios (95% CI) for intake of fiber from breads and cereals from the touchscreen questionnaire and colorectal cancer risk by genetically predicted host short-chain fatty acid production for butyrate (<b>A</b>) and propionate (<i>n</i> = 343,621; <b>B</b>). Models stratified for sex and age at recruitment, and further adjusted for region, first 10 principal components, height, physical activity, Townsend deprivation index, education, employment, smoking, alcohol consumption measured at recruitment, diabetes status, nonsteroidal anti-inflammatory drug use, body mass index, processed and red meat intake, and female-specific covariates: menopausal hormone therapy use and menopausal status. Analyses are restricted to white British participants. χ<sup>2</sup> and <i>P</i> value represents improvement of fit obtained from likelihood ratio tests for including an interaction term between butyrate or propionate polygenic score and fiber from breads and cereals (modeled as a 5 gram/day increment) into the model. g/day, grams per day; <i>N</i>, number of participants; Q, quintile; ref, reference group.</p></jats:p>
Watling CZ, Kelly RK, Murphy N, et al., 2023, Table 1 from Prospective Analysis Reveals Associations between Carbohydrate Intakes, Genetic Predictors of Short-Chain Fatty Acid Synthesis, and Colorectal Cancer Risk
<jats:p><p>Baseline characteristics by lowest and highest quartile of intake of whole grain starch, refined grain starch, and fiber in 114,217 UK Biobank participants.</p></jats:p>
Watling CZ, Kelly RK, Murphy N, et al., 2023, Data from Prospective Analysis Reveals Associations between Carbohydrate Intakes, Genetic Predictors of Short-Chain Fatty Acid Synthesis, and Colorectal Cancer Risk
<jats:p><div>Abstract<p>Whole grain and fiber intakes may decrease the risk of colorectal cancer. The interplay between host genetic factors, colonization of specific bacteria, production of short-chain fatty acids (SCFA), and intake of whole grains and fiber could alter the protective role of carbohydrates against colorectal cancer. Here, we assessed intakes of types and sources of carbohydrates in 114,217 UK Biobank participants with detailed dietary data (2–5 24-hour dietary assessments), and a host polygenic score (PGS) was applied to categorize participants as high or low for intraluminal microbial SCFA production, namely, butyrate and propionate. Multivariable Cox proportional hazards models were used to determine the associations of carbohydrates and SCFA with colorectal cancer incidence. During a median follow-up of 9.4 years, 1,193 participants were diagnosed with colorectal cancer. Risk was inversely associated with intakes of non-free sugar and whole grain fiber. Evidence of heterogeneity was observed by the butyrate PGS; consuming higher amounts of whole grain starch was only associated with a lower risk of colorectal cancer in those with predicted high SCFA production. Similarly, in additional analyses utilizing the larger UK Biobank cohort (<i>N</i> = 343,621) with less detailed dietary assessment, only individuals with a high genetically predicted butyrate production had a lower risk of colorectal cancer per 5 g/day intake of bread and cereal fiber. This study suggests that colorectal cancer risk varies by intake of carbohydrate types and sources, and the impact of whole grain intake may be modified by SCFA production.</p>Significance:<p>Prospective population-level analyses provide evidence supporting the importance of butyrate production in reduction of colorectal cancer risk by whole grain consumption.</p></div></jats:p>
Watling CZ, Kelly RK, Murphy N, et al., 2023, Supplementary Material from Prospective Analysis Reveals Associations between Carbohydrate Intakes, Genetic Predictors of Short-Chain Fatty Acid Synthesis, and Colorectal Cancer Risk
<jats:p><p>Supplementary Material</p></jats:p>
Watling CZ, Kelly RK, Murphy N, et al., 2023, Figure 3 from Prospective Analysis Reveals Associations between Carbohydrate Intakes, Genetic Predictors of Short-Chain Fatty Acid Synthesis, and Colorectal Cancer Risk
<jats:p><p>Multivariable-adjusted hazard ratios (95% CI) for intake of carbohydrates and fiber and colorectal cancer risk separated by genetically predicted host short-chain fatty acid production for butyrate (<b>A</b>) and propionate (<i>n</i> = 87,417; <b>B</b>). All models are stratified by sex, age at recruitment, adjusted for region of recruitment, first 10 genetic principal components, body mass index, height, physical activity, Townsend deprivation index, education, smoking, alcohol consumption, diabetes status, nonsteroidal anti-inflammatory drug use, red and processed meat intake, fruit and vegetable intake (except when fiber from vegetables and/or fruits, and non-free sugar intake was the exposure), energy intake, and female-specific covariates: menopausal hormone therapy use and menopausal status. Analyses are restricted to white British participants. χ<sup>2</sup> and <i>P</i> value represents improvement of fit obtained from likelihood ratio tests for including an interaction term between butyrate or propionate polygenic score and carbohydrate type/source (modeled as a 5% energy increment) or fiber source (modeled as a 5 gram/day increment) into the model.</p></jats:p>
Watling CZ, Kelly RK, Murphy N, et al., 2023, Figure 3 from Prospective Analysis Reveals Associations between Carbohydrate Intakes, Genetic Predictors of Short-Chain Fatty Acid Synthesis, and Colorectal Cancer Risk
<jats:p><p>Multivariable-adjusted hazard ratios (95% CI) for intake of carbohydrates and fiber and colorectal cancer risk separated by genetically predicted host short-chain fatty acid production for butyrate (<b>A</b>) and propionate (<i>n</i> = 87,417; <b>B</b>). All models are stratified by sex, age at recruitment, adjusted for region of recruitment, first 10 genetic principal components, body mass index, height, physical activity, Townsend deprivation index, education, smoking, alcohol consumption, diabetes status, nonsteroidal anti-inflammatory drug use, red and processed meat intake, fruit and vegetable intake (except when fiber from vegetables and/or fruits, and non-free sugar intake was the exposure), energy intake, and female-specific covariates: menopausal hormone therapy use and menopausal status. Analyses are restricted to white British participants. χ<sup>2</sup> and <i>P</i> value represents improvement of fit obtained from likelihood ratio tests for including an interaction term between butyrate or propionate polygenic score and carbohydrate type/source (modeled as a 5% energy increment) or fiber source (modeled as a 5 gram/day increment) into the model.</p></jats:p>
Watling CZ, Kelly RK, Murphy N, et al., 2023, Table 1 from Prospective Analysis Reveals Associations between Carbohydrate Intakes, Genetic Predictors of Short-Chain Fatty Acid Synthesis, and Colorectal Cancer Risk
<jats:p><p>Baseline characteristics by lowest and highest quartile of intake of whole grain starch, refined grain starch, and fiber in 114,217 UK Biobank participants.</p></jats:p>
Watling CZ, Kelly RK, Murphy N, et al., 2023, Supplementary Material from Prospective Analysis Reveals Associations between Carbohydrate Intakes, Genetic Predictors of Short-Chain Fatty Acid Synthesis, and Colorectal Cancer Risk
<jats:p><p>Supplementary Material</p></jats:p>
Watling CZ, Kelly RK, Murphy N, et al., 2023, Prospective Analysis Reveals Associations between Carbohydrate Intakes, Genetic Predictors of Short-Chain Fatty Acid Synthesis, and Colorectal Cancer Risk, CANCER RESEARCH, Vol: 83, Pages: 2066-2076, ISSN: 0008-5472
Fournier A, Cairat M, Severi G, et al., 2023, Use of menopausal hormone therapy and ovarian cancer risk in a French cohort study, JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE, Vol: 115, Pages: 671-679, ISSN: 0027-8874
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