Associations between dietary inflammatory scores and biomarkers of inflammation in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.

BACKGROUND: Since the first version of the dietary inflammatory index (DII®) developed in the past decade, several other versions have been developed. However, to date no study has attempted to compare these versions with respect to their associations with biomarkers of inflammation. OBJECTIVE: We aimed to investigate the relationship between four dietary inflammatory scores [DII, two energy-adjusted derivatives (E-DII and E-DIIr), and the Inflammatory Score of the Diet (ISD)], and circulating levels of several inflammatory markers and adipokines. METHODS: This study included 17 637 participants from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort with at least one marker of inflammation measured in blood. Associations between the four scores and C-reactive protein (CRP), interleukin (IL)6, IL10, IL1RA, tumor necrosis factor-α (TNFα), soluble tumor necrosis factor receptor-1 (sTNFR1), sTNFR2, leptin, soluble leptin receptor (sLeptin R), adiponectin, and High Molecular Weight (HMW) adiponectin were evaluated using multivariable linear regressions adjusted for potential confounders. RESULTS: Positive associations were observed between the four dietary inflammatory scores and levels of CRP, IL6, sTNFR1, sTNFR2 and leptin. However, only the DII and the ISD were positively associated with IL1RA levels and only the DII and the E-DIIr were positively associated with TNFα levels. The proportion of variance of each biomarker explained by the scores was lower than 2%, which was equivalent to the variance explained by smoking status but much lower than that explained by body mass index. CONCLUSIONS: Our results suggest that the four dietary inflammatory scores were associated with some biomarkers of inflammation and could be used to assess the inflammatory potential of diet in European adults but are not sufficient to capture the inflammatory status of an individual. These findings can help to better understand the inflammatory potential of diet, but they need to be replicated in studies with repeated dietary measurements.

Validation of the cutaneous impact location to predict intracranial lesion among elderly admitted to the Emergency Department after a ground-level fall.

INTRODUCTION: In the Emergency Departments, almost one out of two head CT scans are carried out for traumatic brain injuries among elderly victims of ground level-falls. Recently, a new predictive factor for intracranial lesions in this population has been suggested: presence and location of cutaneous impact. The aim of this study was to establish determinants of intracranial lesion among older patients admitted to EDs due to ground-level falls with traumatic brain injury using the head cutaneous impact location. METHODS: A retrospective, observational and monocentric study of patients admitted to Emergency Department for ground-level falls with traumatic brain injury was carried out between 01 January 2017 and 31 July 2017. The primary outcome was identification of an acute intracranial lesion. A bootstrap procedure was employed to evaluate performance and internal validity of the final model. RESULTS: Among the 1036 patients included, the mean age was 85.6 (SD 7.6) years and 94/1036 (9.1%, 95% CI 7.4-10.9) patients presented with an acute intracranial lesion. Multivariable analysis adjusted by bootstrap shrinkage showed that compared with temporal-parietal or occipital impact, Odds Ratio of intracranial lesions were 0.61 (95% CI 0.39-0.95, p = 0.03) in patients with frontal impact, 0.27 (95% CI 0.12-0.59, p = 0.001) in patients with facial impact and 0.21 (95% CI 0.06-0.77, p = 0.018) in patients without cutaneous impact. Subcutaneous hematoma (OR 1.97, p = 0.007), loss of consciousness (OR 4.66, p<0.001), fall-related amnesia (OR 2.58, p = 2.6), vomiting (OR 2.62, p = 0.002) and altered Glasgow Score (OR 6.79, p<0.001) were as well associated with high risk of intracranial lesion. Taking antiplatelets or anticoagulants were not associated with an increased risk of intracranial lesions. The model discrimination was adequate (C-statistic 0.79; 95% CI 0.73 - 0.85). CONCLUSION: Our results establish specific determinants of intracranial lesions among elderly after ground level-falls. The cutaneous impact location may identify patients with high risk of intracranial lesion. Further researches are needed to propose a specific score based on these determinants so as to better target Head CT scan use.

The Plasma Oxylipin Signature Provides a Deep Phenotyping of Metabolic Syndrome Complementary to the Clinical Criteria.

Metabolic syndrome (MetS) is a complex condition encompassing a constellation of cardiometabolic abnormalities. Oxylipins are a superfamily of lipid mediators regulating many cardiometabolic functions. Plasma oxylipin signature could provide a new clinical tool to enhance the phenotyping of MetS pathophysiology. A high-throughput validated mass spectrometry method, allowing for the quantitative profiling of over 130 oxylipins, was applied to identify and validate the oxylipin signature of MetS in two independent nested case/control studies involving 476 participants. We identified an oxylipin signature of MetS (coined OxyScore), including 23 oxylipins and having high performances in classification and replicability (cross-validated AUCROC of 89%, 95% CI: 85-93% and 78%, 95% CI: 72-85% in the Discovery and Replication studies, respectively). Correlation analysis and comparison with a classification model incorporating the MetS criteria showed that the oxylipin signature brings consistent and complementary information to the clinical criteria. Being linked with the regulation of various biological processes, the candidate oxylipins provide an integrative phenotyping of MetS regarding the activation and/or negative feedback regulation of crucial molecular pathways. This may help identify patients at higher risk of cardiometabolic diseases. The oxylipin signature of patients with metabolic syndrome enhances MetS phenotyping and may ultimately help to better stratify the risk of cardiometabolic diseases.

Inflammatory potential of the diet and association with risk of differentiated thyroid cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.

PURPOSE: Chronic inflammation is thought to initiate or promote differentiated thyroid cancer (DTC) and previous studies have shown that diet can modulate this inflammatory process. We aimed to evaluate the association of several dietary scores reflecting the inflammatory potential of the diet with DTC risk. METHODS: Within the EPIC cohort, 450,063 participants were followed during a mean period of 14 years, and 712 newly incident DTC cases were identified. Associations between four dietary inflammatory scores [the dietary inflammatory index (DII®) and two energy-adjusted derivatives (the E-DIIr and the E-DIId), and the Inflammatory Score of the Diet (ISD)] and DTC risk were evaluated in the EPIC cohort using multivariable Cox regression models. RESULTS: Positive associations were observed between DTC risk and the DIIs (HR for 1 SD increase in DII: 1.11, 95%CI: 1.01, 1.23, similar results for its derivatives), but not with the ISD (HR for 1 SD increase: 1.04, 95% CI 0.93, 1.16). CONCLUSION: Diet-associated inflammation, as estimated by the DII and its derivatives, was weakly positively associated with DTC risk in a European adult population. These results suggesting that diet-associated inflammation acts in the etiology of DTC need to be validated in independent studies.

Adapted dietary inflammatory index and differentiated thyroid carcinoma risk in two French population-based case-control studies.

PURPOSE: Thyroid cancer is the most common endocrine cancer and its etiology is still not well understood. The aim of the present study was to assess the association between an adapted dietary inflammatory index and differentiated thyroid cancer (DTC) risk in two population-based case-control studies (CATHY and YOUNG-THYR) conducted in France. METHODS: These studies included a total of 1321 DTC cases and 1502 controls, for which an adapted dietary inflammatory index (ADII) was computed based on food frequency questionnaires in each study separately. The association between ADII and thyroid cancer risk was assessed using logistic regression models controlling for potential confounders. RESULTS: Higher ADII scores, corresponding to a higher pro-inflammatory potential of the diet, were associated with higher DTC risk (odds ratio (OR) for 1 standard deviation (SD) increase: 1.09, 95% confidence interval (CI): 1.01, 1.18, P: 0.03). Associations were stronger in analyses restricted to women (OR for 1-SD increase: 1.14, 95% CI 1.04, 1.25, P: 0.005), as well as in women with lower education level, current smoking, or high body mass index. CONCLUSION: Our study suggests that a pro-inflammatory diet is associated with an increased risk of DTC, especially when combined with other inflammatory conditions such as tobacco smoking or overweight. Our findings will help better understand the role of diet-induced inflammation in DTC etiology.

Lifestyle correlates of eight breast cancer-related metabolites: a cross-sectional study within the EPIC cohort.

BACKGROUND: Metabolomics is a promising molecular tool for identifying novel etiological pathways leading to cancer. In an earlier prospective study among pre- and postmenopausal women not using exogenous hormones, we observed a higher risk of breast cancer associated with higher blood concentrations of one metabolite (acetylcarnitine) and a lower risk associated with higher blood concentrations of seven others (arginine, asparagine, phosphatidylcholines (PCs) aa C36:3, ae C34:2, ae C36:2, ae C36:3, and ae C38:2). METHODS: To identify determinants of these breast cancer-related metabolites, we conducted a cross-sectional analysis to identify their lifestyle and anthropometric correlates in 2358 women, who were previously included as controls in case-control studies nested within the European Prospective Investigation into Cancer and Nutrition cohort and not using exogenous hormones at blood collection. Associations of each metabolite concentration with 42 variables were assessed using linear regression models in a discovery set of 1572 participants. Significant associations were evaluated in a validation set (n = 786). RESULTS: For the metabolites previously associated with a lower risk of breast cancer, concentrations of PCs ae C34:2, C36:2, C36:3, and C38:2 were negatively associated with adiposity and positively associated with total and saturated fat intakes. PC ae C36:2 was also negatively associated with alcohol consumption and positively associated with two scores reflecting adherence to a healthy lifestyle. Asparagine concentration was negatively associated with adiposity. Arginine and PC aa C36:3 concentrations were not associated to any of the factors examined. For the metabolite previously associated with a higher risk of breast cancer, acetylcarnitine, a positive association with age was observed. CONCLUSIONS: These associations may indicate possible mechanisms underlying associations between lifestyle and anthropometric factors, and risk of breast cancer. Further research is needed to identify potential non-lifestyle correlates of the metabolites investigated.

A New Pipeline for the Normalization and Pooling of Metabolomics Data.

Pooling metabolomics data across studies is often desirable to increase the statistical power of the analysis. However, this can raise methodological challenges as several preanalytical and analytical factors could introduce differences in measured concentrations and variability between datasets. Specifically, different studies may use variable sample types (e.g., serum versus plasma) collected, treated, and stored according to different protocols, and assayed in different laboratories using different instruments. To address these issues, a new pipeline was developed to normalize and pool metabolomics data through a set of sequential steps: (i) exclusions of the least informative observations and metabolites and removal of outliers; imputation of missing data; (ii) identification of the main sources of variability through principal component partial R-square (PC-PR2) analysis; (iii) application of linear mixed models to remove unwanted variability, including samples' originating study and batch, and preserve biological variations while accounting for potential differences in the residual variances across studies. This pipeline was applied to targeted metabolomics data acquired using Biocrates AbsoluteIDQ kits in eight case-control studies nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Comprehensive examination of metabolomics measurements indicated that the pipeline improved the comparability of data across the studies. Our pipeline can be adapted to normalize other molecular data, including biomarkers as well as proteomics data, and could be used for pooling molecular datasets, for example in international consortia, to limit biases introduced by inter-study variability. This versatility of the pipeline makes our work of potential interest to molecular epidemiologists.

Plasma Metabolomics for Discovery of Early Metabolic Markers of Prostate Cancer Based on Ultra-High-Performance Liquid Chromatography-High Resolution Mass Spectrometry.

BACKGROUND: The prevention and early screening of PCa is highly dependent on the identification of new biomarkers. In this study, we investigated whether plasma metabolic profiles from healthy males provide novel early biomarkers associated with future risk of PCa. METHODS: Using the Supplémentation en Vitamines et Minéraux Antioxydants (SU.VI.MAX) cohort, we identified plasma samples collected from 146 PCa cases up to 13 years prior to diagnosis and 272 matched controls. Plasma metabolic profiles were characterized using ultra-high-performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS). RESULTS: Orthogonal partial least squares discriminant analysis (OPLS-DA) discriminated PCa cases from controls, with a median area under the receiver operating characteristic curve (AU-ROC) of 0.92 using a 1000-time repeated random sub-sampling validation. Sparse Partial Least Squares Discriminant Analysis (sPLS-DA) identified the top 10 most important metabolites (p < 0.001) discriminating PCa cases from controls. Among them, phosphate, ethyl oleate, eicosadienoic acid were higher in individuals that developed PCa than in the controls during the follow-up. In contrast, 2-hydroxyadenine, sphinganine, L-glutamic acid, serotonin, 7-keto cholesterol, tiglyl carnitine, and sphingosine were lower. CONCLUSION: Our results support the dysregulation of amino acids and sphingolipid metabolism during the development of PCa. After validation in an independent cohort, these signatures may promote the development of new prevention and screening strategies to identify males at future risk of PCa.

Prospective analysis of circulating metabolites and endometrial cancer risk.

BACKGROUND: Endometrial cancer is strongly associated with obesity and dysregulation of metabolic factors such as estrogen and insulin signaling are causal risk factors for this malignancy. To identify additional novel metabolic pathways associated with endometrial cancer we performed metabolomic analyses on pre-diagnostic plasma samples from 853 case-control pairs from the European Prospective Investigation into Cancer and Nutrition (EPIC). METHODS: A total of 129 metabolites (acylcarnitines, amino acids, biogenic amines, glycerophospholipids, hexoses, and sphingolipids) were measured by liquid chromatography-mass spectrometry. Conditional logistic regression estimated the associations of metabolites with endometrial cancer risk. An analysis focusing on clusters of metabolites using the bootstrap lasso method was also employed. RESULTS: After adjustment for body mass index, sphingomyelin [SM] C18:0 was positively (OR1SD: 1.18, 95% CI: 1.05-1.33), and glycine, serine, and free carnitine (C0) were inversely (OR1SD: 0.89, 95% CI: 0.80-0.99; OR1SD: 0.89, 95% CI: 0.79-1.00 and OR1SD: 0.91, 95% CI: 0.81-1.00, respectively) associated with endometrial cancer risk. Serine, C0 and two sphingomyelins were selected by the lasso method in >90% of the bootstrap samples. The ratio of esterified to free carnitine (OR1SD: 1.14, 95% CI: 1.02-1.28) and that of short chain to free acylcarnitines (OR1SD: 1.12, 95% CI: 1.00-1.25) were positively associated with endometrial cancer risk. Further adjustment for C-peptide or other endometrial cancer risk factors only minimally altered the results. CONCLUSION: These findings suggest that variation in levels of glycine, serine, SM C18:0 and free carnitine may represent specific pathways linked to endometrial cancer development. If causal, these pathways may offer novel targets for endometrial cancer prevention.

NMR metabolomic profiles associated with long-term risk of prostate cancer.

INTRODUCTION: Prostate cancer is a multifactorial disease whose aetiology is still not fully understood. Metabolomics, by measuring several hundred metabolites simultaneously, could enhance knowledge on the metabolic changes involved and the potential impact of external factors. OBJECTIVES: The aim of the present study was to investigate whether pre-diagnostic plasma metabolomic profiles were associated with the risk of developing a prostate cancer within the following decade. METHODS: A prospective nested case-control study was set up among the 5141 men participant of the SU.VI.MAX cohort, including 171 prostate cancer cases, diagnosed between 1994 and 2007, and 171 matched controls. Nuclear magnetic resonance (NMR) metabolomic profiles were established from baseline plasma samples using NOESY1D and CPMG sequences. Multivariable conditional logistic regression models were computed for each individual NMR signal and for metabolomic patterns derived using principal component analysis. RESULTS: Men with higher fasting plasma levels of valine (odds ratio (OR) = 1.37 [1.07-1.76], p = .01), glutamine (OR = 1.30 [1.00-1.70], p = .047), creatine (OR = 1.37 [1.04-1.80], p = .02), albumin lysyl (OR = 1.48 [1.12-1.95], p = .006 and OR = 1.51 [1.13-2.02], p = .005), tyrosine (OR = 1.40 [1.06-1.85], p = .02), phenylalanine (OR = 1.39 [1.08-1.79], p = .01), histidine (OR = 1.46 [1.12-1.88], p = .004), 3-methylhistidine (OR = 1.37 [1.05-1.80], p = .02) and lower plasma level of urea (OR = .70 [.54-.92], p = .009) had a higher risk of developing a prostate cancer during the 13 years of follow-up. CONCLUSIONS: This exploratory study highlighted associations between baseline plasma metabolomic profiles and long-term risk of developing prostate cancer. If replicated in independent cohort studies, such signatures may improve the identification of men at risk for prostate cancer well before diagnosis and the understanding of this disease.

Investigation of circulating metabolites associated with breast cancer risk by untargeted metabolomics: a case-control study nested within the French E3N cohort.

BACKGROUND: Perturbations in circulating metabolites prior to a breast cancer diagnosis are not well characterised. We aimed to gain more detailed knowledge to help understand and prevent the disease. METHODS: Baseline plasma samples from 791 breast cancer cases and 791 matched controls from the E3N (EPIC-France) cohort were profiled by nuclear magnetic resonance (NMR)-based untargeted metabolomics. Partial least-squares discriminant analysis (PLS-DA) models were built from NMR profiles to predict disease outcome, and odds ratios and false discovery rate (FDR)-adjusted CIs were calculated for 43 identified metabolites by conditional logistic regression. RESULTS: Breast cancer onset was predicted in the premenopausal subgroup with modest accuracy (AUC 0.61, 95% CI: 0.49-0.73), and 10 metabolites associated with risk, particularly histidine (OR = 1.70 per SD increase, FDR-adjusted CI 1.19-2.41), N-acetyl glycoproteins (OR = 1.53, FDR-adjusted CI 1.18-1.97), glycerol (OR = 1.55, FDR-adjusted CI 1.11-2.18) and ethanol (OR = 1.44, FDR-adjusted CI 1.05-1.97). No predictive capacity or significant metabolites were found overall or for postmenopausal women. CONCLUSIONS: Perturbed metabolism compared to controls was observed in premenopausal but not postmenopausal cases. Histidine and NAC have known involvement in inflammatory pathways, and the robust association of ethanol with risk suggests the involvement of alcohol intake.

Blood polyphenol concentrations and differentiated thyroid carcinoma in women from the European Prospective Investigation into Cancer and Nutrition (EPIC) study.

BACKGROUND: Polyphenols are natural compounds with anticarcinogenic properties in cellular and animal models, but epidemiological evidence determining the associations of these compounds with thyroid cancer (TC) is lacking. OBJECTIVES: The aim of this study was to evaluate the relations between blood concentrations of 36 polyphenols and TC risk in EPIC (the European Prospective Investigation into Cancer and Nutrition). METHODS: A nested case-control study was conducted on 273 female cases (210 papillary, 45 follicular, and 18 not otherwise specified TC tumors) and 512 strictly matched controls. Blood polyphenol concentrations were analyzed by HPLC coupled to tandem MS after enzymatic hydrolysis. RESULTS: Using multivariable-adjusted conditional logistic regression models, caffeic acid (ORlog2: 0.55; 95% CI: 0.33, 0.93) and its dehydrogenated metabolite, 3,4-dihydroxyphenylpropionic acid (ORlog2: 0.84; 95% CI: 0.71, 0.99), were inversely associated with differentiated TC risk. Similar results were observed for papillary TC, but not for follicular TC. Ferulic acid was also inversely associated only with papillary TC (ORlog2: 0.68; 95% CI: 0.51, 0.91). However, none of these relations was significant after Bonferroni correction for multiple testing. No association was observed for any of the remaining polyphenols with total differentiated, papillary, or follicular TC. CONCLUSIONS: Blood polyphenol concentrations were mostly not associated with differentiated TC risk in women, although our study raises the possibility that high blood concentrations of caffeic, 3,4-dihydroxyphenylpropionic, and ferulic acids may be related to a lower papillary TC risk.

Associations between untargeted plasma metabolomic signatures and gut microbiota composition in the Milieu Intérieur population of healthy adults.

Host-microbial co-metabolism products are being increasingly recognised to play important roles in physiological processes. However, studies undertaking a comprehensive approach to consider host-microbial metabolic relationships remain scarce. Metabolomic analysis yielding detailed information regarding metabolites found in a given biological compartment holds promise for such an approach. This work aimed to explore the associations between host plasma metabolomic signatures and gut microbiota composition in healthy adults of the Milieu Intérieur study. For 846 subjects, gut microbiota composition was profiled through sequencing of the 16S rRNA gene in stools. Metabolomic signatures were generated through proton NMR analysis of plasma. The associations between metabolomic variables and α- and ß-diversity indexes and relative taxa abundances were tested using multi-adjusted partial Spearman correlations, permutational ANOVA and multivariate associations with linear models, respectively. A multiple testing correction was applied (Benjamini-Hochberg, 10 % false discovery rate). Microbial richness was negatively associated with lipid-related signals and positively associated with amino acids, choline, creatinine, glucose and citrate (-0·133 ≤ Spearman's ρ ≤ 0·126). Specific associations between metabolomic signals and abundances of taxa were detected (twenty-five at the genus level and nineteen at the species level): notably, numerous associations were observed for creatinine (positively associated with eleven species and negatively associated with Faecalibacterium prausnitzii). This large-scale population-based study highlights metabolites associated with gut microbial features and provides new insights into the understanding of complex host-gut microbiota metabolic relationships. In particular, our results support the implication of a 'gut-kidney axis'. More studies providing a detailed exploration of these complex interactions and their implications for host health are needed.

Untargeted plasma metabolomic profiles associated with overall diet in women from the SU.VI.MAX cohort.

PURPOSE: Dietary intakes are reflected in plasma by the presence of hundreds of exogenous metabolites and variations in endogenous metabolites. The exploration of diet-related plasma metabolic profiles could help to better understand the impact of overall diet on health. Our aim was to identify metabolomic signatures reflecting overall diet in women from the French general population. METHODS: This cross-sectional study included 160 women in the SU.VI.MAX cohort with detailed dietary data (≥ 10 24-h dietary records) selected according to their level of adherence to the French dietary recommendations, represented by the validated score mPNNS-GS; 80 women from the 10th decile of the score were matched with 80 women from the 1st decile. Plasma metabolomic profiles were acquired using untargeted UPLC-QToF mass spectrometry analysis. The associations between metabolomic profiles and the mPNNG-GS, its components and Principal Component Analyses-derived dietary patterns were investigated using multivariable conditional logistic regression models and partial correlations. RESULTS: Adherence to the dietary recommendations was positively associated with 3-indolepropionic acid and pipecolic acid (also positively associated with fruit and vegetable intake and a healthy diet)-2 metabolites linked to microbiota and inversely associated with lysophosphatidylcholine (LysoPC(17:1)), acylcarnitine C9:1 (also inversely associated with a healthy diet), acylcarnitine C11:1 and 2-deoxy-D-glucose. Increased plasma levels of piperine and Dihydro4mercapto-3(2H) furanone were observed in women who consumed a Western diet and a healthy diet, respectively. Ethyl-ß-D-glucopyranoside was positively associated with alcohol intake. Plasma levels of LysoPC(17:1), cholic acid, phenylalanine-phenylalanine and phenylalanine and carnitine C9:1 decreased with the consumption of vegetable added fat, sweetened food, milk and dairy products and fruit and vegetable intakes, respectively. CONCLUSION: This study highlighted several metabolites from both host and microbial metabolism reflecting the long-term impact of the overall diet. TRIAL REGISTRATION: SU.VI.MAX, clinicaltrials.gov NCT00272428. Registered 3 January 2006, https://clinicaltrials.gov/show/NCT00272428.

Diet-Related Metabolomic Signature of Long-Term Breast Cancer Risk Using Penalized Regression: An Exploratory Study in the SU.VI.MAX Cohort.

BACKGROUND: Diet has been recognized as a modifiable risk factor for breast cancer. Highlighting predictive diet-related biomarkers would be of great public health relevance to identify at-risk subjects. The aim of this exploratory study was to select diet-related metabolites discriminating women at higher risk of breast cancer using untargeted metabolomics. METHODS: Baseline plasma samples of 200 incident breast cancer cases and matched controls, from a nested case-control study within the Supplémentation en Vitamines et Minéraux Antioxydants (SU.VI.MAX) cohort, were analyzed by untargeted LC-MS. Diet-related metabolites were identified by partial correlation with dietary exposures, and best predictors of breast cancer risk were then selected by Elastic Net penalized regression. The selection stability was assessed using bootstrap resampling. RESULTS: 595 ions were selected as candidate diet-related metabolites. Fourteen of them were selected by Elastic Net regression as breast cancer risk discriminant ions. A lower level of piperine (a compound from pepper) and higher levels of acetyltributylcitrate (an alternative plasticizer to phthalates), pregnene-triol sulfate (a steroid sulfate), and 2-amino-4-cyano butanoic acid (a metabolite linked to microbiota metabolism) were observed in plasma from women who subsequently developed breast cancer. This metabolomic signature was related to several dietary exposures such as a "Western" dietary pattern and higher alcohol and coffee intakes. CONCLUSIONS: Our study suggested a diet-related plasma metabolic signature involving exogenous, steroid metabolites, and microbiota-related compounds associated with long-term breast cancer risk that should be confirmed in large-scale independent studies. IMPACT: These results could help to identify healthy women at higher risk of breast cancer and improve the understanding of nutrition and health relationship.

Plasma Metabolomic Signatures Associated with Long-term Breast Cancer Risk in the SU.VI.MAX Prospective Cohort.

BACKGROUND: Breast cancer is a major cause of death in occidental women. The role of metabolism in breast cancer etiology remains unclear. Metabolomics may help to elucidate novel biological pathways and identify new biomarkers to predict breast cancer long before symptoms appear. The aim of this study was to investigate whether untargeted metabolomic signatures from blood draws of healthy women could contribute to better understand and predict the long-term risk of developing breast cancer. METHODS: A nested case-control study was conducted within the SU.VI.MAX prospective cohort (13 years of follow-up) to analyze baseline plasma samples of 211 incident breast cancer cases and 211 matched controls by LC/MS. Multivariable conditional logistic regression models were computed. RESULTS: A total of 3,565 ions were detected and 1,221 were retained for statistical analysis. A total of 73 ions were associated with breast cancer risk (P < 0.01; FDR ≤ 0.2). Notably, we observed that a lower plasma level of O-succinyl-homoserine (OR = 0.70, 95%CI = [0.55-0.89]) and higher plasma levels of valine/norvaline [1.45 (1.15-1.83)], glutamine/isoglutamine [1.33 (1.07-1.66)], 5-aminovaleric acid [1.46 (1.14-1.87)], phenylalanine [1.43 (1.14-1.78)], tryptophan [1.40 (1.10-1.79)], γ-glutamyl-threonine [1.39 (1.09-1.77)], ATBC [1.41 (1.10-1.79)], and pregnene-triol sulfate [1.38 (1.08-1.77)] were associated with an increased risk of developing breast cancer during follow-up.Conclusion: Several prediagnostic plasmatic metabolites were associated with long-term breast cancer risk and suggested a role of microbiota metabolism and environmental exposure. IMPACT: After confirmation in other independent cohort studies, these results could help to identify healthy women at higher risk of developing breast cancer in the subsequent decade and to propose a better understanding of the complex mechanisms involved in its etiology.

NMR metabolomic signatures reveal predictive plasma metabolites associated with long-term risk of developing breast cancer.

Background: Combination of metabolomics and epidemiological approaches opens new perspectives for ground-breaking discoveries. The aim of the present study was to investigate for the first time whether plasma untargeted metabolomic profiles, established from a simple blood draw from healthy women, could contribute to predict the risk of developing breast cancer within the following decade and to better understand the aetiology of this complex disease. Methods: A prospective nested case-control study was set up in the Supplémentation en Vitamines et Minéraux Antioxydants (SU.VI.MAX) cohort, including 206 breast cancer cases diagnosed during a 13-year follow-up and 396 matched controls. Untargeted nuclear magnetic resonance (NMR) metabolomic profiles were established from baseline plasma samples. Multivariable conditional logistic regression models were computed for each individual NMR variable and for combinations of variables derived by principal component analysis. Results: Several metabolomic variables from 1D NMR spectroscopy were associated with breast cancer risk. Women characterized by higher fasting plasma levels of valine, lysine, arginine, glutamine, creatine, creatinine and glucose, and lower plasma levels of lipoproteins, lipids, glycoproteins, acetone, glycerol-derived compounds and unsaturated lipids had a higher risk of developing breast cancer. P-values ranged from 0.00007 [odds ratio (OR)T3vsT1=0.37 (0.23-0.61) for glycerol-derived compounds] to 0.04 [ORT3vsT1=1.61 (1.02-2.55) for glutamine]. Conclusion: This study highlighted associations between baseline NMR plasma metabolomic signatures and long-term breast cancer risk. These results provide interesting insights to better understand complex mechanisms involved in breast carcinogenesis and evoke plasma metabolic disorders favourable for carcinogenesis initiation. This study may contribute to develop screening strategies for the identification of at-risk women for breast cancer well before symptoms appear.

Antioxidant intake from diet and supplements and risk of digestive cancers in middle-aged adults: results from the prospective NutriNet-Santé cohort.

Experimental studies suggest beneficial effects of antioxidants in digestive cancer prevention. However, epidemiological results are contrasting and few studies quantitatively assessed supplemental intake. This study aimed at investigating the associations between antioxidant intakes (dietary, supplemental and total) and digestive cancer risk. This prospective study included 38 812 middle-aged subjects (≥45 years) from the NutriNet-Santé cohort (2009-2016). Dietary data were collected using repeated 24 h records. A specific questionnaire assessed dietary supplement use over a 12-month period. A composition database of about 8000 dietary supplements was developed. Associations between continuous and sex-specific quartiles of vitamins C and E, ß-carotene and Se intakes and digestive cancer risk were characterised using multivariable Cox proportional hazard models. A total of 167 incident digestive cancers (120 colorectal, twenty-six pancreatic, nine oesophagus, seven stomach and five liver) were diagnosed during follow-up investigation. Dietary (hazard ratios (HR)Q4 v. Q1=0·56; 95 % CI 0·34, 0·91, P trend=0·01) and total (HRQ4 v. Q1=0·51; 95 % CI 0·30, 0·84, P trend=0·008) vitamin C intakes, dietary (HRQ4 v. Q1=0·56; 95 % CI 0·34, 0·92, P trend=0·005) and total (HRQ4 v. Q1=0·58; 95 % CI 0·36, 0·94, P trend=0·003) vitamin E intakes, and dietary (HRfor an increment of 10 µg/d=0·92; 95 % CI 0·85, 1·00, P=0·04) and total (HRfor an increment of 10 µg/d=0·92; 95 % CI 0·86, 0·99, P=0·03) Se intakes were associated with a decreased digestive cancer risk. Statistically significant interactions were observed between dietary and total Se intakes and alcohol consumption as well as between total vitamin E intake and smoking status. This prospective cohort study with quantitative assessment of supplemental intakes suggests a potential protective effect of several antioxidants (vitamins C and E and Se) on digestive cancer risk, and a modulation of some of these relationships by alcohol consumption and smoking status.

Are self-reported unhealthy food choices associated with an increased risk of breast cancer? Prospective cohort study using the British Food Standards Agency nutrient profiling system.

OBJECTIVES: French authorities are considering the implementation of a simplified nutrition labelling system on food products to help consumers make healthier food choices. One of the most documented candidates (Five-Colour Nutrition Label/Nutri-score) is based on the British Food Standards Agency Nutrient Profiling System (FSA-NPS), a score calculated for each food/beverage using the 100 g amount of energy, sugar, saturated fatty acid, sodium, fibres, proteins, and fruits and vegetables. To assess its potential public health relevance, studies were conducted on the association between the nutritional quality of the diet, measured at the individual level by an energy-weighted mean of all FSA-NPS scores of foods usually consumed (FSA-NPS dietary index (FSA-NPS DI)), and the risk of chronic diseases. The present study aimed at investigating the relationship between the FSA-NPS DI and breast cancer risk. DESIGN: Prospective study. SETTING: Population based, NutriNet-Santé cohort, France. PARTICIPANTS: 46 864 women aged ≥35 years who completed ≥3 24-hour dietary records during their first 2 year of follow-up. PRIMARY OUTCOME MEASURE: Associations between FSA-NPS DI and breast cancer risk (555 incident breast cancers diagnosed between 2009 and 2015) were characterised by multivariable-adjusted Cox proportional hazard models. RESULTS: A higher FSA-NPS DI (lower nutritional quality of the diet) was associated with an increased breast cancer risk (HR1-point increment=1.06 (1.02-1.11), p=0.005; HRQ5vs.Q1=1.52 (1.11-2.08), p trend=0.002). Similar trends were observed in premenopausal and postmenopausal women (HR1-point increment=1.09 (1.01-1.18) and 1.05 (1.00-1.11), respectively).This study was based on an observational cohort using self-reported dietary data, thus residual confounding cannot be entirely ruled out. Finally, this holistic approach does not allow investigating which factors in the diet most specifically influence breast cancer risk. CONCLUSIONS: These results suggested that unhealthy food choices, as characterised by the FSA-NPS, may be associated with an increase in breast cancer risk, supporting the potential public health relevance of using this profiling system in the framework of public health nutritional measures.

B-Vitamin Intake from Diet and Supplements and Breast Cancer Risk in Middle-Aged Women: Results from the Prospective NutriNet-Santé Cohort.

Experimental studies suggest a protective effect of B-vitamins on breast cancer risk, potentially modulated by alcohol intake. However, epidemiological studies are limited, especially regarding non-folate B-vitamins. Furthermore, few studies included quantitative assessment of supplemental intake. This prospective study aimed to investigate the associations between intakes of B-vitamins (dietary, supplemental, total) and breast cancer risk. 27,853 women aged ≥45 years from the NutriNet-Santé cohort (2009-2016) were included, with a median follow-up time of 4.2 years. Dietary data were collected using repeated 24 h records. A specific questionnaire assessed dietary supplement use over a 12-month period. A composition database of 8000 supplements was developed. Associations were characterized by multivariable Cox models, and 462 incident breast cancers were diagnosed. Dietary (HRQ4vs.Q1 = 0.74 (0.55, 0.99), P-trend = 0.05), supplemental (HRQ4vs.Q1 = 0.61 (0.38, 0.98), P-trend = 0.05), and total (HRQ4vs.Q1 = 0.67 (0.50, 0.91), P-trend = 0.01) pyridoxine intakes were inversely associated with breast cancer risk. Total thiamin intake was borderline inversely associated with breast cancer risk (HRper 1-unit increment = 0.78 (0.61, 1.00), P = 0.05). Statistically significant interactions between alcohol consumption and B-vitamin (thiamin, riboflavin, niacin, pantothenic acid, pyridoxine, folate, and cobalamin) supplemental intake were observed, the latter being inversely associated with breast cancer risk in non-to-low alcohol drinkers but not in higher drinkers. This large prospective study, including quantitative assessment of supplemental intake, suggests a potential protective effect of pyridoxine and thiamin on breast cancer risk in middle-aged women.