Prognostic role of pre-diagnostic circulating inflammatory biomarkers in breast cancer survival: evidence from the EPIC cohort study.

BACKGROUND: Inflammation influences tumour progression and cancer prognosis, but its role preceding breast cancer (BC) and its prognostic implications remain inconclusive. METHODS: We studied pre-diagnostic plasma inflammatory biomarkers in 1538 women with BC from the EPIC study. Cox proportional hazards models assessed their relationship with all-cause and BC-specific mortality, adjusting for tumour characteristics and lifestyle factors. RESULTS: Over a 7-year follow-up after diagnosis, 229 women died, 163 from BC. Elevated IL-6 levels were associated with increased all-cause mortality risk (HR1-SD 1.25, 95% CI 1.07-1.47). Among postmenopausal, IL-6 was associated with higher all-cause (HR1-SD 1.41, 95% CI 1.18-1.69) and BC-specific mortality (HR1-SD 1.31, 95% CI 1.03-1.66), (PHeterogeneity (pre/postmenopausal) < 0.05 for both), while IL-10 and TNFα were associated with all-cause mortality only (HR1-SD 1.19, 95% CI 1.02-1.40 and HR1-SD 1.28, 95% CI 1.06-1.56). Among ER+PR+, IL-10 was associated with all-cause and BC-specific mortality (HR1-SD 1.35, 95% CI 1.10-1.65 and HR1-SD 1.42 95% CI 1.08-1.86), while TNF-α was associated with all-cause mortality in HER2- (HR1-SD 1.31, 95% CI 1.07-1.61). An inflammatory score predicted higher all-cause mortality, especially in postmenopausal women (HR1-SD 1.30, 95% CI 1.07-1.58). CONCLUSIONS: Higher pre-diagnosis IL-6 levels suggest poorer long-term survival among BC survivors. In postmenopausal survivors, elevated IL-6, IL-10, and TNFα and inflammatory scores seem to predict all-cause mortality.

Consumption of milk and other dairy products and incidence of Parkinson's disease: a prospective cohort study in French women.

Previous studies showed positive associations between milk intake and Parkinson's disease (PD) in men but not in women, but few studies were available in women. Due to the long prodromal PD phase, reverse causation represents a major threat to investigations of diet in PD; cohort studies with a long follow-up are needed. We investigated associations between intake of milk and other dairy products with PD incidence in women from the E3N cohort study (1993-2018). PD diagnoses were validated using medical records and drug claim databases. Diet was assessed via a dietary questionnaire. Hazard ratios (HR) were estimated using multivariable Cox regression models. Exposures were lagged by 5y in main analyses and longer lags in sensitivity analyses. We examined the impact of adjustment for premotor symptoms (constipation/depression). During a mean follow-up of 18.8y, 845 of 71,542 women developed PD. Main analyses showed a J-shaped association between total milk intake and PD (P-non linearity = 0.045), with a significant linear positive association among drinkers (HR/1-SD = 1.09, 95% CI = 1.01-1.18, P = 0.024), that was explained in secondary analyses by a different pattern of association for plain milk (alone or with cereals) and milk added to drinks (tea/coffee/chicory). PD incidence increased significantly with plain milk consumption (HR/1-SD = 1.08 [1.02-1.14], P = 0.014). A U-shaped relation was observed for milk added to drinks (P-non linearity = 0.038), with lower PD incidence in women with moderate consumption (HR = 0.77 [0.61-0.97], P = 0.030) and no difference between non-drinkers and those with the highest consumption (HR = 0.98 [0.79-1.21], P = 0.848). Findings were similar in analyses using longer lags and adjusted for constipation/depression. Consumption of other dairy products was not associated with PD. A J-shaped association between total milk intake and PD was explained by a different pattern of association for plain milk intake and milk added to drinks. Reverse causation is unlikely to explain a positive association of plain milk with PD incidence in women. The U-shaped relation for milk added to drinks could be explained by an interaction between milk and coffee/tea/chicory. Further studies are warranted to elucidate the underlying mechanisms.

Blood levels of persistent organic pollutants among women in France in the 90's: Main profiles and individual determinants.

CONTEXT AND OBJECTIVES: Persistent organic pollutants (POPs) are a group of organic chemical compounds potentially toxic to human health. The objectives of this study were 1) to describe the levels of POPs biomarkers in blood samples from French women collected during the 1990s and to compare them with levels measured in two more recent French studies, 2) to identify POPs exposure profiles, and 3) to explore their main determinants. METHODS: 73 POPs biomarkers were measured in the blood of 468 women from the French E3N cohort (aged 45-73 years), collected between 1994 and 1999: 28 per- and polyfluoroalkyl substances, 27 organochlorine pesticides, 14 polychlorinated biphenyls and 4 polybrominated diphenyl ethers. POPs biomarker levels were described and compared with levels measured in two more recent French studies conducted by the French National Public Health Agency, the ENNS and Esteban studies. Principal component analysis was performed on POPs quantified in at least 75% of samples to identify the main exposure profiles. Linear regression models were used to estimate the associations between anthropometric, socio-demographic and lifestyle characteristics and exposure to these profiles. RESULTS: Among the 73 biomarkers measured, 41 were quantified in more than 75% of samples. Levels of most pollutants that were also measured in the Esteban of ENNS studies have decreased over time. Six POPs exposure profiles were revealed, explaining 62.1% of the total variance. Most of the characteristics studied were associated with adherence to at least one of these profiles. CONCLUSION: This study highlighted that most of the pollutants for which a comparison was possible decreased over the 10 or 20 years following the E3N blood collection, and identified those which, on the contrary, tended to increase. The health effects of the profiles identified could be assessed in future studies. The determinants identified should be confirmed in larger populations.

Trajectories of long-term exposure to PCB153 and Benzo[a]pyrene (BaP) air pollution and risk of breast cancer.

BACKGROUND: While genetic, hormonal, and lifestyle factors partially elucidate the incidence of breast cancer, emerging research has underscored the potential contribution of air pollution. Polychlorinated biphenyls (PCBs) and benzo[a]pyrene (BaP) are of particular concern due to endocrine-disrupting properties and their carcinogenetic effect. OBJECTIVE: To identify distinct long term trajectories of exposure to PCB153 and BaP, and estimate their associations with breast cancer risk. METHODS: We used data from the XENAIR case-control study, nested within the ongoing prospective French E3N cohort which enrolled 98,995 women aged 40-65 years in 1990-1991. Cases were incident cases of primary invasive breast cancer diagnosed from cohort entry to 2011. Controls were randomly selected by incidence density sampling, and individually matched to cases on delay since cohort entry, and date, age, department of residence, and menopausal status at cohort entry. Annual mean outdoor PCB153 and BaP concentrations at residential addresses from 1990 to 2011 were estimated using the CHIMERE chemistry-transport model. Latent class mixed models were used to identify profiles of exposure trajectories from cohort entry to the index date, and conditional logistic regression to estimate their association with the odds of breast cancer. RESULTS: 5058 cases and 5059 controls contributed to the analysis. Five profiles of trajectories of PCB153 exposure were identified. The class with the highest PCB153 concentrations had a 69% increased odds of breast cancer compared to the class with the lowest concentrations (95% CI 1.08, 2.64), after adjustment for education and matching factors. The association between identified BaP trajectories and breast cancer was weaker and suffered from large CI. CONCLUSIONS: Our results support an association between long term exposure to PCB153 and the risk of breast cancer, and encourage further studies to account for lifetime exposure to persistent organic pollutants.

Prediagnostic alterations in circulating bile acid profiles in the development of hepatocellular carcinoma.

Bile acids (BAs) play different roles in cancer development. Some are carcinogenic and BA signaling is also involved in various metabolic, inflammatory and immune-related processes. The liver is the primary site of BA synthesis. Liver dysfunction and microbiome compositional changes, such as during hepatocellular carcinoma (HCC) development, may modulate BA metabolism increasing concentration of carcinogenic BAs. Observations from prospective cohorts are sparse. We conducted a study (233 HCC case-control pairs) nested within a large observational prospective cohort with blood samples taken at recruitment when healthy with follow-up over time for later cancer development. A targeted metabolomics method was used to quantify 17 BAs (primary/secondary/tertiary; conjugated/unconjugated) in prediagnostic plasma. Odd ratios (OR) for HCC risk associations were calculated by multivariable conditional logistic regression models. Positive HCC risk associations were observed for the molar sum of all BAs (ORdoubling  = 2.30, 95% confidence intervals [CI]: 1.76-3.00), and choline- and taurine-conjugated BAs. Relative concentrations of BAs showed positive HCC risk associations for glycoholic acid and most taurine-conjugated BAs. We observe an association between increased HCC risk and higher levels of major circulating BAs, from several years prior to tumor diagnosis and after multivariable adjustment for confounders and liver functionality. Increase in BA concentration is accompanied by a shift in BA profile toward higher proportions of taurine-conjugated BAs, indicating early alterations of BA metabolism with HCC development. Future studies are needed to assess BA profiles for improved stratification of patients at high HCC risk and to determine whether supplementation with certain BAs may ameliorate liver dysfunction.

The impact of left truncation of exposure in environmental case-control studies: evidence from breast cancer risk associated with airborne dioxin.

In epidemiology, left-truncated data may bias exposure effect estimates. We analyzed the bias induced by left truncation in estimating breast cancer risk associated with exposure to airborne dioxins. Simulations were run with exposure estimates from a Geographic Information System (GIS)-based metric and considered two hypotheses for historical exposure, three scenarios for intra-individual correlation of annual exposures, and three exposure-effect models. For each correlation/model combination, 500 nested matched case-control studies were simulated and data fitted using a conditional logistic regression model. Bias magnitude was assessed by estimated odds-ratios (ORs) versus theoretical relative risks (TRRs) comparisons. With strong intra-individual correlation and continuous exposure, left truncation overestimated the Beta parameter associated with cumulative dioxin exposure. Versus a theoretical Beta of 4.17, the estimated mean Beta (5%; 95%) was 73.2 (67.7; 78.8) with left-truncated exposure and 4.37 (4.05; 4.66) with lifetime exposure. With exposure categorized in quintiles, the TRR was 2.0, the estimated ORQ5 vs. Q1 2.19 (2.04; 2.33) with truncated exposure versus 2.17 (2.02; 2.32) with lifetime exposure. However, the difference in exposure between Q5 and Q1 was 18× smaller with truncated data, indicating an important overestimation of the dose effect. No intra-individual correlation resulted in effect dilution and statistical power loss. Left truncation induced substantial bias in estimating breast cancer risk associated with exposure with continuous and categorical models. With strong intra-individual exposure correlation, both models detected associations, but categorical models provided better estimates of effect trends. This calls for careful consideration of left truncation-induced bias in interpreting environmental epidemiological data.

Associations between plasma levels of brominated flame retardants and methylation of DNA from peripheral blood: A cross-sectional study in a cohort of French women.

BACKGROUND: Brominated flame retardants (BFRs) are organic compounds that are widespread in the environment. Because of their persistence, they are able to bioaccumulate with major impacts on human health. It has been hypothesized that the effect of BFRs on human health is mediated by alterations of DNA methylation. OBJECTIVE: The aim of this study was to examine the association between methylation of DNA extracted from peripheral blood and circulating levels of BFRs measured in plasma. METHODS: We conducted a methylation wide association study on 336 blood samples from a study within the E3N (Etude Epidémiologique auprès de femmes de l'Education Nationale) cohort, a long-term longitudinal cohort of French women. DNA methylation at more than 850 000 cytosine-guanine dinucleotide (CpG) sites was measured with the Illumina Infinium HumanMethylation - EPIC BeadChip. Circulating levels of seven BFRs (BDE-28, BDE-47, BDE-99, BDE-100, BDE-153, BDE-154 and PBB-153) were measured by gas chromatography coupled to high-resolution mass spectrometry in plasma samples. The association between DNA methylation and BFRs plasma levels was assessed through linear mixed-effects models followed by gene-set enrichment analyses (GSEA). RESULTS: We identified 253 CpG sites whose methylation levels were significantly associated with exposure to BFRs after Bonferroni correction. For 50 of these CpGs the p-values were less than 2.2x10-9 with the strongest association being between BDE-154 and cg23619365 (4.32x10-13). GSEA of CpG sites associated with exposure to BFRs identified significant enrichment of genes involved in hypoxia, glycolysis and adipogenesis. CONCLUSIONS: Exposure to BFRs appears to be related to numerous alterations in DNA methylation. These findings, if replicated in independent studies, provide insights into the biological and health effects of BFRs.

Application of two statistical approaches (Bayesian Kernel Machine Regression and Principal Component Regression) to assess breast cancer risk in association to exposure to mixtures of brominated flame retardants and per- and polyfluorinated alkylated substances in the E3N cohort.

BACKGROUND: Brominated flame retardants (BFR) and per- and polyfluorinated alkylated substances (PFAS) are two groups of substances suspected to act as endocrine disruptors. Such substances could therefore be implicated in the occurrence of breast cancer, nevertheless, previous studies have led to inconstant results. Due to the large correlation between these substances, and the possibly non-linear effects they exert, evaluating their joint impact as mixtures on health remains challenging. This exploratory study aimed to generate hypotheses on the relationship between circulating levels of 7 BFR (6 polybrominated diphenyl ethers and 1 polybrominated biphenyls) and 11 PFAS and the risk of breast cancer in a case-control study nested in the E3N French prospective cohort by performing two methods: Principal Component Regression (PCR) models, and Bayesian Kernel Machine Regression (BKMR) models. METHODS: 194 post-menopausal breast cancer cases and 194 controls were included in the present study. Circulating levels of BFR and PFAS were measured by gas chromatography coupled to high-resolution mass spectrometry and liquid chromatography coupled to tandem mass spectrometry, respectively. The first statistical approach was based on Principal Component Analysis (PCA) followed by logistic regression models that included the identified principal components as main exposure variables. The second approach used BKMR models with hierarchical variable selection, this latter being suitable for highly correlated exposures. Both approaches were also run separately for Estrogen Receptor positive (ER +) and Estrogen Receptor negative (ER-) breast cancer cases. RESULTS: PCA identified four principal components accounting for 67% of the total variance. Component 3 showed a marginal association with ER + breast cancer risk. No clear association between BFR and PFAS mixtures and breast cancer was identified using BKMR models, and the credible intervals obtained were very wide. Finally, the BKMR models suggested a negative cumulative effect of BFR and PFAS on ER- breast cancer risk, and a positive cumulative effect on ER + breast cancer risk. CONCLUSION: Although globally no clear association was identified, both approaches suggested a differential effect of BFR and PFAS mixtures on ER + and ER- breast cancer risk. However, the results for ER- breast cancer should be interpreted carefully due to the small number of ER- cases included in the study. Further studies evaluating mixtures of substances on larger study populations are needed.

Metabolic perturbations prior to hepatocellular carcinoma diagnosis: Findings from a prospective observational cohort study.

Hepatocellular carcinoma (HCC) development entails changes in liver metabolism. Current knowledge on metabolic perturbations in HCC is derived mostly from case-control designs, with sparse information from prospective cohorts. Our objective was to apply comprehensive metabolite profiling to detect metabolites whose serum concentrations are associated with HCC development, using biological samples from within the prospective European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (>520 000 participants), where we identified 129 HCC cases matched 1:1 to controls. We conducted high-resolution untargeted liquid chromatography-mass spectrometry-based metabolomics on serum samples collected at recruitment prior to cancer diagnosis. Multivariable conditional logistic regression was applied controlling for dietary habits, alcohol consumption, smoking, body size, hepatitis infection and liver dysfunction. Corrections for multiple comparisons were applied. Of 9206 molecular features detected, 220 discriminated HCC cases from controls. Detailed feature annotation revealed 92 metabolites associated with HCC risk, of which 14 were unambiguously identified using pure reference standards. Positive HCC-risk associations were observed for N1-acetylspermidine, isatin, p-hydroxyphenyllactic acid, tyrosine, sphingosine, l,l-cyclo(leucylprolyl), glycochenodeoxycholic acid, glycocholic acid and 7-methylguanine. Inverse risk associations were observed for retinol, dehydroepiandrosterone sulfate, glycerophosphocholine, γ-carboxyethyl hydroxychroman and creatine. Discernible differences for these metabolites were observed between cases and controls up to 10 years prior to diagnosis. Our observations highlight the diversity of metabolic perturbations involved in HCC development and replicate previous observations (metabolism of bile acids, amino acids and phospholipids) made in Asian and Scandinavian populations. These findings emphasize the role of metabolic pathways associated with steroid metabolism and immunity and specific dietary and environmental exposures in HCC development.

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.

The associations of the Palaeolithic diet alone and in combination with lifestyle factors with type 2 diabetes and hypertension risks in women in the E3N prospective cohort.

PURPOSE: Patterns of change from the traditional Palaeolithic lifestyle to the modern lifestyle may partly explain the epidemic proportions of non-communicable diseases (NCDs). We investigated to what extent adherence to the Palaeolithic diet (PD) and the Palaeolithic-like lifestyle was associated with type 2 diabetes (T2D) and hypertension risks. METHODS: A study of 70,991 women from the E3N (Etude Epidémiologique auprès de femmes de la Mutuelle Générale de l'Education Nationale) cohort, followed up for nearly 20 years. There were 3292 incident T2D and 12,504 incident hypertension cases that were validated. Dietary data were collected at baseline in 1993 via a food frequency questionnaire. The PD score and the Palaeolithic-like lifestyle score (PD, physical activity, smoking status, and body mass index [BMI]) were derived and considered in quintiles. Multivariable Cox regression models were employed to estimate hazard ratios (HR) and 95% confidence intervals (CI) for incident T2D and hypertension. RESULTS: In the fully adjusted models, a 1-SD increase of the PD score was associated with 4% and 3% lower risks of T2D and hypertension, respectively. Those in the highest versus the lowest quintile of the score had HR (95% CI) of 0.88 (0.79, 0.98) and 0.91 (0.86, 0.96) for T2D and hypertension, respectively (P-trend < 0.0001). Associations were stronger for the Palaeolithic-like lifestyle score; in the fully adjusted model, a 1-SD increase of the score was associated with 19% and 6% lower risks of T2D and hypertension, respectively. Risks lowered successively with each increase in quintile; those in the highest versus the lowest quintile had HR (95% CI) of 0.58 (0.52, 0.65) and 0.85 (0.80, 0.90) for T2D and hypertension, respectively (P-trend < 0.0001). CONCLUSIONS: Our data suggest that adhering to a PD based on fruit, vegetables, lean meats, fish, and nuts, and incorporating a Palaeolithic-like lifestyle could be promising options to prevent T2D and hypertension.

Dietary exposure to polychlorinated biphenyls (PCB) and risk of Non-Hodgkin's lymphoma: Evidence from the French E3N prospective cohort.

INTRODUCTION: Polychlorinated biphenyls (PCB) are persistent and bioaccumulative lipophilic substances, mostly used in the past by industry. Known to be cancerogenic, PCB are suspected to increase Non-Hodgkin's Lymphoma (NHL) risk in the general population mainly due to evidence from cases-controls studies. Since their interdiction in 1987, diet represents the main route of exposure for the general population, nevertheless no study has assessed the relationship between PCB dietary exposure and NHL risk. The aim of this study was to analyze the association between dietary exposures to dioxin like PCB (DL PCB) and non-dioxin like PCB (NDL PCB) and NHL risk in the E3N prospective cohort of French women. MATERIALS AND METHODS: Among 67,879 women included in this study, 457 cases of NHL were confirmed during 21 years of follow-up. Dietary exposure to PCB was estimated combining food consumption data collected in E3N and food contamination data provided by French Agency for Food, Environmental and Occupational Health & Safety (ANSES) in the second French total diet study. Cox regression models, adjusted for potential confounders, were used to estimate hazard ratio (HR) and 95% confidence intervals (CI). RESULTS: Average age at diagnosis was 67 years. The median dietary exposure to DL PCB and NDL PCB was, 18.5 pg TEQ/d and 138,843.2 pg/d, respectively. While no association was found between dietary exposure to DL PCB or NDL PCB and overall NHL risk, analyses by NHL histological subgroups showed a positive association between dietary exposures to DL PCB and Diffuse Large B Cell Lymphoma (OR3vs1 1.90, 95%CI [1.03-3.51], ptrend 0.02). Nevertheless these findings were no longer statistically significant when the models were adjusted for fish and dairy products consumption. In addition, an inverse association was found between dietary exposure to NDL PCB and the risk of follicular lymphoma (OR3vs1 0.46, 95%CI [0.24-0.87], ptrend 0.01). CONCLUSION: This is the first study to evaluate the association between dietary exposure to DL and NDL PCB and the risk of NHL in a prospective cohort study. Overall, the findings suggest a lack of association between dietary exposure to DL or NDL PCB and NHL risk. Additional studies are needed to reproduce these findings.

Long-term atmospheric exposure to PCB153 and breast cancer risk in a case-control study nested in the French E3N cohort from 1990 to 2011.

BACKGROUND: Although the genetic and hormonal risk factors of breast cancer are well identified, they cannot fully explain the occurrence of all cases. Epidemiological and experimental studies have suggested that exposure to environmental pollutants, especially those with potential estrogenic properties, as polychlorinated biphenyls (PCBs) may have a role in breast cancer development. Being the most abundantly detected in human tissues and in the environment, congener 153 (PCB153) is widely used in epidemiological studies as indicator for total PCBs exposure. OBJECTIVES: We aimed to estimate the association between cumulative atmospheric exposure to PCB153 and breast cancer risk. METHODS: We conducted a case-control study of 5222 cases and 5222 matched controls nested within the French E3N cohort from 1990 to 2011. Annual atmospheric PCB153 concentrations were simulated with the deterministic chemistry-transport model (CHIMERE) and were assigned to women using their geocoded residential history. Their cumulative PCB153 exposure was calculated for each woman from their cohort inclusion to their index date. Breast cancer odds ratios (ORs) associated with cumulative PCB153 exposure and their 95% confidence intervals (95% CIs) were estimated using multivariate conditional logistic regression models. RESULTS: Overall, our results showed a statistically significant linear increase in breast cancer risk related to cumulative atmospheric exposure to PCB153 as a continuous variable (adjusted OR = 1.19; 95% CI: 1.08-1.31, for an increment of one standard deviation among controls (55 pg/m3)). Among women who became postmenopausal during follow-up, the association remained statistically significant (adjusted OR = 1.23; 95% CI: 1.09-1.39). In analyses by hormone receptors status, the positive association remained significant only for ER-positive breast cancer (adjusted OR = 1.18; 95% CI: 1.05-1.33). DISCUSSION: This study is the first to have estimated the impact of atmospheric exposure to PCB153 on breast cancer risk. Our results showed a statistically significant increase in breast cancer risk, which may be limited to ER-positive breast cancer. These results warrant confirmation in further independent studies but raise the possibility that exposure to PCB153 increase breast cancer risk.

Autoimmunity plays a role in the onset of diabetes after 40 years of age.

AIMS/HYPOTHESIS: Type 1 and type 2 diabetes differ with respect to pathophysiological factors such as beta cell function, insulin resistance and phenotypic appearance, but there may be overlap between the two forms of diabetes. However, there are relatively few prospective studies that have characterised the relationship between autoimmunity and incident diabetes. We investigated associations of antibodies against the 65 kDa isoform of GAD (GAD65) with type 1 diabetes and type 2 diabetes genetic risk scores and incident diabetes in adults in European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct, a case-cohort study nested in the EPIC cohort. METHODS: GAD65 antibodies were analysed in EPIC participants (over 40 years of age and free of known diabetes at baseline) by radioligand binding assay in a random subcohort (n = 15,802) and in incident diabetes cases (n = 11,981). Type 1 diabetes and type 2 diabetes genetic risk scores were calculated. Associations between GAD65 antibodies and incident diabetes were estimated using Prentice-weighted Cox regression. RESULTS: GAD65 antibody positivity at baseline was associated with development of diabetes during a median follow-up time of 10.9 years (HR for GAD65 antibody positive vs negative 1.78; 95% CI 1.43, 2.20) after adjustment for sex, centre, physical activity, smoking status and education. The genetic risk score for type 1 diabetes but not type 2 diabetes was associated with GAD65 antibody positivity in both the subcohort (OR per SD genetic risk 1.24; 95% CI 1.03, 1.50) and incident cases (OR 1.97; 95% CI 1.72, 2.26) after adjusting for age and sex. The risk of incident diabetes in those in the top tertile of the type 1 diabetes genetic risk score who were also GAD65 antibody positive was 3.23 (95% CI 2.10, 4.97) compared with all other individuals, suggesting that 1.8% of incident diabetes in adults was attributable to this combination of risk factors. CONCLUSIONS/INTERPRETATION: Our study indicates that incident diabetes in adults has an element of autoimmune aetiology. Thus, there might be a reason to re-evaluate the present subclassification of diabetes in adulthood.

Nutrient-wide association study of 92 foods and nutrients and breast cancer risk.

BACKGROUND: Several dietary factors have been reported to be associated with risk of breast cancer, but to date, unequivocal evidence only exists for alcohol consumption. We sought to systematically assess the association between intake of 92 foods and nutrients and breast cancer risk using a nutrient-wide association study. METHODS: Using data from 272,098 women participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) study, we assessed dietary intake of 92 foods and nutrients estimated by dietary questionnaires. Cox regression was used to quantify the association between each food/nutrient and risk of breast cancer. A false discovery rate (FDR) of 0.05 was used to select the set of foods and nutrients to be replicated in the independent Netherlands Cohort Study (NLCS). RESULTS: Six foods and nutrients were identified as associated with risk of breast cancer in the EPIC study (10,979 cases). Higher intake of alcohol overall was associated with a higher risk of breast cancer (hazard ratio (HR) for a 1 SD increment in intake = 1.05, 95% CI 1.03-1.07), as was beer/cider intake and wine intake (HRs per 1 SD increment = 1.05, 95% CI 1.03-1.06 and 1.04, 95% CI 1.02-1.06, respectively), whereas higher intakes of fibre, apple/pear, and carbohydrates were associated with a lower risk of breast cancer (HRs per 1 SD increment = 0.96, 95% CI 0.94-0.98; 0.96, 95% CI 0.94-0.99; and 0.96, 95% CI 0.95-0.98, respectively). When evaluated in the NLCS (2368 cases), estimates for each of these foods and nutrients were similar in magnitude and direction, with the exception of beer/cider intake, which was not associated with risk in the NLCS. CONCLUSIONS: Our findings confirm a positive association of alcohol consumption and suggest an inverse association of dietary fibre and possibly fruit intake with breast cancer risk.

Chronic long-term exposure to cadmium air pollution and breast cancer risk in the French E3N cohort.

Cadmium, due to its estrogen-like activity, has been suspected to increase the risk of breast cancer; however, epidemiological studies have reported inconsistent findings. We conducted a case-control study (4,059 cases and 4,059 matched controls) nested within the E3N French cohort study to estimate the risk of breast cancer associated with long-term exposure to airborne cadmium pollution, and its effect according to molecular subtype of breast cancer (estrogen receptor negative/positive [ER-/ER+] and progesterone receptor negative/positive [PR-/PR+]). Atmospheric exposure to cadmium was assessed using a Geographic Information System-based metric, which included subject's residence-to-cadmium source distance, wind direction, exposure duration and stack height. Adjusted odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression. Overall, there was no significant association between cumulative dose of airborne cadmium exposure and the risk of overall, premenopausal and postmenopausal breast cancer. However, by ER and PR status, inverse associations were observed for ER- (ORQ5 vs. Q1 = 0.63; 95% CI: 0.41-0.95, ptrend = 0.043) and for ER-/PR- breast tumors (ORQ4 vs. Q1 = 0.62; 95% CI: 0.40-0.95, ORQ5 vs. Q1 = 0.68; 95% CI: 0.42-1.07, ptrend = 0.088). Our study provides no evidence of an association between exposure to cadmium and risk of breast cancer overall but suggests that cadmium might be related to a decreased risk of ER- and ER-/PR- breast tumors. These observations and other possible effects linked to hormone receptor status warrant further investigations.

Perfluorinated alkylated substances serum concentration and breast cancer risk: Evidence from a nested case-control study in the French E3N cohort.

Endocrine-disrupting chemicals are proposed to increase breast cancer (BC) incidence. Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), two perfluorinated alkylated substances (PFASs), are suspected to be ubiquitously present in the blood of human population worldwide. We investigated the associations between serum concentrations of these substances and BC risk. Etude Epidémiologique auprès de femmes de l'Education Nationale is a cohort of 98,995 French women born in 1925-1950 and followed up since 1990. We sampled 194 BC cases and 194 controls from women with available blood samples. Serum concentrations of PFASs were measured by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). Adjusted conditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). All statistical tests were two sided. While PFASs concentrations were not associated with BC risk overall, we found positively linear associations between PFOS concentrations and the risk of ER+ (3rd quartile: OR = 2.22 [CI = 1.05-4.69]; 4th quartile: OR = 2.33 [CI = 1.11-4.90]); Ptrend = 0.04) and PR+ tumors (3rd quartile: OR = 2.47 [CI = 1.07-5.65]; 4th quartile: OR = 2.76 [CI = 1.21-6.30]; Ptrend = 0.02). When considering receptor-negative tumors, only the 2nd quartile of PFOS was associated with risk (ER-: OR = 15.40 [CI = 1.84-129.19]; PR-: OR = 3.47 [CI = 1.29-9.15]). While there was no association between PFOA and receptor-positive BC risk, the 2nd quartile of PFOA was positively associated with the risk of receptor-negative tumors (ER-: OR = 7.73 [CI = 1.46-41.08]; PR-: OR = 3.44 [CI = 1.30-9.10]). PFAS circulating levels were differentially associated with BC risk. While PFOS concentration was linearly associated with receptor-positive tumors, only low concentrations of PFOS and PFOA were associated with receptor-negative tumors. Our findings highlight the importance of considering exposure to PFASs as a potential risk factor for BC.

Polyphenol intake and differentiated thyroid cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.

Polyphenols are bioactive compounds with several anticarcinogenic activities; however, human data regarding associations with thyroid cancer (TC) is still negligible. Our aim was to evaluate the association between intakes of total, classes and subclasses of polyphenols and risk of differentiated TC and its main subtypes, papillary and follicular, in a European population. The European Prospective Investigation into Cancer and Nutrition cohort included 476,108 men and women from 10 European countries. During a mean follow-up of 14 years, there were 748 incident differentiated TC cases, including 601 papillary and 109 follicular tumors. Polyphenol intake was estimated at baseline using validated center/country-specific dietary questionnaires and the Phenol-Explorer database. In multivariable-adjusted Cox regression models, no association between total polyphenol and the risks of overall differentiated TC (HRQ4 vs. Q1 = 0.99, 95% confidence interval [CI] 0.77-1.29), papillary (HRQ4 vs. Q1 = 1.06, 95% CI 0.80-1.41) or follicular TC (HRQ4 vs. Q1 = 1.10, 95% CI 0.55-2.22) were found. No associations were observed either for flavonoids, phenolic acids or the rest of classes and subclasses of polyphenols. After stratification by body mass index (BMI), an inverse association between the intake of polyphenols (p-trend = 0.019) and phenolic acids (p-trend = 0.007) and differentiated TC risk in subjects with BMI ≥ 25 was observed. In conclusion, our study showed no associations between dietary polyphenol intake and differentiated TC risk; although further studies are warranted to investigate the potential protective associations in overweight and obese individuals.

Consumption of nuts and seeds and pancreatic ductal adenocarcinoma risk in the European Prospective Investigation into Cancer and Nutrition.

Four epidemiologic studies have assessed the association between nut intake and pancreatic cancer risk with contradictory results. The present study aims to investigate the relation between nut intake (including seeds) and pancreatic ductal adenocarcinoma (PDAC) risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Cox proportional hazards models were used to estimate hazards ratio (HR) and 95% confidence intervals (95% CI) for nut intake and PDAC risk. Information on intake of nuts was obtained from the EPIC country-specific dietary questionnaires. After a mean follow-up of 14 years, 476,160 participants were eligible for the present study and included 1,283 PDAC cases. No association was observed between consumption of nuts and PDAC risk (highest intake vs nonconsumers: HR, 0.89; 95% CI, 0.72-1.10; p-trend = 0.70). Furthermore, no evidence for effect-measure modification was observed when different subgroups were analyzed. Overall, in EPIC, the highest intake of nuts was not statistically significantly associated with PDAC risk.

Urinary flavanone concentrations as biomarkers of dietary flavanone intakes in the European Prospective Investigation into Cancer and Nutrition (EPIC) study.

In the present study, the aim was to investigate the correlation between the acute and habitual dietary intake of flavanones, their main food sources and the concentrations of aglycones naringenin and hesperetin in 24 h urine in a European population. A 24-h dietary recall (24-HDR) and a 24-h urine sample were collected the same day from a subsample of 475 people from four different countries of the European Prospective Investigation into Cancer and Nutrition study. Acute and habitual dietary data were captured through a standardised 24-HDR and a country/centre-specific validated dietary questionnaire (DQ). The intake of dietary flavanones was estimated using the Phenol-Explorer database. Urinary flavanones (naringenin and hesperetin) were analysed using tandem MS with a previous enzymatic hydrolysis. Weak partial correlation coefficients were found between urinary flavanone concentrations and both acute and habitual dietary flavanone intakes (Rpartial = 0·14-0·17). Partial correlations were stronger between urinary excretions and acute intakes of citrus fruit and juices (Rpartial ∼ 0·6) than with habitual intakes of citrus fruit and juices (Rpartial ∼ 0·24). In conclusion, according to our results, urinary excretion of flavanones can be considered a good biomarker of acute citrus intake. However, low associations between habitual flavanone intake and urinary excretion suggest a possible inaccurate estimation of their intake or a too sporadic intake. For assessing habitual exposures, multiple urinary collections may be needed. These results show that none of the approaches tested is ideal, and the use of both DQ and biomarkers can be recommended.