Circulating free insulin-like growth factor-I and prostate cancer: a case-control study nested in the European prospective investigation into cancer and nutrition

Background: Circulating total insulin-like growth factor-I (IGF-I) is an established risk factor for prostate cancer. However, only a small proportion of circulating IGF-I is free or readily dissociable from IGF-binding proteins (its bioavailable form), and few studies have investigated the association of circulating free IGF-I with prostate cancer risk. Methods: We analyzed data from 767 prostate cancer cases and 767 matched controls nested within the European Prospective Investigation into Cancer and Nutrition cohort, with an average of 14-years (interquartile range = 2.9) follow-up. Matching variables were study center, length of follow-up, age, and time of day and fasting duration at blood collection. Circulating free IGF-I concentration was measured in serum samples collected at recruitment visit (mean age 55 years old; standard deviation = 7.1) using an enzyme-linked immunosorbent assay (ELISA). Conditional logistic regressions were performed to examine the associations of free IGF-I with risk of prostate cancer overall and subdivided by time to diagnosis (≤ 14 and > 14 years), and tumor characteristics. Results: Circulating free IGF-I concentrations (in fourths and as a continuous variable) were not associated with prostate cancer risk overall (odds ratio [OR] = 1.00 per 0.1 nmol/L increment, 95% CI: 0.99, 1.02) or by time to diagnosis, or with prostate cancer subtypes, including tumor stage and histological grade. Conclusions: Estimated circulating free IGF-I was not associated with prostate cancer risk. Further research may consider other assay methods that estimate bioavailable IGF-I to provide more insight into the well-substantiated association between circulating total IGF-I and subsequent prostate cancer risk

Association of body shape phenotypes and body fat distribution indexes with inflammatory biomarkers in the European Prospective Investigation into Cancer and Nutrition (EPIC) and UK Biobank

Background: The allometric body shape index (ABSI) and hip index (HI), as well as multi-trait body shape phenotypes, have not yet been compared in their associations with inflammatory markers. The aim of this study was to examine the relationship between novel and traditional anthropometric indexes with inflammation using data from the European Prospective Investigation into Cancer and Nutrition (EPIC) and UK Biobank cohorts. Methods: Participants from EPIC (n = 17,943, 69.1% women) and UK Biobank (n = 426,223, 53.2% women) with data on anthropometric indexes and C-reactive protein (CRP) were included in this cross-sectional analysis. A subset of women in EPIC also had at least one measurement for interleukins, tumour necrosis factor alpha, interferon gamma, leptin, and adiponectin. Four distinct body shape phenotypes were derived by a principal component (PC) analysis on height, weight, body mass index (BMI), waist (WC) and hip circumferences (HC), and waist-to-hip ratio (WHR). PC1 described overall adiposity, PC2 tall with low WHR, PC3 tall and centrally obese, and PC4 high BMI and weight with low WC and HC, suggesting an athletic phenotype. ABSI, HI, waist-to-height ratio and waist-to-hip index (WHI) were also calculated. Linear regression models were carried out separately in EPIC and UK Biobank stratified by sex and adjusted for age, smoking status, education, and physical activity. Results were additionally combined in a random-effects meta-analysis. Results: Traditional anthropometric indexes, particularly BMI, WC, and weight were positively associated with CRP levels, in men and women. Body shape phenotypes also showed distinct associations with CRP. Specifically, PC2 showed inverse associations with CRP in EPIC and UK Biobank in both sexes, similarly to height. PC3 was inversely associated with CRP among women, whereas positive associations were observed among men. Conclusions: Specific indexes of body size and body fat distribution showed differential associations with inflammation in adults. Notably, our results suggest that in women, height may mitigate the impact of a higher WC and HC on inflammation. This suggests that subtypes of adiposity exhibit substantial variation in their inflammatory potential, which may have implications for inflammation-related chronic diseases

Metabolically-Defined Body Size Phenotypes and Risk of Endometrial Cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC)

Background: Obesity is a risk factor for endometrial cancer but whether metabolic dysfunction is associated with endometrial cancer independent of body size is not known. Methods: The association of metabolically defined body size phenotypes with endometrial cancer risk was investigated in a nested case-control study (817 cases/ 817 controls) within the European Prospective Investigation into Cancer and Nutrition (EPIC). Concentrations of C-peptide were used to define metabolically healthy (MH; _1st tertile) status among the control participants. These metabolic health definitions were combined with normal weight (NW); body mass index (BMI)_25 kg/m2 or WC >_80 cm or WHR >_0. 8) status, generating four phenotype groups for each anthropometric measure: (i) MH/NW, (ii) MH/OW, (iii) MU/ NW, and (iv) MU/OW. Results: In a multivariable-adjusted conditional logistic regression model, compared with MH/NW individuals, endometrial cancer risk was higher among those classified as MU/NW [ORWC, 1.48; 95% confidence interval (CI), 1.05-2.10 and ORWHR, 1.68; 95% CI, 1.21- 2.35] and MU/OW (ORBMI, 2.38; 95% CI, 1.73-3.27; ORWC, 2.69; 95% CI, 1.92-3.77 and ORWHR, 1.83; 95% CI, 1.32-2.54). MH/OW individuals were also at increased endometrial cancer risk compared with MH/NW individuals (ORWC, 1.94; 95% CI, 1.24-3.04). Conclusions: Women with metabolic dysfunction appear to have higher risk of endometrial cancer regardless of their body size. However, OW status raises endometrial cancer risk even among women with lower insulin levels, suggesting that obesity related pathways are relevant for the development of this cancer beyond insulin. Impact: Classifying women by metabolic health may be of greater utility in identifying those at higher risk for endometrial cancer than anthropometry per se

The association between body fatness and mortality among breast cancer survivors: results from a prospective cohort study

Evidence linking body fatness to breast cancer (BC) prognosis is limited. While it seems that excess adiposity is associated with poorer BC survival, there is uncertainty over whether weight changes reduce mortality. This study aimed to assess the association between body fatness and weight changes pre- and postdiagnosis and overall mortality and BC-specific mortality among BC survivors. Our study included 13,624 BC survivors from the European Prospective Investigation into Cancer and Nutrition (EPIC) study, with a mean follow-up of 8.6 years after diagnosis. Anthropometric data were obtained at recruitment for all cases and at a second assessment during follow-up for a subsample. We measured general obesity using the body mass index (BMI), whereas waist circumference and A Body Shape Index were used as measures of abdominal obesity. The annual weight change was calculated for cases with two weight assessments. The association with overall mortality and BC-specific mortality were based on a multivariable Cox and Fine and Gray models, respectively. We performed Mendelian randomization (MR) analysis to investigate the potential causal association. Five-unit higher BMI prediagnosis was associated with a 10% (95% confidence interval: 5–15%) increase in overall mortality and 7% (0–15%) increase in dying from BC. Women with abdominal obesity demonstrated a 23% (11–37%) increase in overall mortality, independent of the association of BMI. Results related to weight change postdiagnosis suggested a U-shaped relationship with BC-specific mortality, with higher risk associated with losing weight or gaining > 2% of the weight annually. MR analyses were consistent with the identified associations. Our results support the detrimental association of excess body fatness on the survival of women with BC. Substantial weight changes postdiagnosis may be associated with poorer survival

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

This work was funded by the French National Cancer Institute (grant number 2015-166). Mathilde His' work reported here was undertaken during the tenure of a postdoctoral fellowship awarded by the International Agency for Research on Cancer, financed by the Fondation ARC. The coordination of EPIC is financially supported by International Agency for Research on Cancer (IARC) and also by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, which has additional infrastructure support provided by the NIHR Imperial Biomedical Research Centre (BRC). The national cohorts are supported by Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Generale de l'Education Nationale, Institut National de la Sante et de la Recherche Medicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Federal Ministry of Education and Research (BMBF) (Germany); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, Compagnia di SanPaolo and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF) (The Netherlands); Health Research Fund (FIS) - Instituto de Salud Carlos III (ISCIII), Regional Governments of Andalucia, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology-ICO (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Skane and Vasterbotten (Sweden); and Cancer Research UK (14136 to EPIC-Norfolk (DOI 10.22025/2019.10.105.00004); C8221/A29017 to EPIC-Oxford), Medical Research Council (1000143, MR/N003284/1, MC-UU_12015/1 and MC_UU_00006/1 to EPIC-Norfolk; MR/M012190/1 to EPIC-Oxford) (UK). The funders were not involved in designing the study; collecting, analyzing, or interpreting the data; or writing or submitting the manuscript for publication.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.Institut National du Cancer (INCA) France 2015-166International Agency for Research on Cancer - Fondation ARCWorld Health OrganizationDepartment of Epidemiology and Biostatistics, School of Public Health, Imperial College LondonDanish Cancer SocietyLigue Contre le Cancer (France)Institut Gustave Roussy (France)Mutuelle Generale de l'Education Nationale (France)Institut National de la Sante et de la Recherche Medicale (Inserm)Deutsche KrebshilfeGerman Cancer Research Center (DKFZ) (Germany)German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE) (Germany)Federal Ministry of Education & Research (BMBF)Fondazione AIRC per la ricerca sul cancroCompagnia di San PaoloConsiglio Nazionale delle Ricerche (CNR)Netherlands GovernmentWorld Cancer Research Fund International (WCRF)Health Research Fund (FIS) - Instituto de Salud Carlos III (ISCIII) (Spain)Junta de AndaluciaRegional Government of Asturias (Spain)Regional Government of Basque Country (Spain)Regional Government of Murcia (Spain)Regional Government of Navarra (Spain)Catalan Institute of Oncology-ICO (Spain)Swedish Cancer SocietySwedish Research CouncilCounty Council of Skane (Sweden)County Council of Vasterbotten (Sweden)Cancer Research UK 14136 C8221/A29017UK Research & Innovation (UKRI)Medical Research Council UK (MRC) 1000143 MR/N003284/1 MC-UU_12015/1 MC_UU_00006/1 MR/M012190/

Prediagnostic selenium status, selenoprotein gene variants and association with breast cancer risk in a european cohort study

Selenium (Se) may help prevent breast cancer (BC) development. Owing to limited observational evidence, we investigated whether prediagnostic Se status and/or variants in the selenoprotein genes are associated with BC risk in a large European cohort. Se status was assessed by plasma measures of Se and its major circulating proteins, selenoprotein P (SELENOP) and glutathione peroxidase 3 (GPX3), in matched BC case-control pairs (2208 for SELENOP; 1785 for GPX3 and Se) nested within the European Prospective Investigation into Cancer and Nutrition (EPIC). Single nucleotide polymorphisms (SNPs, n = 452) in 55 selenoprotein and Se metabolic pathway genes and an additional 18 variants previously associated with Se concentrations were extracted from existing genotyping data within EPIC for 1564 case-control pairs. Multivariable-adjusted logistic regression models were used to calculate the odds ratios (ORs) and 95 % confidence intervals (CIs) of the association between Se status markers, SNP variants and BC risk. Overall, there was no statistically significant association of Se status with BC risk. However, higher GPX3 activity was associated with lower risk of premenopausal BC (4th versus 1st quartile, OR = 0.54, 95 % CI: 0.30-0.98, Ptrend = 0.013). While none of the genetic variant associations (P ≤ 0.05) retained significance after multiple testing correction, rs1004243 in the SELENOM selenoprotein gene and two SNPs in the related antioxidant TXN2 gene (rs4821494 and rs5750261) were associated with respective lower and higher risks of BC at a significance threshold of P ≤ 0.01. Fourteen SNPs in twelve Se pathway genes (P ≤ 0.01) in interaction with Se status were also associated with BC risk. Higher Se status does not appear to be associated with BC risk, although activity of the selenoenzyme GPX3 may be inversely associated with premenopausal BC risk, and SNPs in the Se pathway alone or in combination with suboptimal Se status may influence BC risk.</p

Plant foods, dietary fibre and risk of ischaemic heart disease in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.

BACKGROUND: Epidemiological evidence indicates that diets rich in plant foods are associated with a lower risk of ischaemic heart disease (IHD), but there is sparse information on fruit and vegetable subtypes and sources of dietary fibre. This study examined the associations of major plant foods, their subtypes and dietary fibre with risk of IHD in the European Prospective Investigation into Cancer and Nutrition (EPIC). METHODS: We conducted a prospective analysis of 490 311 men and women without a history of myocardial infarction or stroke at recruitment (12.6 years of follow-up, n cases = 8504), in 10 European countries. Dietary intake was assessed using validated questionnaires, calibrated with 24-h recalls. Multivariable Cox regressions were used to estimate hazard ratios (HR) of IHD. RESULTS: There was a lower risk of IHD with a higher intake of fruit and vegetables combined [HR per 200 g/day higher intake 0.94, 95% confidence interval (CI): 0.90-0.99, P-trend = 0.009], and with total fruits (per 100 g/day 0.97, 0.95-1.00, P-trend = 0.021). There was no evidence for a reduced risk for fruit subtypes, except for bananas. Risk was lower with higher intakes of nuts and seeds (per 10 g/day 0.90, 0.82-0.98, P-trend = 0.020), total fibre (per 10 g/day 0.91, 0.85-0.98, P-trend = 0.015), fruit and vegetable fibre (per 4 g/day 0.95, 0.91-0.99, P-trend = 0.022) and fruit fibre (per 2 g/day 0.97, 0.95-1.00, P-trend = 0.045). No associations were observed between vegetables, vegetables subtypes, legumes, cereals and IHD risk. CONCLUSIONS: In this large prospective study, we found some small inverse associations between plant foods and IHD risk, with fruit and vegetables combined being the most strongly inversely associated with risk. Whether these small associations are causal remains unclear

The association between body fatness and mortality among breast cancer survivors: results from a prospective cohort study

Evidence linking body fatness to breast cancer (BC) prognosis is limited. While it seems that excess adiposity is associated with poorer BC survival, there is uncertainty over whether weight changes reduce mortality. This study aimed to assess the association between body fatness and weight changes pre- and postdiagnosis and overall mortality and BC-specific mortality among BC survivors. Our study included 13,624 BC survivors from the European Prospective Investigation into Cancer and Nutrition (EPIC) study, with a mean follow-up of 8.6 years after diagnosis. Anthropometric data were obtained at recruitment for all cases and at a second assessment during follow-up for a subsample. We measured general obesity using the body mass index (BMI), whereas waist circumference and A Body Shape Index were used as measures of abdominal obesity. The annual weight change was calculated for cases with two weight assessments. The association with overall mortality and BC-specific mortality were based on a multivariable Cox and Fine and Gray models, respectively. We performed Mendelian randomization (MR) analysis to investigate the potential causal association. Five-unit higher BMI prediagnosis was associated with a 10% (95% confidence interval: 5-15%) increase in overall mortality and 7% (0-15%) increase in dying from BC. Women with abdominal obesity demonstrated a 23% (11-37%) increase in overall mortality, independent of the association of BMI. Results related to weight change postdiagnosis suggested a U-shaped relationship with BC-specific mortality, with higher risk associated with losing weight or gaining > 2% of the weight annually. MR analyses were consistent with the identified associations. Our results support the detrimental association of excess body fatness on the survival of women with BC. Substantial weight changes postdiagnosis may be associated with poorer survival

Plasma concentrations of persistent organic pollutants and pancreatic cancer risk

dyab115Findings and limitations of previous studies on persistent organic pollutants (POPs) and pancreatic cancer risk support conducting further research in prospective cohorts.We conducted a prospective case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Participants were 513 pancreatic cancer cases and 1020 matched controls. Concentrations of 22 POPs were measured in plasma collected at baseline.Some associations were observed at higher concentrations of p, p’-DDT, trans-nonachlor, β-hexachlorocyclohexane and the sum of six organochlorine pesticides and of 16 POPs. The odds ratio (OR) for the upper quartile of trans-nonachlor was 1.55 (95\.06-2.26; P for trend = 0.025). Associations were stronger in the groups predefined as most valid (participants having fasted \gt;6 h, with microscopic diagnostic confirmation, normal weight, and never smokers), and as most relevant (follow-up ≥10 years). Among participants having fasted \gt;6 h, the ORs were relevant for 10 of 11 exposures. Higher ORs were also observed among cases with microscopic confirmation than in cases with a clinical diagnosis, and among normal-weight participants than in the rest of participants. Among participants with a follow-up ≥10 years, estimates were higher than in participants with a shorter follow-up (for trans-nonachlor: OR = 2.14, 1.01 to 4.53, P for trend = 0.035). Overall, trans-nonachlor, three PCBs and the two sums of POPs were the exposures most clearly associated with pancreatic cancer risk.Individually or in combination, most of the 22 POPs analysed did not or only moderately increased the risk of pancreatic cancer.Peer reviewe