Metabolomic analysis of vitamin E supplement use in the prostate, lung, colorectal, and ovarian cancer screening trial

The effects of vitamin E supplementation on cancer and other chronic diseases are not clear. We compared the serum metabolomic profile of differing vitamin E dosages in order to re-examine the previously observed changes in a novel C22 lactone sulfate compound, androgenic steroids, and other metabolites. A total of 3409 women and men previously selected for metabolomics studies in the PLCO Cancer Screening Trial were included in this investigation. Serum metabolites were profiled using ultrahigh-performance liquid and gas chromatography/tandem mass spectrometry. Seventy known metabolites including C22 lactone sulfate and androgens were significantly associated with vitamin E supplementation. In the sex-stratified analysis, 10 cofactors and vitamins (e.g., alpha-CEHC sulfate and alpha-CEHC glucuronide), two carbohydrates (glyceric and oxalic acids), and one lipid (glycocholenate sulfate) were significantly associated with vitamin E dose in both males and females (FDR-adjusted p-value < 0.01). However, the inverse association between C22 lactone sulfate and daily vitamin E supplementation was evident in females only, as were two androgenic steroids, 5-androstenediol and androsterone glucuronide. Our study provides evidence of distinct steroid hormone pathway responses based on vitamin E dosages. Further studies are needed to gain biological insights into vitamin E biochemical effects relevant to cancer and other chronic diseases

Pre-diagnosis diet and survival after a diagnosis of ovarian cancer

BACKGROUND: The relationship between diet and survival after ovarian cancer diagnosis is unclear as a result of a limited number of studies and inconsistent findings. METHODS: We examined the association between pre-diagnostic diet and overall survival in a population-based cohort (n=811) of Australian women diagnosed with invasive epithelial ovarian cancer between 2002 and 2005. Diet was measured by validated food frequency questionnaire. Deaths were ascertained up to 31 August 2014 via medical record review and Australian National Death Index linkage. We conducted Cox proportional hazards regression analysis, controlling for diagnosis age, tumour stage, grade and subtype, residual disease, smoking status, body mass index, physical activity, marital status, and energy intake. RESULTS: We observed improved survival with highest compared with lowest quartile of fibre intake (hazard ratio (HR)=0.69, 95% CI: 0.53-0.90, P-trend=0.002). There was a suggestion of better survival for women with highest compared with lowest intake category of green leafy vegetables (HR=0.79, 95% CI: 0.62-0.99), fish (HR=0.74, 95% CI: 0.57-0.95), poly- to mono-unsaturated fat ratio (HR=0.76, 95% CI: 0.59-0.98), and worse survival with higher glycaemic index (HR=1.28, 95% CI: 1.01-1.65, P-trend=0.03). CONCLUSIONS: The associations we observed between healthy components of diet pre-diagnosis and ovarian cancer survival raise the possibility that dietary choices after diagnosis may improve survival

Weight Loss and Mortality in Overweight and Obese Cancer Survivors: A Systematic Review

Background Excess adiposity is a risk factor for poorer cancer survival, but there is uncertainty over whether losing weight reduces the risk. We conducted a critical review of the literature examining weight loss and mortality in overweight or obese cancer survivors. Methods We systematically searched PubMed and EMBASE for articles reporting associations between weight loss and mortality (cancer-specific or all-cause) in overweight/obese patients with obesity-related cancers. Where available, data from the same studies on non-overweight patients were compared. Results Five articles describing observational studies in breast cancer survivors were included. Four studies reported a positive association between weight loss and mortality in overweight/obese survivors, and the remaining study observed no significant association. Results were similar for non-overweight survivors. Quality assessment indicated high risk of bias across studies. Conclusions There is currently a lack of observational evidence that weight loss improves survival for overweight and obese cancer survivors. However, the potential for bias in these studies is considerable and the results likely reflect the consequences of disease-related rather than intentional weight loss. There is a need for stronger study designs, incorporating measures of intentionality of weight loss, and extended to other cancers

Determinants of the urinary and serum metabolome in children from six European populations

Background Environment and diet in early life can affect development and health throughout the life course. Metabolic phenotyping of urine and serum represents a complementary systems-wide approach to elucidate environment–health interactions. However, large-scale metabolome studies in children combining analyses of these biological fluids are lacking. Here, we sought to characterise the major determinants of the child metabolome and to define metabolite associations with age, sex, BMI and dietary habits in European children, by exploiting a unique biobank established as part of the Human Early-Life Exposome project (http://www.projecthelix.eu). Methods Metabolic phenotypes of matched urine and serum samples from 1192 children (aged 6–11) recruited from birth cohorts in six European countries were measured using high-throughput 1H nuclear magnetic resonance (NMR) spectroscopy and a targeted LC-MS/MS metabolomic assay (Biocrates AbsoluteIDQ p180 kit). Results We identified both urinary and serum creatinine to be positively associated with age. Metabolic associations to BMI z-score included a novel association with urinary 4-deoxyerythronic acid in addition to valine, serum carnitine, short-chain acylcarnitines (C3, C5), glutamate, BCAAs, lysophosphatidylcholines (lysoPC a C14:0, lysoPC a C16:1, lysoPC a C18:1, lysoPC a C18:2) and sphingolipids (SM C16:0, SM C16:1, SM C18:1). Dietary-metabolite associations included urinary creatine and serum phosphatidylcholines (4) with meat intake, serum phosphatidylcholines (12) with fish, urinary hippurate with vegetables, and urinary proline betaine and hippurate with fruit intake. Population-specific variance (age, sex, BMI, ethnicity, dietary and country of origin) was better captured in the serum than in the urine profile; these factors explained a median of 9.0% variance amongst serum metabolites versus a median of 5.1% amongst urinary metabolites. Metabolic pathway correlations were identified, and concentrations of corresponding metabolites were significantly correlated (r > 0.18) between urine and serum. Conclusions We have established a pan-European reference metabolome for urine and serum of healthy children and gathered critical resources not previously available for future investigations into the influence of the metabolome on child health. The six European cohort populations studied share common metabolic associations with age, sex, BMI z-score and main dietary habits. Furthermore, we have identified a novel metabolic association between threonine catabolism and BMI of children

The effectiveness of home versus community-based weight control programmes initiated soon after breast cancer diagnosis: a randomised controlled trial

BackgroundBreast cancer diagnosis may be a teachable moment for lifestyle behaviour change and to prevent adjuvant therapy associated weight gain. We assessed the acceptability and effectiveness of two weight control programmes initiated soon after breast cancer diagnosis to reduce weight amongst overweight or obese women and prevent gains in normal-weight women.MethodsOverweight or obese (n?=?243) and normal weight (n?=?166) women were randomised to a three-month unsupervised home (home), a supervised community weight control programme (community) or to standard written advice (control). Primary end points were change in weight and body fat at 12 months. Secondary end points included change in insulin, cardiovascular risk markers, quality of life and cost-effectiveness of the programmes.ResultsForty-three percent of eligible women were recruited. Both programmes reduced weight and body fat: home vs. control mean (95% CI); weight ?2.3 (?3.5, ?1.0) kg, body fat ?1.6 (?2.6, ?0.7) kg, community vs. control; weight ?2.4 (?3.6, ?1.1) kg, body fat ?1.4 (?2.4, ?0.5) kg (all p?&#x3c;?0.001). The community group increased physical activity, reduced insulin, cardiovascular disease risk markers, increased QOL and was cost-effective.ConclusionsThe programmes were equally effective for weight control, but the community programme had additional benefits.Clinical trial registrationISRCTN6857614

Pilot randomised controlled trial of Weight Watchers® referral with or without dietitian-led group support for weight loss in women treated for breast cancer: the BRIGHT (BReast cancer weIGHT loss) trial

RN was supported by a PhD studentship from the Fraserburgh Ladies Moonlight Prowl and Cancer Research Aberdeen and North East Scotland (CRANES). LCAC and GMcN acknowledge support from the RESAS programme of the Scottish Government.Peer reviewedPublisher PD

Pre-diagnosis diet and survival after a diagnosis of ovarian cancer

BACKGROUND: The relationship between diet and survival after ovarian cancer diagnosis is unclear as a result of a limited number of studies and inconsistent findings. METHODS: We examined the association between pre-diagnostic diet and overall survival in a population-based cohort (n=811) of Australian women diagnosed with invasive epithelial ovarian cancer between 2002 and 2005. Diet was measured by validated food frequency questionnaire. Deaths were ascertained up to 31 August 2014 via medical record review and Australian National Death Index linkage. We conducted Cox proportional hazards regression analysis, controlling for diagnosis age, tumour stage, grade and subtype, residual disease, smoking status, body mass index, physical activity, marital status, and energy intake. RESULTS: We observed improved survival with highest compared with lowest quartile of fibre intake (hazard ratio (HR)=0.69, 95% CI: 0.53-0.90, P-trend=0.002). There was a suggestion of better survival for women with highest compared with lowest intake category of green leafy vegetables (HR=0.79, 95% CI: 0.62-0.99), fish (HR=0.74, 95% CI: 0.57-0.95), poly- to mono-unsaturated fat ratio (HR=0.76, 95% CI: 0.59-0.98), and worse survival with higher glycaemic index (HR=1.28, 95% CI: 1.01-1.65, P-trend=0.03). CONCLUSIONS: The associations we observed between healthy components of diet pre-diagnosis and ovarian cancer survival raise the possibility that dietary choices after diagnosis may improve survival

Identifying biomarkers of dietary patterns by using metabolomics

BACKGROUND: Healthy dietary patterns that conform to national dietary guidelines are related to lower chronic disease incidence and longer life span. However, the precise mechanisms involved are unclear. Identifying biomarkers of dietary patterns may provide tools to validate diet quality measurement and determine underlying metabolic pathways influenced by diet quality. OBJECTIVE: The objective of this study was to examine the correlation of 4 diet quality indexes [the Healthy Eating Index (HEI) 2010, the Alternate Mediterranean Diet Score (aMED), the WHO Healthy Diet Indicator (HDI), and the Baltic Sea Diet (BSD)] with serum metabolites. DESIGN: We evaluated dietary patterns and metabolites in male Finnish smokers (n = 1336) from 5 nested case-control studies within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort. Participants completed a validated food-frequency questionnaire and provided a fasting serum sample before study randomization (1985-1988). Metabolites were measured with the use of mass spectrometry. We analyzed cross-sectional partial correlations of 1316 metabolites with 4 diet quality indexes, adjusting for age, body mass index, smoking, energy intake, education, and physical activity. We pooled estimates across studies with the use of fixed-effects meta-analysis with Bonferroni correction for multiple comparisons, and conducted metabolic pathway analyses. RESULTS: The HEI-2010, aMED, HDI, and BSD were associated with 23, 46, 23, and 33 metabolites, respectively (17, 21, 11, and 10 metabolites, respectively, were chemically identified; r-range: -0.30 to 0.20; P = 6 × 10(-15) to 8 × 10(-6)). Food-based diet indexes (HEI-2010, aMED, and BSD) were associated with metabolites correlated with most components used to score adherence (e.g., fruit, vegetables, whole grains, fish, and unsaturated fat). HDI correlated with metabolites related to polyunsaturated fat and fiber components, but not other macro- or micronutrients (e.g., percentages of protein and cholesterol). The lysolipid and food and plant xenobiotic pathways were most strongly associated with diet quality. CONCLUSIONS: Diet quality, measured by healthy diet indexes, is associated with serum metabolites, with the specific metabolite profile of each diet index related to the diet components used to score adherence. This trial was registered at clinicaltrials.gov as NCT00342992

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

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; &lt;1st tertile) and metabolically unhealthy (MU; &gt;=1st tertile) status among the control participants. These metabolic health definitions were combined with normal weight (NW; Body Mass Index (BMI)&lt;25kg/m2 or Waist Circumference (WC)&lt;80cm or Waist-to-Hip Ratio (WHR)&lt;0.8) and overweight (OW; BMI&gt;=25kg/m2 or WC&gt;=80cm or WHR&gt;=0.8) status, generating four phenotype groups for each anthropometric measure: (1)MH/NW, (2)MH/OW (3)MU/NW and (4)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 (OR/WC=1.48; 95%CI 1.05-2.10 and OR/WHR=1.68; 95%CI 1.21-2.35) and MU/OW (OR/BMI=2.38, 95%CI 1.73-3.27; OR/WC=2.69, 95%CI 1.92-3.77 and OR/WHR=1.83, 95%CI 1.32-2.54). MH/OW individuals were also at increased endometrial cancer risk compared to MH/NW individuals (OR/WC=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, overweight 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