Nutritional metabolomics and breast cancer risk in a prospective study

Abstract

Background: The epidemiologic evidence for associations between dietary factors and breast cancer is weak and etiologic mechanisms are often unclear. Exploring the role of dietary biomarkers with metabolomics can potentially facilitate objective dietary characterization, mitigate errors related to self-reported diet, agnostically test metabolic pathways, and identify mechanistic mediators.Objective: The aim of this study was to evaluate associations of diet-related metabolites with the risk of breast cancer in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial.Design: We examined prediagnostic serum concentrations of diet-related metabolites in a nested case-control study in 621 postmenopausal invasive breast cancer cases and 621 matched controls in the multicenter PLCO cohort. We calculated partial Pearson correlations between 617 metabolites and 55 foods, food groups, and vitamin supplements on the basis of the 2015 Dietary Guidelines for Americans and derived from a 137-item self-administered food-frequency questionnaire. Diet-related metabolites (P-correlation < 1.47 × 10-6) were evaluated in breast cancer analyses. ORs for the 90th compared with the 10th percentile were calculated by using conditional logistic regression, with body mass index, physical inactivity, other breast cancer risk factors, and caloric intake controlled for (false discovery rate <0.2).Results: Of 113 diet-related metabolites, 3 were associated with overall breast cancer risk (621 cases): caprate (10:0), a saturated fatty acid (OR: 1.77; 95% CI = 1.28, 2.43); γ-carboxyethyl hydrochroman (γ-CEHC), a vitamin E (γ-tocopherol) derivative (OR: 1.64; 95% CI: 1.18, 2.28); and 4-androsten-3β,17β-diol-monosulfate (1), an androgen (OR: 1.61; 95% CI: 1.20, 2.16). Nineteen metabolites were significantly associated with estrogen receptor (ER)-positive (ER+) breast cancer (418 cases): 12 alcohol-associated metabolites, including 7 androgens and α-hydroxyisovalerate (OR: 2.23; 95% CI: 1.50, 3.32); 3 vitamin E (tocopherol) derivatives (e.g., γ-CEHC; OR: 1.80; 95% CI: 1.20, 2.70); butter-associated caprate (10:0) (OR: 1.81; 95% CI: 1.23, 2.67); and fried food-associated 2-hydroxyoctanoate (OR: 1.46; 95% CI: 1.03, 2.07). No metabolites were significantly associated with ER-negative breast cancer (144 cases).Conclusions: Prediagnostic serum concentrations of metabolites related to alcohol, vitamin E, and animal fats were moderately strongly associated with ER+ breast cancer risk. Our findings show how nutritional metabolomics might identify diet-related exposures that modulate cancer risk. This trial was registered at clinicaltrials.gov as NCT00339495.

Keywords: alcohol; androgen; biomarker; breast cancer; diet; fat; metabolomics; nutrition; tocopherol.

© 2017 American Society for Nutrition.

Figures

FIGURE 1

Serum nonfasting metabolites associated with food, diet quality, dietary supplements, and beverages (Bonferroni correction) in a nested case-control study within the PLCO cancer screening trial cohort (cases and controls: n = 1127). Partial Pearson correlations adjusted for case status (case, control), age at blood draw (years), smoking history (never or missing, former, or current), diabetes history (no or yes), BMI (in kg/m2; <25, 25 to <30 or missing, or ≥30), education (≤high school, post–high school training other than college, some college, college graduate, or postgraduate), vigorous physical activity (in hours per week; none, <1, 1, 2, 3, ≥4, or missing), and daily caloric intake (quintiles). Analyses were adjusted for multiple comparisons by using Bonferroni correction [P < 0.05/(617 × 55) = 1.5 × 10−6]. Alcohol use was adjusted for coffee intake and vice versa. The Healthy Eating Index–2010 was adjusted for any supplement use. Individual vitamin supplement use was adjusted for multivitamin use. Metabolites associated with oranges and grapefruit, separately, can be found in Supplemental Table 2. Information on mass-to-charge ratio, retention index, number of metabolites below the limit of detection, metabolomics platform, metabolite identification number [Human Metabolome Database (http://www.hmdb.ca/metabolites/) or PubChem (https://pubchem.ncbi.nlm.nih.gov/)], and metabolic pathways is available in Supplemental Table 2. ADMA, asymmetric dimethylarginine; AHB, α-hydroxybutyrate; CEHC, carboxyethyl hydrochroman; CMPF, 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid; DHEAS, dehydroepiandrosterone sulfate; GPC, glycerophosphocholine; PLCO, Prostate, Lung, Colorectal and Ovarian; SDMA, symmetric dimethylarginine; veg., vegetables.

FIGURE 2

ORs for the association between diet-related metabolites and ER+ breast cancer in the PLCO cancer screening trial cohort. (A) Caprate (10:0) (butter-related; P-linearity = 0.003, P-nonlinearity = 0.99); (B) γ-CEHC (dessert-related; P-linearity = 0.003, P-nonlinearity = 0.66); (C) α-hydroxyisovalerate (alcohol-related; P-linearity = 0.003, P-nonlinearity = 0.57); (D) 4-androsten-3β,17β-diol disulfate (2) (alcohol-related; P-linearity = 0.0003, P-nonlinearity = 0.75); (E) α-tocopherol (multivitamin- and vitamin E supplement–related; P-linearity = 0.02, P-nonlinearity = 0.56). Estimates were obtained from restricted cubic spline logistic regression models. All models were significant for a linear relation; thus, the linear relations are presented. Models were adjusted for age at blood draw (years), age at menarche (<12 y, 12–13 y or missing, or ≥14 y), age at first child and number of live births (nulliparous, <20 y and ≥1 live birth, 20–29 y and 1–2 live births, 20–29 y and ≥3 live births or missing, or ≥30 y and ≥1 live birth), type of menopause and age at menopause (natural and <45 y, natural and 45–49 y, natural and 50–54 y, natural and ≥55 y, bilateral oophorectomy or drug therapy or radiation, or hysterectomy or missing), menopausal hormone therapy use (never, former, or current), history of benign breast disease (no or missing, or yes), first-degree female family history of breast cancer (no or missing, or yes), education (≤12 y, post–high school training besides college, some college or missing, college, or postgraduate), smoking history (never or missing, former, or current), drinking history (never or missing, former, or current), diabetes history (no or yes), vigorous physical activity (in hours per week; none, <1, 1, 2, 3, ≥4, or missing), and daily caloric intake (quintiles). Alcohol-related metabolites were not adjusted for self-reported alcohol use. ER+, estrogen receptor–positive; PLCO, Prostate, Lung, Colorectal, and Ovarian; γ-CEHC, γ-carboxyethyl hydrochroman.

FIGURE 3

Gaussian graphical model of 113 diet-related metabolites measured in a nested case-control study within the PLCO cancer screening trial cohort. Metabolites are pictured as hexagons, and those pairs with an absolute value of conditional correlation >0.2 are connected by a line. Pink lines represent positive conditional correlations. Purple lines represent inverse conditional correlations. Hexagons are color-coded by their association with ER+ breast cancer. Metabolites highlighted pink are positively associated with ER+ breast cancer. Metabolites highlighted purple are inversely associated with ER+ breast cancer. CEHC, carboxyethyl hydrochroman; ER+, estrogen receptor–positive; PLCO, Prostate, Lung, Colorectal, and Ovarian.