title: Metabolomic analysis of prostate cancer risk in a prospective cohort: The alpha-tocolpherol, beta-carotene cancer prevention (ATBC) study.
abstract: Despite decades of concerted epidemiological research, relatively little is known about the etiology of prostate cancer. As genome-wide association studies have identified numerous genetic variants, so metabolomic profiling of blood and other tissues represents an agnostic, "broad-spectrum" approach for examining potential metabolic biomarkers of prostate cancer risk. To this end, we conducted a prospective analysis of prostate cancer within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort based on 200 cases (100 aggressive) and 200 controls (age- and blood collection date-matched) with fasting serum collected up to 20 years prior to case diagnoses. Ultrahigh performance liquid chromatography/mass spectroscopy and gas chromatography/mass spectroscopy identified 626 compounds detected in >95% of the men and the odds ratio per 1-standard deviation increase in log-metabolite levels and risk were estimated using conditional logistic regression. We observed strong inverse associations between energy and lipid metabolites and aggressive cancer (p = 0.018 and p = 0.041, respectively, for chemical class over-representation). Inositol-1-phosphate showed the strongest association (OR = 0.56, 95% CI = 0.39-0.81, p = 0.002) and glycerophospholipids and fatty acids were heavily represented; e.g., oleoyl-linoleoyl-glycerophosphoinositol (OR = 0.64, p = 0.004), 1-stearoylglycerophosphoglycerol (OR=0.65, p = 0.025), stearate (OR=0.65, p = 0.010) and docosadienoate (OR = 0.66, p = 0.014). Both alpha-ketoglutarate and citrate were associated with aggressive disease risk (OR = 0.69, 95% CI = 0.51-0.94, p = 0.02; OR = 0.69, 95% CI = 0.50-0.95, p = 0.02), as were elevated thyroxine and trimethylamine oxide (OR = 1.65, 95% CI = 1.08-2.54, p = 0.021; and OR = 1.36, 95% CI = 1.02-1.81, p = 0.039). Serum PSA adjustment did not alter the findings. Our data reveal several metabolomic leads that may have pathophysiological relevance to prostate carcinogenesis and should be examined through additional research.
authors.affiliation: Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Mondul
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, MD.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Moore
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, MD.
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Weinstein
authors.affiliation: Metabolon, Morrisville, NC.
authors.forename: Edward D
authors.initials: ED
authors.lastname: Karoly
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, MD.
authors.forename: Joshua N
authors.initials: JN
authors.lastname: Sampson
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, MD.
authors.forename: Demetrius
authors.initials: D
authors.lastname: Albanes
mesh_terms: D000230:Adenocarcinoma / Q000097:blood* / Q000517:prevention & control; D014408:Biomarkers, Tumor / Q000097:blood*; D006801:Humans; D008297:Male; D055442:Metabolome; D055432:Metabolomics; D008875:Middle Aged; D011446:Prospective Studies; D011471:Prostatic Neoplasms / Q000097:blood* / Q000517:prevention & control; D024502:alpha-Tocopherol / Q000627:therapeutic use*; D019207:beta Carotene / Q000627:therapeutic use*
chemical_list: D014408:Biomarkers, Tumor; D019207:beta Carotene; D024502:alpha-Tocopherol
keywords: TCA cycle; TMAO; Warburg; biomarkers; energy metabolism; lipid metabolism; metabolomics; prostate cancer; serology; thyroxine