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Int J Cancer. 2015 Nov 1;137(9):2124-32. doi: 10.1002/ijc.29576. Epub 2015 May 9.

Metabolomic analysis of prostate cancer risk in a prospective cohort: The alpha-tocolpherol, beta-carotene cancer prevention (ATBC) study.

Author information

1
Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI.
2
Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, MD.
3
Metabolon, Morrisville, NC.

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.

KEYWORDS:

TCA cycle; TMAO; Warburg; biomarkers; energy metabolism; lipid metabolism; metabolomics; prostate cancer; serology; thyroxine

PMID:
25904191
PMCID:
PMC4537663
DOI:
10.1002/ijc.29576
[Indexed for MEDLINE]
Free PMC Article

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