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

摘要

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.