Mondul Alison M, Moore Steven C, Weinstein Stephanie J, Karoly Edward D, Sampson Joshua N, Albanes Demetrius
Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI.
Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, MD.
Int J Cancer. 2015 Nov 1;137(9):2124-32. doi: 10.1002/ijc.29576. Epub 2015 May 9.
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.
尽管经过了数十年的协同流行病学研究，但对前列腺癌的病因仍知之甚少。随着全基因组关联研究已经确定了众多基因变异，血液和其他组织的代谢组学分析代表了一种无偏见的“广谱”方法，用于检查前列腺癌风险的潜在代谢生物标志物。为此，我们在α-生育酚、β-胡萝卜素癌症预防研究队列中对前列腺癌进行了一项前瞻性分析，该队列基于200例病例（100例侵袭性病例）和200例对照（年龄和采血日期匹配），病例诊断前20年内收集了空腹血清。超高效液相色谱/质谱联用仪和气相色谱/质谱联用仪鉴定出在超过95%的男性中检测到的626种化合物，并使用条件逻辑回归估计每1个标准差对数代谢物水平增加与风险的比值比。我们观察到能量和脂质代谢物与侵袭性癌症之间存在强烈的负相关（化学类别过度代表性的p值分别为0.018和0.041）。肌醇-1-磷酸显示出最强的相关性（OR = 0.56，95% CI = 0.39 - 0.81，p = 0.002），甘油磷脂和脂肪酸大量存在；例如，油酰-亚油酰-甘油磷酸肌醇（OR = 0.64，p = 0.004）、1-硬脂酰甘油磷酸甘油（OR = 0.65，p = 0.025）、硬脂酸（OR = 0.65，p = 0.010）和二十二碳二烯酸（OR = 0.66，p = 0.014）。α-酮戊二酸和柠檬酸均与侵袭性疾病风险相关（OR = 0.69，95% CI = 0.51 - 0.94，p = 0.02；OR = 0.69，95% CI = 0.50 - 0.95，p = 0.02），甲状腺素和氧化三甲胺升高也与之相关（OR = 1.65，95% CI = 1.08 - 2.54，p = 0.021；OR = 1.36，95% CI = 1.02 - 1.81，p = 0.039）。血清前列腺特异抗原（PSA）校正并未改变研究结果。我们的数据揭示了几个可能与前列腺癌发生具有病理生理相关性的代谢组学线索，应通过进一步研究进行检验。
