Al-Sayegh Thuraya, Song Shuang, Lipworth Loren, Cai Hui, Lan Qing, Gao Yutang, Rothman Nathaniel, Cai Qiuyin, Zheng Wei, Shu Xiao-Ou
Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37203, United States.
Division of Cancer Epidemiology and Genetics, National Cancer Institute Rockville, MD 20892, United States.
Carcinogenesis. 2025 Apr 3;46(2). doi: 10.1093/carcin/bgaf029.
Kidney cancer incidence has increased worldwide in recent decades. While metabolomic studies have shown promise in unveiling mechanisms underlying disease development, few studies have investigated prediagnostic urinary metabolites and kidney cancer risk. We conducted a case-control study nested within the Shanghai Women's and Men's Health Studies to prospectively investigate the association between urinary metabolites and kidney cancer risk to understand its etiology and the underlying biological mechanisms. Two hundred primary kidney cancer cases and their individually matched controls were included. A total of 1301 metabolites were evaluated, and 67 metabolites were found nominally associated with kidney cancer using conditional logistic regression. After backward selection, 11 urine metabolites remained significantly associated with kidney cancer: lipids (e.g. picolinoylglycine, odds ratio [OR]; 95% confidence interval [CI]: 2.01 [1.44, 2.79], and pregnanediol-3-glucuronide, OR; 95% CI: 0.56 [0.39, 0.82]), xenobiotics (e.g. beta-guanidinopropanoate, OR; 95% CI: 1.75 [1.32, 2.32] and 4-vinylphenol sulfate, OR; 95% CI: 0.66 [0.49, 0.90]), and nucleotides (e.g. allantoic acid, OR; 95% CI: 0.71 [0.54, 0.92]). Time lag analysis showed that metabolite-kidney cancer associations were stronger for beta-guanidinopropanoate (OR; 95% CI: 8.22 [1.68, 40.18]) and picolinoylglycine (OR; 95% CI: 6.45 [1.28, 32.43]), but weaker for allantoic acid (OR; 95% CI: 0.87 [0.37, 2.06]) and 3-methylglutarate/2-methylglutarate (OR; 95% CI: 0.62 [0.19, 2.00]) when urinary samples were collected within 3 years between urine sample collection and cancer diagnosis (Pinteraction < .05 for all). Future metabolomics studies with large sample sizes, particularly from multiple ancestry populations, are needed to validate our findings.
近几十年来，全球肾癌发病率呈上升趋势。虽然代谢组学研究在揭示疾病发展潜在机制方面显示出前景，但很少有研究调查诊断前尿液代谢物与肾癌风险之间的关系。我们在上海男性和女性健康研究中开展了一项巢式病例对照研究，以前瞻性地调查尿液代谢物与肾癌风险之间的关联，从而了解其病因及潜在生物学机制。研究纳入了200例原发性肾癌病例及其个体匹配的对照。共评估了1301种代谢物，使用条件逻辑回归发现67种代谢物与肾癌存在名义上的关联。经过向后选择，11种尿液代谢物仍与肾癌显著相关：脂质（如吡啶甲酰甘氨酸，比值比[OR]；95%置信区间[CI]：2.01[1.44, 2.79]，以及孕二醇-3-葡萄糖醛酸苷，OR；95% CI：0.56[0.39, 0.82]）、外源性物质（如β-胍基丙酸，OR；95% CI：1.75[1.32, 2.32]和4-乙烯基苯酚硫酸盐，OR；95% CI：0.66[0.49, 0.90]）和核苷酸（如尿囊酸，OR；95% CI：0.71[0.54, 0.92]）。时间滞后分析表明，对于β-胍基丙酸（OR；95% CI：8.22[1.68, 40.18]）和吡啶甲酰甘氨酸（OR；95% CI：6.45[1.28, 32.43]），代谢物与肾癌的关联更强，但对于尿囊酸（OR；95% CI：0.87[0.37, 2.06]）和3-甲基戊二酸/2-甲基戊二酸（OR；95% CI：0.62[0.19, 2.00]），当尿液样本采集与癌症诊断之间的时间间隔在3年内时，关联较弱（所有P交互作用<0.05）。未来需要开展大样本量的代谢组学研究，特别是来自多个祖先群体的研究，以验证我们的发现。
