Yuan Fangcheng, Jia Guochong, Wen Wanqing, Xu Shuai, Gunchick Valerie, Deng Kui, Long Jirong, Yu Danxia, Shu Xiao-Ou, Zheng Wei
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
Br J Cancer. 2025 Apr 30. doi: 10.1038/s41416-025-02997-4.
Emerging evidence suggests metabolic dysregulation may contribute to colorectal cancer (CRC) aetiology. We aimed to identify pre-diagnostic metabolic biomarkers for CRC risk in 230,420 UK Biobank participants.
Nuclear magnetic resonance spectroscopy was used to quantify 249 metabolic biomarkers in plasma samples collected at baseline. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals (CIs) for associations of metabolic biomarkers with CRC risk after adjusting for potential confounders. To infer the potential causality of biomarkers that were associated with CRC independent of the others, we performed genome-wide association analyses among 199,732 UK Biobank participants of European ancestry to identify biomarker-associated genetic variants, followed by two-sample Mendelian randomization (MR) analyses using summary statistics of 78,473 CRC cases and 107,143 controls of European ancestry.
During a median follow-up time of 9.7 years, 2,410 incident primary CRC cases were identified. Among 43 CRC-associated (P-value < 0.001) metabolic biomarkers, ten biomarkers including fatty acids (FAs), inflammation, ketone bodies, and lipoprotein lipids were associated with CRC risk after mutual adjustment. MR analyses provided strong evidence for potential causal associations of CRC risk with percentages of linolic acid [odds ratio (OR) = 0.89, 95% CI = 0.83-0.96, P-value = 3 × 10] and saturated FAs (OR = 1.14, 95% CI = 1.03-1.25, P-value = 9 × 10) to total FAs.
We identified multiple CRC-associated metabolic biomarkers. Perturbed lipid and lipoprotein metabolism may promote colorectal carcinogenesis.
新出现的证据表明，代谢失调可能与结直肠癌（CRC）的病因有关。我们旨在确定230420名英国生物银行参与者中结直肠癌风险的诊断前代谢生物标志物。
采用核磁共振波谱法对基线时采集的血浆样本中的249种代谢生物标志物进行定量。在调整潜在混杂因素后，使用Cox比例风险模型估计代谢生物标志物与结直肠癌风险关联的风险比和95%置信区间（CI）。为了推断与结直肠癌独立相关的生物标志物的潜在因果关系，我们对199732名欧洲血统的英国生物银行参与者进行了全基因组关联分析，以识别与生物标志物相关的基因变异，随后使用78473例结直肠癌病例和107143例欧洲血统对照的汇总统计数据进行两样本孟德尔随机化（MR）分析。
在中位随访时间9.7年期间，共识别出2410例原发性结直肠癌病例。在43种与结直肠癌相关（P值<0.001）的代谢生物标志物中，包括脂肪酸（FAs）、炎症、酮体和脂蛋白脂质在内的10种生物标志物在相互调整后与结直肠癌风险相关。MR分析为结直肠癌风险与亚油酸百分比[比值比（OR）=0.89，95%CI=0.83-0.96，P值=3×10]和饱和脂肪酸与总脂肪酸的百分比（OR=1.14，95%CI=1.03-1.25，P值=9×10）之间的潜在因果关联提供了有力证据。
我们识别出多种与结直肠癌相关的代谢生物标志物。脂质和脂蛋白代谢紊乱可能促进结直肠癌的发生。
