PDF(Pubmed)
Abstract：
Deleterious effects of environmental exposures may contribute to the rising incidence of early-onset colorectal cancer (eoCRC). We assessed the metabolomic differences between patients with eoCRC, average-onset CRC (aoCRC), and non-CRC controls, to understand pathogenic mechanisms. Patients with stage I-IV CRC and non-CRC controls were categorized based on age ≤ 50 years (eoCRC or young non-CRC controls) or ≥ 60 years (aoCRC or older non-CRC controls). Differential metabolite abundance and metabolic pathway analyses were performed on plasma samples. Multivariate Cox proportional hazards modeling was used for survival analyses. All P values were adjusted for multiple testing (false discovery rate, FDR P < 0.15 considered significant). The study population comprised 170 patients with CRC (66 eoCRC and 104 aoCRC) and 49 non-CRC controls (34 young and 15 older). Citrate was differentially abundant in aoCRC vs. eoCRC in adjusted analysis (Odds Ratio = 21.8, FDR P = 0.04). Metabolic pathways altered in patients with aoCRC versus eoCRC included arginine biosynthesis, FDR P = 0.02; glyoxylate and dicarboxylate metabolism, FDR P = 0.005; citrate cycle, FDR P = 0.04; alanine, aspartate, and glutamate metabolism, FDR P = 0.01; glycine, serine, and threonine metabolism, FDR P = 0.14; and amino-acid t-RNA biosynthesis, FDR P = 0.01. 4-hydroxyhippuric acid was significantly associated with overall survival in all patients with CRC (Hazards ratio, HR = 0.4, 95% CI 0.3-0.7, FDR P = 0.05). We identified several unique metabolic alterations, particularly the significant differential abundance of citrate in aoCRC versus eoCRC. Arginine biosynthesis was the most enriched by the differentially altered metabolites. The findings hold promise in developing strategies for early detection and novel therapies.
摘要：
环境暴露的有害影响可能导致早发性结直肠癌（eoCRC）的发病率上升。我们评估了eoCRC患者之间的代谢组学差异，平均起病CRC（aoCRC），和非CRC控制，了解致病机制。I-IV期CRC和非CRC对照的患者根据年龄≤50岁（eoCRC或年轻的非CRC对照）或≥60岁（aoCRC或更老的非CRC对照）进行分类。对血浆样品进行差异代谢物丰度和代谢途径分析。多变量Cox比例风险模型用于生存分析。所有P值都进行了多次测试调整(错误发现率，FDRP<0.15被认为是显著的)。研究人群包括170例CRC患者（66例eoCRC和104例aoCRC）和49例非CRC对照（34例年轻人和15例老年人）。aoCRC与aoCRC中柠檬酸盐含量不同校正分析中的eoCRC(赔率比=21.8，FDRP=0.04)。aoCRC与eoCRC患者的代谢途径改变包括精氨酸生物合成，FDRP=0.02；乙醛酸和二羧酸代谢，FDRP=0.005；柠檬酸盐循环，FDRP=0.04；丙氨酸，天冬氨酸,和谷氨酸代谢，FDRP=0.01;甘氨酸,丝氨酸,苏氨酸代谢，FDRP=0.14;和氨基酸t-RNA生物合成，FDRP=0.01。4-羟基马尿酸与所有CRC患者的总生存率显着相关（危害比，HR=0.4，95%CI0.3-0.7，FDRP=0.05）。我们发现了几种独特的代谢改变，特别是aoCRC与eoCRC中柠檬酸盐丰度的显著差异。精氨酸生物合成是差异改变的代谢物最富集的。这些发现有望开发早期发现和新疗法的策略。
