How metabolome changes influence the early process of colorectal cancer (CRC) development remains unknown. We conducted a 1:2 matched nested case–control study to examine the associations of pre-diagnostic plasma metabolome (profiled using LC–MS) with risk of CRC precursors, including conventional adenomas (n = 586 vs. 1141) and serrated polyps (n = 509 vs. 993), in the Nurses' Health Study (NHS) and NHSII. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). We used the permutation-based Westfall and Young approach to account for multiple testing. Subgroup analyses were performed for advanced conventional adenomas (defined as at least one adenoma of ≥ 10 mm or with high-grade dysplasia, or tubulovillous or villous histology) and high-risk serrated polyps that were located in the proximal colon or with size of ≥ 10 mm. After multiple testing correction, among 207 metabolites, higher levels of C36:3 phosphatidylcholine (PC) plasmalogen were associated with lower risk of conventional adenomas, with the OR (95% CI) comparing the 90th to the 10th percentile of 0.62 (0.48–0.81); C54:8 triglyceride (TAG) was associated with higher risk of serrated polyps (OR = 1.79, 95% CI: 1.31–2.43), and phenylacetylglutamine (PAG) was associated with lower risk (OR = 0.57, 95% CI:0.43–0.77). PAG was also inversely associated with advanced adenomas (OR = 0.57, 95% CI: 0.36–0.89) and high-risk serrated polyps (OR = 0.54, 95% CI: 0.32–0.89), although the multiple testing-corrected p value was > 0.05. Our findings suggest potential roles of lipid metabolism and phenylacetylglutamine, a microbial metabolite, in the early stage of colorectal carcinogenesis, particularly for the serrated pathway.

代谢组变化如何影响结直肠癌 (CRC) 发展的早期过程仍然未知。我们进行了一项 1:2 匹配的巢式病例对照研究，以检查诊断前血浆代谢组（使用 LC-MS 分析）与 CRC 前体风险的关联，包括常规腺瘤（n = 586 对 1141）和锯齿状息肉（ n = 509 对 993)，在护士健康研究 (NHS) 和 NHSII 中。条件逻辑回归用于估计比值比 (OR) 和 95% 置信区间 (CI)。我们使用基于排列的 Westfall 和 Young 方法来解释多重测试。对晚期常规腺瘤（定义为至少一个 ≥ 10 mm 的腺瘤或高度异型增生，或管状绒毛状或绒毛状组织学）和位于近端结肠或大小≥10 mm 的高危锯齿状息肉。经过多次检验校正后，在 207 种代谢物中，较高水平的 C36:3 磷脂酰胆碱 (PC) 缩醛磷脂与较低的常规腺瘤风险相关，OR (95% CI) 将第 90 个百分位数与第 10 个百分位数进行比较，为 0.62 (0.48–0.81) ); C54:8 甘油三酯 (TAG) 与锯齿状息肉的高风险相关（OR = 1.79, 95% CI: 1.31–2.43），苯乙酰谷氨酰胺 (PAG) 与较低风险相关（OR = 0.57, 95% CI:0.43– 0.77）。PAG 也与晚期腺瘤 (OR = 0.57, 95% CI: 0.36–0.89) 和高风险锯齿状息肉 (OR = 0.54, 95% CI: 0.32–0.89) 呈负相关，尽管多重检验校正的 p 值是> 0.05。