Plasma metabolic profiling as a novel fingerprint for diagnosis of colorectal carcinogenesis and malignant progression

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, and non-invasive diagnostic tools for early detection are urgently needed. This study aimed to characterize plasma metabolic profiles associated with colorectal carcinogenesis and malignant progression, and to evaluate their diagnostic value across the disease spectrum from precancerous lesions to advanced CRC. Blood specimens were collected from 556 participants, including healthy controls (HC, n = 128), patients with colorectal polyp (CRP, n = 71), colorectal adenoma (CRA, n = 118), early-stage colorectal cancer (ECRC, n = 50), and advanced colorectal cancer (ACRC, n = 189) at the First Affiliated Hospital of Nanchang University from March to December 2019. Plasma metabolites were profiled using liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS). A total of 898 metabolites were annotated by comparing the KEGG database. Fifty-four metabolic dysregulation variables, including lipid metabolism, glycerophospholipid metabolism, purine metabolism, amino acids and caffeine metabolism, were characterized by multivariate statistical analysis methods in the CRC group compared to the HC group. Multivariate ROC analyses of 42 metabolites with AUC values exceeding 0.8 revealed that the discovery cohort had an AUC value of 0.9893, and that the validation cohort had an AUC value of 0.9227. In the validation cohort, 44 (60.3%) of 73 CRC patients were CEA-negative (CEA < 6.5 ng/ml), whereas only 1 (1.3%) of the metabolic classifications were incorrectly classified as healthy controls. Similarly, 45 dysregulated metabolites were identified in the comparison of HC and colorectal non-cancer disease (CRNC, including CRP, CRA) groups, with AUC values of 0.9793 and 0.8816 in the discovery and validation cohorts, respectively. In addition, a multivariate discriminant model was constructed from candidate metabolic features, with AUC values of 0.995, 0.962, 0.936, 0.968, and 0.942 in the discovery cohort for HC, CRP, CRA, ECRC, and ACRC, respectively. The AUC values in the validation cohort for HC, CRP, CRA, ECRC and ACRC were 0.841, 0.622, 0.680, 0.656 and 0.936, respectively. Plasma metabolic profiles are associated with colorectal carcinogenesis and malignant progression and may represent candidate metabolic signatures for CRC detection that require further validation.