Serum Metabolomic Profiling Reveals Biomarkers for Early Detection and Prognosis of Esophageal Squamous Cell Carcinoma

Abstract

Esophageal squamous cell carcinoma (ESCC) is one of the most common aggressive malignancies worldwide, particularly in northern China. The absence of specific early symptoms and biomarkers leads to late-stage diagnosis, while early diagnosis and risk stratification are crucial for improving overall prognosis. We performed UPLC-MS/MS on 450 ESCC patients and 588 controls consisting of a discovery group and two validation groups to identify biomarkers for early detection and prognosis. Bioinformatics and clinical statistical methods were used for profiling metabolites and evaluating potential biomarkers. A total of 105 differential metabolites were identified as reliable biomarker candidates for ESCC with the same tendency in three cohorts, mainly including amino acids and fatty acyls. A predictive model of 15 metabolites [all-trans-13,14-dihydroretinol, (±)-myristylcarnitine, (2S,3S)-3-methylphenylalanine, 3-(pyrazol-1-yl)-L-alanine, carnitine C10:1, carnitine C10:1 isomer1, carnitine C14-OH, carnitine C16:2-OH, carnitine C9:1, formononetin, hyodeoxycholic acid, indole-3-carboxylic acid, PysoPE 20:3, PysoPE 20:3(2n isomer1), and resolvin E1] was developed by logistic regression after LASSO and random forest analysis. This model held high predictive accuracies on distinguishing ESCC from controls in the discovery and validation groups (accuracies > 89%). In addition, the levels of four downregulated metabolites [hyodeoxycholic acid, (2S,3S)-3-methylphenylalanine, carnitine C9:1, and indole-3-carboxylic acid] were significantly higher in early cancer than advanced cancer. Furthermore, three independent prognostic markers were identified by multivariate Cox regression analyses with and without clinical indicators: a high level of MG(20:4)isomer and low levels of 9,12-octadecadienoic acid and L-isoleucine correlated with an unfavorable prognosis; the risk score based on these three metabolites was able to stratify patients into low or high risk. Moreover, pathway analysis indicated that retinol metabolism and linoleic acid metabolism were prominent perturbed pathways in ESCC. In conclusion, metabolic profiling revealed that perturbed amino acids and lipid metabolism were crucial metabolic signatures of ESCC. Both panels of diagnostic and prognostic markers showed excellent predictive performances. Targeting retinol and linoleic acid metabolism pathways may be new promising mechanism-based therapeutic approaches. Thus, this study would provide novel insights for the early detection and risk stratification for the clinical management of ESCC and potentially improve the outcomes of ESCC.

Identifying the Novel Gut Microbial Metabolite Contributing to Metabolic Syndrome in Children Based on Integrative Analyses of Microbiome-Metabolome Signatures

“…In our study, the processes of retinol metabolism with all-trans-13,14-dihydroretinol were significantly increased in the MS group. It has been previously reported that retinol metabolism was closely correlated with MS in adults ( 37 ), and the elevated level of all-trans-13,14-dihydroretinol was also observed in other diseases, including atherosclerosis and cancer ( 38 , 39 ). All-trans-13,14-dihydroretinol was a metabolite of retinol that was produced by retinol saturase (RetSat) ( 40 , 41 ).…”

Postoperative Metabolic Phenoreversion in Clear Cell Renal Cell Carcinoma

“…The alteration of the linoleic acid metabolism pathway has been associated with different tumor types. − Altered content of membrane PCs and phospholipid (PL) profiles have also been associated with cancer development and progression. − Lower plasma LPC levels have been suggested as markers of severity in cancer, including RCC with lower levels exhibited in more aggressive tumors, and increased levels in patients who were in remission 6 months after surgery . However, different trends were reported for PC 16:0 in RCC. , More studies are needed to understand how the PL metabolism is altered and regulated and to decipher the particular role of specific PLs in a pathological context.…”

Metabolites, Healthy Lifestyle, and Polygenic Risk Score Associated with Upper Gastrointestinal Cancer: Findings from the UK Biobank Study

“…Due to these metabolic changes, the dysregulated expression levels of these three amino acids have been previously confirmed by multiple studies as biomarkers that can be used to discriminate or predict gastric and esophageal cancers. ,− Unsaturated fatty acids can reduce fat accumulation and regulate blood lipids and also play an important role in immune regulation. There have been several findings supporting the notion that fatty acids are often accompanied by changes in cancer patients and are used as biomarkers to identify upper gastrointestinal cancers. − Our analysis displayed a decline in the degree of unsaturation in UGI cancer patients compared with controls, which is in agreement with existing evidence. , The reduced levels of unsaturated fatty acids in upper gastrointestinal cancer patients can be attributed to the high utilization of fatty acids by active cancer cells for cell membrane synthesis and energy production. , Due to these factors, unsaturated fatty acids are significantly different between UGI cancer patients and healthy controls, suggesting their potential as biomarkers. The level of albumin serves as an indicator for assessing the nutritional status and the severity of inflammation.…”