Profiling of polar urine metabolite extracts from Chinese colorectal cancer patients to screen for potential diagnostic and adverse-effect biomarkers

Abstract

Background: Metabolomics has demonstrated its potential in the early diagnosis, drug safety evaluation and personalized toxicology research of various cancers. Objectives: We aim to screen for potential diagnostic and capecitabine-related adverse effect (CRAE) biomarkers from urinary endogenous metabolites in Chinese colorectal cancer (CRC) patients. Methods: The metabolic profiles of 139 CRC patients and 50 non-neoplastic controls were analyzed using ultra-high-performance liquid chromatography combined with quadrupole time-of-flight mass spectrometry. Results: There were 41 metabolites identified between the CRC patients and the non-neoplastic controls, and 19 metabolites were identified between CRC patients with and without CRAE. Based on these identified metabolites, bioinformatic analysis and prediction model construction were completed. Most of these differential metabolites have important roles in cell proliferation and differentiation and the immune system. Based on binary logistic regression, a CRC prediction model, composed of 3-methylhistidine, N-heptanoylglycine, N 1 ,N 12 -diacetylspermine and hippurate, was established, with an area under curve (AUC) of 0.980 (95% CI: 0.953-1.000; sensitivity: 94.3%; specificity: 92.0%) in the training set, and an AUC of 0.968 (95% CI: 0.933-1.000; sensitivity: 89.9%; specificity: 92.0%) in the testing set. In addition, methionine and 4-pyridoxic acid can be combined to predict hand foot syndrome, with an AUC of 0.884; ubiquinone-1 and 4-pyridoxic acid can be combined to predict anemia, with an AUC of 0.889; and 5-acetamidovalerate and 3,4-methylenesebacic acid can be combined to predict neutropenia, with an AUC of 0.882. Conclusion: The profiling of urine polar metabolites has great potential in the early detection of CRC and the prediction of CRAE.

Spermine-Related DNA Hypermethylation and Elevated Expression of Genes for Collagen Formation are Susceptible Factors for Chemotherapy-Induced Hand-Foot Syndrome in Chinese Colorectal Cancer Patients

“…Our results constituted the first demonstration that variations in multi-omics profiles could predict the HFS susceptibility ( Figures 1D,E , 2 ). This was consistent with our previous report that variations in the endogenous urine metabolome correlated positively with HFS ( Deng et al, 2020 ). As the CRT metabolome bears more similarities to that of skin than of plasma and urine in terms of their chemical composition, histology pattern, and cell developmental programs, changes in the CRT metabolome afford the best correlation with the HFS susceptibility.…”

“…Owing to the cytotoxicity of capecitabine, however, XELOX can cause various chemotherapy-related adverse events (CRAEs), one of the most common of which is the hand-foot syndrome (HFS, also called palmar-plantar erythrodysesthesia). It ranks within the top 3 CRAEs with an incidence rate of up to 70% ( Lou et al, 2016 ; Yap et al, 2017 ; Deng et al, 2020 ; Li et al, 2021 ). HFS symptoms include redness, swelling, as well as pain on the palms of the hands and the soles of the feet.…”

“…Nonetheless, the response to a particular cytotoxic substance (including a drug) may vary amongst individuals, which can also contribute to the sensitivity to CRAEs. Notably, our preliminary study has revealed potential valuable CRAE biomarkers derived from both endogenous urine metabolites ( Deng et al, 2020 ) and germline DNA methylation (M et al, 2021). Second, the pathological mechanism of HFS requires further investigation.…”

Milk and Egg Are Risk Factors for Adverse Effects of Capecitabine-Based Chemotherapy in Chinese Colorectal Cancer Patients

“… 35 Consistently, our previous work has also identified several pro-inflammatory metabolites associated with HFS susceptibility. 12 However, a prospective study reported that pyridoxine, which suppresses inflammation, cannot effectively prevent HFS. 5 Herein we found that milk was a risk factor for HFS.…”

“…The exclusion criteria were: (1) pregnant and lactating women, (2) patients with hypersensitivity to fluorouracil or severe metabolic failure, (3) patients with severe infection, (4) patients with cancers other than CRC within the first 5 years of CRC surgery, and (5) patients with any pre-operative anti-neoplastic medication. 12 This study was approved by Biomedical Research Ethics Committee of Shanghai Changzheng Hospital (No. 2016SL007), and written informed consent was obtained from every patient.…”