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

Abstract

Hand-foot syndrome (HFS) is a common capecitabine-based chemotherapy-related adverse event (CRAE) in patients with colorectal cancer (CRC). It is of great significance to comprehensively identify susceptible factors for HFS, and further to elucidate the biomolecular mechanism of HFS susceptibility. We performed an untargeted multi-omics analysis integrating DNA methylation, transcriptome, and metabolome data of 63 Chinese CRC patients who had complete CRAE records during capecitabine-based chemotherapy. We found that the metabolome changes for each of matched plasma, urine, and normal colorectal tissue (CRT) in relation to HFS were characterized by chronic tissue damage, which was indicated by reduced nucleotide salvage, elevated spermine level, and increased production of endogenous cytotoxic metabolites. HFS-related transcriptome changes of CRT showed an overall suppressed inflammation profile but increased M2 macrophage polarization. HFS-related DNA methylation of CRT presented gene-specific hypermethylation on genes mainly for collagen formation. The hypermethylation was accumulated in the opensea and shore regions, which elicited a positive effect on gene expression. Additionally, we developed and validated models combining relevant biomarkers showing reasonably good discrimination performance with the area under the receiver operating characteristic curve values from 0.833 to 0.955. Our results demonstrated that the multi-omics variations associated with a profibrotic phenotype were closely related to HFS susceptibility. HFS-related biomolecular variations in CRT contributed more to the relevant biomolecular mechanism of HFS than in plasma and urine. Spermine-related DNA hypermethylation and elevated expression of genes for collagen formation were closely associated with HFS susceptibility. These findings provided new insights into the susceptible factors for chemotherapy-induced HFS, which can promote the implementation of individualized treatment against HFS.

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

“… 36 Furthermore, our recent study showed that HFS-related transcriptome changes of normal colorectal tissue had an overall suppressed inflammation profile. 7 Our food/nutritional findings are also in accordance with the well-established function of milk in anti-inflammation. The fat content and fermentation effect do not affect the anti-inflammation effect.…”

“…The plasma metabolome data of the 36 patients was acquired from published data. 7 To put it briefly, an UHPLC system coupled to a quadruple time-of-flight mass spectrometer was utilized for the metabolome assays. All the samples were screened separately under both positive and negative ionization modes, and the detailed methods of data pre-processing about metabolome were described in our previous study.…”

“…All the samples were screened separately under both positive and negative ionization modes, and the detailed methods of data pre-processing about metabolome were described in our previous study. 7 …”

“…Nausea and vomiting (NV), hand-foot syndrome (HFS), and bone marrow suppression (BMS) are the 3 common adverse effects caused by capecitabine according to literatures and our ongoing observational clinical trial. 4 - 10 These CIAEs hamper the successful completion of anti-cancer treatment, bringing a highly burdensome condition for patients, and even threaten life if left untreated. 11 …”

A Systematic Review of Clinical Validated and Potential miRNA Markers Related to the Efficacy of Fluoropyrimidine Drugs

“…Last but not least, screening miRNAs from normal tissues other than tumors may provide more informative clues. Accumulating evidence suggests that the efficacy and safety of chemotherapy are not solely dependent on drug metabolism but also on the overall physiological functions [44,[48][49][50][51][52][53]. Individual differences in cell maintenance, proliferation, and immune function also influence the response to chemotherapy.…”