Genome-wide maps of colorectal cancer diagnosis and toxicity of capecitabine-based chemotherapy [methylation array]

Background: Capecitabine-based adjuvant chemotherapy is the first-line treatment for patients with colorectal cancer (CRC). Although this therapy generally reduces the incidence of CRC recurrence and mortality, it can cause various chemotherapy-related adverse events (CRAEs), one of the most frequent of which is hand-foot syndrome (HFS). Most of the currently available HFS prediction markers focus on the pharmacokinetic parameters of drugs or their metabolites, yet our understanding of the biomolecular mechanism of HFS remains limited. Methods: We conducted an integrated multi-omics analysis of 63 Chinese patients with colorectal cancer (CRC) who had chemotherapy related adverse effect (CRAE) records during adjuvant chemotherapy. The metabolomic profiles for each of plasma, urine, and colorectal tissue as well as profiles for colorectal-tissue transcriptomics and genome methylation were analyzed based on samples collected before and during surgery. Results: Susceptibility to HFS was found to be associated with profibrotic changes in several aspects of cellular biochemistry and physiology, characterized by reduced nucleotide salvage (indicating potential tissue damage, elevated spermine release, increased M2 macrophage polarization, and hypermethylation of genes for collagen formation. All these aspects were found to promote fibrosis, even before patients received chemotherapeutic drugs or developed any HFS symptoms. Additionally, we developed and validated relevant biomarkers with reasonably good discrimination performance and a high AUROC (area under the receiver operating characteristic curve) value, i.e., from 0.848 to 1.000. Conclusions: Our results demonstrate that a profibrotic phenotype characterized by multi-omics variation in colorectal tissue, plasma, and urine is closely related to the susceptibility to chemotherapy-induced HFS. Our findings provide a better understanding of the molecular mechanism underlying HFS. Bisulphite converted DNA from the 56 samples were hybridised to the Illumina Infinium Human MethylationEPIC Beadchip