Genomic methylation variations predict the susceptibility of six chemotherapy related adverse effects and cancer development for Chinese colorectal cancer patients

Colorectal cancer (CRC) remains a major concern with high morbidity and mortality worldwide. Despite the positive influence of chemotherapy on the decline in CRC mortality, the negative influence of chemotherapy-related adverse effects (CRAEs) caused by capecitabine (Cap) remains a challenging problem. DNA methylation alteration plays a pivotal role in gene expression regulation. Here, we aimed to screen reliable and novel biomarkers for CRC diagnosis and CRAE prediction using the advanced Illumina Infinium MethylationEPIC (850 K) BeadChip. Paired tumor and normal tissues from 21 Chinese CRC patients who received Cap-based adjuvant chemotherapy were analyzed. CRC-related methylation was characterized by hypermethylated promoter islands and hypomethylated intragenic openseas; CRAE-related methylation was characterized by hyper- (or hypo-) methylated intragenic (or intergenic) regions. Based on three types of methylation profiles (differentially methylated probes, differentially methylated regions, and gene-function-differentially methylated regions), pathway enrichment analyses revealed that CRC-related genes were significantly enriched in the neuronal system, metabolism of RNA, and extracellular matrix organization; CRAE-related genes were abundantly enriched in pathways controlling regeneration functions and immune response. Finally, based on genes within the mostly related pathways and LASSO logistic regression selection, the integrated-methylation-marker systems developed here demonstrated high discriminative accuracy in both CRC diagnosis (AUROC = 1) and CRAE prediction (AUROC = 0.817–1). In conclusion, we conducted a comprehensive DNA methylation analysis of CRC patients with chemotherapy, which provided new insights into the formation of CRC and CRAEs. Most importantly, our findings identified potentially CRAE-related metabolic pathways and markers, providing a valuable reference for personalized medicine promising better safety. Trail registration: ClinicalTrials.gov , NCT03030508 , Registered 25 January 2017, https://www.clinicaltrials.gov/ct2/show/NCT03030508?term=NCT03030508&draw=2&rank=1 .