Folate-Associated DNA Methylation and Chemotherapy-Induced Toxicities in Patients With Colorectal Cancer

Patients with stage II-III colorectal cancer (CRC) often receive fluoropyrimidine-based chemotherapy, usually combined with other regimens, of which ∼50% experience severe chemotherapy-induced toxicities. The B-vitamin folate has been associated with toxicity risk, possibly through effects on DNA methylation. Here, we examined the potential role of folate-associated DNA methylation in the context of chemotherapy-induced toxicities. Systematic literature searches were conducted to identify studies investigating either DNA methylation profiles associated with folate status/intake or with toxicities. Overlapping CpG sites and genes across studies investigating associations for "folate-DNA methylation" and "DNA methylation-toxicities" were identified. The probability of overlap was tested using hypergeometric tests and Gene Ontology and KEGG pathway analyses were performed. Six studies were included. A significant number of CpGs and genes overlapped with altered methylation in response to both folate and hand-foot syndrome (HFS) or thrombocytopenia. Moreover, methylation of genes within the KEGG pathway "focal adhesion" was related to folate status/intake and occurrence of HFS, thrombocytopenia, and neutropenia. We identified some overlapping DNA methylation profiles related to both folate exposures and toxicities. This provides preliminary evidence implying folate-associated DNA methylation may determine risk of toxicities, and therefore may be considered a modifiable factor for improving patient outcomes.