Alterations to DNA methylation patterns induced by chemotherapy treatment are associated with negative impacts on the olfactory pathway

Abstract

Background Exposure to cytotoxic chemotherapy treatment may alter DNA methylation (DNAm) in breast cancer patients. Methods We performed DNAm analysis in 125 breast cancer patients with blood drawn before and after chemotherapy, using the Illumina MethylationEPIC array. DNAm changes of 588,798 individual CpGs and 41,222 promoters were evaluated using linear regression models adjusted for monocyte proportion. Gene set enrichment analyses (GSEA) were conducted to identify key Gene Ontology (GO) biological processes or KEGG pathways associated with chemotherapy. Results were validated in a separate cohort of breast cancer patients who were treated (n = 1,244) and not treated (n = 897) by chemotherapy (1,817 blood, 337 saliva). Results A total of 142 differentially methylated CpGs and 11 promoters were significantly associated with chemotherapy after multiple testing corrections in both the paired sample and single time point analyses. GSEA of 41,222 chemotherapy-associated promoters (pre-ranked by Z scores) revealed six suppressed biological processes that survived Bonferroni correction (GO:0007606, sensory perception of chemical stimulus; GO:0007608, sensory perception of smell; GO:0009593, detection of chemical stimulus; GO:0050906, detection of stimulus involved in sensory perception; GO:0050907, detection of chemical stimulus involved in sensory perception; and GO:0050911, detection of chemical stimulus involved in sensory perception of smell). The same six biological processes were significantly suppressed in the validation dataset. The KEGG pathway olfactory transduction (hsa04740) was also found to be significantly suppressed (uncorrected ppaired−samples=6.65e-5, psingle−timepoint−blood=1.01e-15 and p single−timepoint−saliva=3.10e-55). Conclusion The enrichment of imprinted genes within biological processes and pathways suggests a biological mechanism by which chemotherapy could affect the perception of smell.