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

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

Breast Cancer Research

10.1186/s13058-023-01730-4

http://dx.doi.org/10.1186/s13058-023-01730-4

Peh Joo Ho, Alexis Jiaying Khng, Benita Kiat-Tee Tan, Geok Hoon Lim, Su-Ming Tan, Veronique Kiak Mien Tan, Ryan Shea Ying Cong Tan, Elaine Hsuen Lim, Philip Tsau-Choong Iau, Ying Jia Chew, Yi Ying Lim, Mikael Hartman, Ern Yu Tan, Jingmei Li

06 November 2023

Ho, P. J., Khng, A. J., Tan, B. K.-T., Lim, G. H., Tan, S.-M., Tan, V. K. M., Tan, R. S. Y. C., Lim, E. H., Iau, P. T.-C., Chew, Y. J., Lim, Y. Y., Hartman, M., Tan, E. Y., & Li, J. (2023). Alterations to DNA methylation patterns induced by chemotherapy treatment are associated with negative impacts on the olfactory pathway. Breast Cancer Research, 25(1). https://doi.org/10.1186/s13058-023-01730-4

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 (including 41,207 promoter regions) 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 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways associated with chemotherapy. Results were validated in a separate cohort of breast cancer patients who were treated (n = 1273) and not treated (n = 872) by chemotherapy (1808 blood, 337 saliva). Results A total of 141 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 promoter regions (pre-ranked by test statistics) identified six suppressed biological processes (p < 4.67e−8) related to sensory perception and detection of chemical stimuli, including smell perception (GO:0007606, GO:0007608, GO:0009593, GO:0050906, GO:0050907, and GO:0050911). The same six biological processes were significantly suppressed in the validation dataset (p < 9.02e−14). The KEGG pathway olfactory transduction (hsa04740) was also found to be significantly suppressed (ppaired-samples = 1.72e−9, psingle-timepoint-blood = 2.03e−15 and psingle-timepoint-saliva = 7.52e−56). Conclusion The enrichment of imprinted genes within biological processes and pathways suggests a biological mechanism by which chemotherapy could affect the perception of smell.

Attribution 4.0 International (CC BY 4.0)

This research / project is supported by the A*STAR - BMRC Central Research Fund (Applied Translational Research)
Grant Reference no. : NA

This research / project is supported by the National University Singapore - NUS start-up Grant
Grant Reference no. : NA

This research / project is supported by the National Medical Research Council - National University Cancer Institute Singapore (NCIS) Centre Grant
Grant Reference no. : NMRC/CG/NCIS/2010, NMRC/CG/012/2013, CGAug16M005, CG21APR1005

This research / project is supported by the National University Singapore - Breast Cancer Prevention Programme (BCPP)
Grant Reference no. : NA

This research / project is supported by the National University Singapore - Asian Breast Cancer Research Fund
Grant Reference no. : NA

This research / project is supported by the National Medical Research Council - NMRC Clinician Scientist Award (SI Category)
Grant Reference no. : NMRC/CSA-SI/0015/2017

https://oar.a-star.edu.sg/communities-collections/articles/19450

1465-542X

Genome Institute of Singapore

https://doi.org/10.1186/s13058-023-01730-4