Background: Approximately one-third of breast cancer (BC) patients show poorer cognitive function (CF) before receiving adjuvant therapy compared with age-matched healthy controls. However, the biological mechanisms driving CF variation in the context of BC remain unclear. In this study, we aimed to identify genes and biological pathways associated with CF in postmenopausal women with early-stage hormone receptor-positive (HR+) BC using DNA methylation (DNAm) data, a dynamic regulator of gene activity.
Methods: Epigenome-wide association studies (EWAS) and differentially methylated region analyses were performed for each CF phenotype (seven objective domains and one subjective phenotype) using DNAm data from whole blood samples (n=109) taken at time of enrollment. Post-EWAS functional analyses were performed to enhance the understanding of the CF-related cytosine-phosphate-guanine (CpG) sites.
Results: When adjusting for age, verbal IQ scores, and global DNAm signature, cg10331779 near CTNND2 (p-value= 9.65 × 10 -9 ) and cg25906741 in MLIP (p-value= 2.01 × 10 -8 ) were associated with processing speed and subjective CF, respectively, while regions in/near SLC6A11 , PRKG1/CSTF2T , and FAM3B for processing speed, and regions in/near PI4KB and SGCE/PEG10 for mental flexibility were differentially methylated. In addition, beta-estradiol was identified as a common upstream regulator for all the CF phenotypes, suggesting an essential role of estrogen in explaining variation in CF of HR+ BC patients.
Conclusions: In our EWAS of 8 CF phenotypes, we found two epigenome-wide significant signals, one at cg10331779 near CTNND2 with processing speed and the other at cg25906741 in MLIP with subjective CF. We also found three differentially methylated regions associated with processing speed and two associated with mental flexibility. These findings need replication in larger cohorts.