DNA methylation associations with cognitive function in early-stage hormone receptor-positive breast cancer patients

Approximately one-third of breast cancer (BC) patients show poorer cognitive function (CF). Using DNA methylation (DNAm) data, here we aimed to identify genes and biological pathways associated with CF in postmenopausal women with early-stage hormone receptor-positive (HR+) BC. 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 (<i>n</i> = 109) taken at the time of enrollment. When adjusting for age, verbal IQ scores, and global DNAm signature, cg10331779 near <i>CTNND2</i> (p-value = 9.65×10−9) and cg25906741 in <i>MLIP</i> (p-value = 2.01×10−8) were associated with processing speed and subjective CF, respectively, while regions in/near <i>SLC6A11</i>, <i>PRKG1/CSTF2T</i>, and <i>FAM3B</i> for processing speed, and regions in/near <i>PI4KB</i> and <i>SGCE/PEG10</i> 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. In our EWAS of 8 CF phenotypes, we found two epigenome-wide significant signals, one for processing speed and the other for subjective CF. We also found three differentially methylated regions associated with processing speed and two associated with mental flexibility. www.clinicaltrials.gov identifier is NCT02793921. Many breast cancer patients experience problems remembering things, thinking clearly, or paying attention. Our study looked at how a chemical change called ‘DNA methylation’ – which controls how genes work without actually changing the genetic code itself – is related to these thought problems in 109 women with early-stage breast cancer. We found that methylation levels near the <i>CTNND2</i> gene were related to how quickly the brain processes information. Methylation levels near the <i>MLIP</i> gene were related to patients’ reports of their thought problems. We also discovered that beta-estradiol, a type of estrogen hormone, seemed to be a key player in all the thought problems we looked at. Our results give us new clues about why some breast cancer patients have thinking problems and point to other opportunities for future research.