Differential DNA methylation following chemotherapy for breast cancer is associated with lack of memory improvement at one year

Abstract

The biological basis underlying cognitive dysfunction in women with early-stage breast cancer (BC) remains unclear, but could reflect gene expression changes that arise from the acquisition and long-term retention of soma-wide alterations in DNA methylation in response to chemotherapy. In this longitudinal study, we identified differences in peripheral methylation patterns present in women prior to treatment (T1) and 1 year after receiving chemotherapy (T4) and evaluated relationships among the differential methylation (DM) ratios with changes in cognitive function. A total of 58 paired (T1 and T4) blood specimens were evaluated. Methylation values were determined for DNA isolated from whole blood using a genome-wide array . Cognitive function was measured using the validated, computerized CNS Vital Signs platform. Relationships between methylation patterns and cognitive domain scores were compared using a stepwise linear regression analysis, with demographic variables as covariates. The symptom comparison analysis was restricted to 2,199 CpG positions showing significant methylation ratio changes between T1 and T4. The positions with DM were enriched for genes involved in the modulation of cytokine concentrations. Significant DM ratios were associated with memory domain (56 CpGs). Eight of the ten largest DM ratio changes associated with lack of memory improvement were localized to genes involved in either neural function (ECE2, PPFIBP2) or signalling processes (USP6NL, RIPOR2, KLF5, UBE2V1, DGKA, RPS6KA1). These results suggest that epigenetic changes acquired and retained for at least one year in non-tumour cells following chemotherapy may be associated with a lack of memory improvement following treatment in BC survivors.

Blood and neuroimaging biomarkers of cognitive sequelae in breast cancer patients throughout chemotherapy: A systematic review

“…Lastly, increases in methylation ratios (as can be seen with gene ‘silencing’) were associated with lower memory scores one year after chemotherapy and with decreased memory scores from pre-to one year after post-chemotherapy, while no other domains (i.e. processing speed, attention and executive function) were found to be associated [22] .…”

“…Changes in blood cells/proteins were also present, with decreases in G-CSF specifically [17] . Methylation ratios changed for 2199 CpG positions one year post-chemotherapy [22] .…”

Cross-Sectional Characterization of Local Brain Network Connectivity Pre and Post Breast Cancer Treatment and Distinct Association With Subjective Cognitive and Psychological Function

“…Although many studies have demonstrated that primary breast cancer and/or its treatments significantly alter brain function and structure, it remains unclear how or why. Several studies, including our own, suggest genetic and/or epigenetic risk factors may play an important role (9,39,(65)(66)(67)(68)(69). However, these findings have been limited to the candidate variants selected and have shown some inconsistent results, which may relate to what brain regions were examined.…”

Dysregulation of miR-138-5p/RPS6KA1-AP2M1 Is Associated With Poor Prognosis in AML

“…RPS6KA1 belongs to the family of the ribosomal protein S6 kinase (RPS6K) ( Li et al, 2012 ; Czaplinska et al, 2018 ). The RPS6K family is reported to be involved in a lot of pathways, which are important for tumor occurrence and progression ( Hajj et al, 2020 ; Lai et al, 2020 ; Yang et al, 2020 ). A new study indicates that RPS6KA1 is a potential target of new treatment strategies for drug-resistant AML patients with FLT3-ITD mutation, especially combining PI3K, PIM, or Bcl-2 family members ( Watanabe et al, 2019 ).…”