Abstract
Strong evidence suggests that genetic variations in DNA methyltransferases (DNMTs) may alter the downstream expression and DNA methylation patterns of neuronal genes and influence cognition. This study investigates the association between a DNMT1 polymorphism, rs2162560, and chemotherapy-associated cognitive impairment (CACI) in a cohort of breast cancer patients. This is a prospective, longitudinal cohort study. From 2011 to 2017, 351 early-stage breast cancer patients receiving chemotherapy were assessed at baseline, the midpoint, and the end of chemotherapy. DNA was extracted from whole blood, and genotyping was performed using Sanger sequencing. Patients’ self-perceived cognitive function and cognitive performance were assessed at three different time points using FACT-Cog (v.3) and a neuropsychological battery, respectively. The association between DNMT1 rs2162560 and cognitive function was evaluated using logistic regression analyses. Overall, 33.3% of the patients reported impairment relative to baseline in one or more cognitive domains. Cognitive impairment was observed in various objective cognitive domains, with incidences ranging from 7.2% to 36.9%. The DNMT1 rs2162560 A allele was observed in 21.8% of patients and this was associated with lower odds of self-reported cognitive decline in the concentration (OR = 0.45, 95% CI: 0.25–0.82, P = 0.01) and functional interference (OR = 0.48, 95% CI: 0.24–0.95, P = 0.03) domains. No significant association was observed between DNMT1 rs2162560 and objective cognitive impairment. This is the first study to show a significant association between the DNMT1 rs2162560 polymorphism and CACI. Our data suggest that epigenetic processes could contribute to CACI, and further studies are needed to validate these findings.
Highlights
(DNMT) enzymes and involves the addition of a methyl group to the 5′-position of cytosine bases, primarily at cytosine-phosphate-guanine (CpG) dinucleoside sites, which results in gene silencing[10]
We found an association between the DNMT1 rs2162560 SNP and self-perceived cognitive impairment in breast cancer patients; carriers of the A allele experienced lower odds of self-reported cognitive decline in two cognitive domains: concentration and functional interference
To the best of our knowledge, this is the first study to evaluate the genetic association between a DNMT1 polymorphism and chemotherapyassociated cognitive impairment (CACI)
Summary
(DNMT) enzymes and involves the addition of a methyl group to the 5′-position of cytosine bases, primarily at cytosine-phosphate-guanine (CpG) dinucleoside sites, which results in gene silencing[10]. DNMT1 is the most abundant form of DNA methyltransferases. It is primarily responsible for maintaining methylation and has a higher affinity for hemimethylated DNA11. A prospective study reported cognitive decline is associated with DNA methylation of leukocytes in breast cancer patients receiving chemotherapy, providing evidence of epigenetic links to CACI17. The extent of methylation is controlled by the expression and function of DNMT1, which can be altered by single nucleotide polymorphisms (SNPs) situated within its genetic code[18]. Using a candidate gene approach, we identified the DNMT1 SNP rs2162560 from the literature[19,20] and evaluated its association with CACI in a cohort of breast cancer patients. We hypothesize that carriers of the A allele of the rs2162560 polymorphism have increased DNA methylation activity that protects them from CACI
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