1 SCIENTIFIC REPORTS | (2019) 9:14570 | https://doi.org/10.1038/s41598-019-51203-y www.nature.com/scientificreports An Evaluation of DNA Methyltransferase 1 (DNMT1) Single Nucleotide Polymorphisms and Chemotherapy-Associated Cognitive Impairment: A Prospective, Longitudinal Study Alexandre Chan 1,2,3 , Angie Yeo 1 , Maung Shwe 1 , Chia Jie Tan 1 , Koon Mian Foo 4 , Pat Chu 5 , Chiea Chuen Khor 6,7 & Han Kiat Ho 1 Strong evidence suggests that genetic variations in DNA methyltransferases (DNMTs) may alter the downstream expression and DNA methylation patterns of neuronal genes and infuence 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 diferent 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 signifcant association was observed between DNMT1 rs2162560 and objective cognitive impairment. This is the frst study to show a signifcant 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 fndings. Chemotherapy-associated cognitive impairment (CACI) is highly prevalent among cancer patients receiving chemotherapy 1–3 . Reports have shown that CACI negatively afects patients’ social functioning and quality of life 3,4 . Te exact mechanism underlying CACI has yet to be elucidated. However, genetic factors are known to contribute to CACI 5–8 . Epigenetic modifications such as DNA methylation can modify intermediate neuronal gene expres- sion, leading to changes in cognitive performance 9 . DNA methylation is catalyzed by DNA methyltransferase 1 Department of Pharmacy, National University of Singapore, Singapore, Singapore. 2 Department of Pharmacy, National Cancer Centre Singapore, Singapore, Singapore. 3 Duke-N.U.S. Graduate Medical School Singapore, Singapore, Singapore. 4 Department of Pharmacy, K.K. Women’s and Children’s Hospital, Singapore, Singapore. 5 Singapore Cord Blood Bank, Singapore, Singapore. 6 Human Genetics, Genome Institute of Singapore, Singapore, Singapore. 7 Singapore Eye Research Institute, Singapore, Singapore. Correspondence and requests for materials should be addressed to A.C. (email: phaac@nus.edu.sg) Received: 4 July 2019 Accepted: 26 September 2019 Published: xx xx xxxx OPEN