Simple SummaryWhile numerous publications have shown that some patients experience cancer- and treatment-related cognitive decline, the role of genetics in risk for cognitive decline has not yet been established. In this study, our goal was to identify genetic factors affecting risk for cognitive decline in older female breast cancer survivors. The study identified several genetic variants and genes that were associated with differences in patterns of cognitive decline in cancer patients compared to controls, suggesting that genetics can play an important role in modifying risk for cognitive decline in older cancer survivors. It will be important for additional research to replicate these findings in other cancer populations; if validated, these findings could inform therapeutic research, as well as inform evaluations of risk for cognitive decline in older cancer survivors.AbstractBackground:There have been no published genome-wide studies of the genetics of cancer- and treatment-related cognitive decline (CRCD); the purpose of this study is to identify genetic variants associated with CRCD in older female breast cancer survivors.Methods:Analyses included white non-Hispanic women with non-metastatic breast cancer aged 60+ (N= 325) and age-, racial/ethnic group-, and education-matched controls (N= 340) with pre-systemic treatment and one-year follow-up cognitive assessment. CRCD was evaluated using longitudinal domain scores on cognitive tests of attention, processing speed, and executive function (APE), and learning and memory (LM). Linear regression models of one-year cognition included an interaction term for SNP or gene SNP enrichment*cancer case/control status, controlling for demographic variables and baseline cognition.Results:Cancer patients carrying minor alleles for two SNPs, rs76859653 (chromosome 1) in the hemicentin 1 (HMCN1)gene (p= 1.624 × 10−8), and rs78786199 (chromosome 2,p= 1.925 × 10−8) in an intergenic region had lower one-year APE scores than non-carriers and controls. Gene-level analyses showed the POC5 centriolar protein gene was enriched for SNPs associated with differences in longitudinal LM performance between patients and controls.Conclusions:The SNPs associated with cognition in survivors, but not controls, were members of the cyclic nucleotide phosphodiesterase family, that play important roles in cell signaling, cancer risk, and neurodegeneration. These findings provide preliminary evidence that novel genetic loci may contribute to susceptibility to CRCD.