Genetic variants associated with longitudinal cognitive performance in older breast cancer patients and controls

Background 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 breast cancer 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 outcomes. CRCD was assessed using longitudinal domain scores on neurocognitive 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. Conclusion The SNPs associated with cognition in survivors, but not controls, were members of the cyclic nucleotide phosphodiesterase family, which play important roles in cell signaling, cancer risk, and neurodegeneration. These findings provide preliminary evidence that novel genetic loci may drive susceptibility to CRCD.