Abstract
Genetic polymorphisms in select genes, including APOE (apolipoprotein E), COMT (Catechol-O-Methyltransferase), MDR1 (multi-drug resistance 1), BDNF (brain derived neurotrophic factor), and GST (glutathione-S-transferase), have been associated with vulnerability to cognitive impairment. In this study, we evaluated the relationship of these genetic variants to measures of brain health in patients with breast cancer, including neurocognitive testing and functional connectome analysis. Women with breast cancer (n = 83) and female healthy controls (n = 53) were evaluated. They underwent resting-state functional MRI scans and neurocognitive testing. Polymerase chain reaction (PCR) was performed on saliva samples to identify single nucleotide polymorphisms (SNPs) in candidate genes: APOE, COMT, MDR1, BDNF, and GST. Breast cancer patients treated with chemotherapy had slower processing speed (p = 0.04) and poorer reported executive function (p < 0.0001) than healthy controls. Those chemotherapy-treated patients that were APOE e4 carriers had significantly slower processing speed. A greater number of risk-related alleles was associated with poorer connectivity in the regions of the left cuneus and left calcarine. While breast cancer patients that are APOE e4 carriers may have a select vulnerability to processing speed impairments, other risk-related alleles were not found to influence cognitive test performance in this population. Conversely, regions of impaired functional connectivity appeared to be related to risk-related genetic polymorphisms in breast cancer patients. This suggests that a cancer patient’s SNPs in candidate genes may influence the risk of neurotoxicity. Further study evaluating the impact of genotype on biomarkers of brain health in cancer survivors is warranted.
Highlights
Genetic polymorphisms in select genes, including APOE, COMT (Catechol-OMethyltransferase), MDR1, BDNF, and GST, have been associated with vulnerability to cognitive impairment
The chemotherapy group demonstrated lower processing speed as measured by the Symbol Search test (F = 3.2, p = 0.04). They rated themselves as having significantly more difficulties with executive functions than the other two groups (F = 20.4, p < 0.0001). It differed between groups, Clinical Assessment of Depression (CAD) score was not significantly associated with any objective cognitive scores but was related to Behavioral Rating Inventory of Executive Function (BRIEF) score (r = 0.62, p < 0.0001)
There was not enough variance to conduct comparisons for the COMT genotype. This innovative study evaluates the relationship of genetic polymorphisms associated with neural ageing and vulnerability to neurologic insults on cerebral connectivity
Summary
Genetic polymorphisms in select genes, including APOE (apolipoprotein E), COMT (Catechol-OMethyltransferase), MDR1 (multi-drug resistance 1), BDNF (brain derived neurotrophic factor), and GST (glutathione-S-transferase), have been associated with vulnerability to cognitive impairment. We evaluated the relationship of these genetic variants to measures of brain health in patients with breast cancer, including neurocognitive testing and functional connectome analysis. Age Age range Education (yr) Breast radiation Endocrine therapy (tamoxifen) Disease stage at diagnosis (0, I, II, III) Time since primary treatment (yr) Postmenopausal Clinical assessment of depression score APOE e4 BDNF Met MDR1 T GST Null COMT Val. Neuroimaging studies have demonstrated changes in brain structure and function in cancer patients, lending insight into the pathophysiology of cognitive impairment in these patients[6]. We focused on evaluation of regional effects using network-based analysis which represents an improvement over our previous approach
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