Protective Effects of APOE ε2 Genotype on Cognition in Older Breast Cancer Survivors: The Thinking and Living With Cancer Study

Abstract

Background Cancer-related cognitive decline (CRCD) has been linked to apolipoprotein E (APOE) gene ε4 polymorphisms. APOE ε4 polymorphisms are also the strongest genetic risk for late-onset Alzheimer’s disease (AD), while ε2 polymorphisms protect against AD. However, the effects of ε2 polymorphisms on CRCD have not been evaluated. Methods We evaluated non-metastatic breast cancer survivors (n = 427) and matched non-cancer controls (n = 407) ages 60–98 assessed pre-systemic therapy/enrollment from August 2010-December 2017 with annual follow-up to 24 months. Neuropsychological assessment measured attention, processing speed, and executive function, and learning and memory. Linear mixed-effects models tested the effects of having an ε2 allele (vs. none) on longitudinal cognitive domain z-scores by treatment group (chemotherapy +/- hormonal therapy, hormonal therapy, and control) controlling for covariates; participants with ε2/ε4 genotype were excluded. Sensitivity analyses examined effects of other covariates and any ε4 positivity. Results There was an interaction with genotype for attention, processing speed, and executive functioning domain scores (Beta = 0.32 (95% CI : 0.00, 0.65)): the chemotherapy group with an ε2 allele had higher scores at baseline and maintained higher scores over time compared to those without an ε2 allele, and this protective effect was not seen for other groups. There was no effect of ε2 on learning and memory domain scores. Conclusions APOE ε2 polymorphisms may protect against CRCD in older breast cancer survivors receiving chemotherapy. With replication, this information could be useful for survivorship care and informing future studies of possible links to AD and defining mechanisms of protection.

Alpha‐2‐Heremans‐Schmid‐glycoprotein (AHSG) a potential biomarker associated with prognosis of chromophobe renal cell carcinoma: The PROPOLIS study

“…The result showed that the top 20 proteins interacting with AHSG (Figure 9B ) mainly functioned in tumor suppressor, signal transduce, cancer development. 26 , 27 , 29 , 30 , 33 , 34 , 35 , 36 , 37 , 38 , 39…”

“…The top 20 proteins interacting with AHSG by GeneMANIA were partially associated with tumor development or tumor suppression, which also suggests that AHSG is a potential key gene for chRCC. 26 , 27 , 29 , 30 , 33 , 34 , 35 , 37 , 38 …”

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

“…While FOXN2 has not been specifically identified in neurodegenerative disease or cognitive functional research, perturbations in these molecular pathways have been identified in Alzheimer's disease as well as cancer 30 . Additionally, rs78786199 is in a predicted binding site for several transcription factors, including Zinc Finger Imprinted 3,Interferon Regulatory Factors 1,4,7,and 8,Signal Transducer and Activator of Transcription 2, and Zinc Finger Protein 317. These transcription factors regulate numerous cellular processes, including hematopoiesis, inflammation, immune responses, cell proliferation, regulation of the cell cycle, and induction of growth arrest and programmed cell death in response to DNA damage, suggesting multiple mechanisms that could connect this locus with cancer and CRCD [31][32][33][34][35][36] .…”

“…Raw scores were standardized using the control group mean and standard deviation at baseline stratified by age and education. Standardized scores were then used to calculate z-scores for each domain for every participant, as described previously 11,12 . These domains were chosen because research has shown them to be relevant to CRCD 3 .…”

“…For example, studies have shown that the APOE e4 allele, the major risk factor for Alzheimer’s disease (AD), is associated with worse neurocognitive outcomes in some cancer patients 3,5-7 . More recently, there has been some evidence that APOE e2 may protect against CRCD in cancer survivors 8 . However, there have not been any published studies using a genome-wide analysis approach to identify loci associated with CRCD, and no genetic studies have focused on older survivors.…”