An exploratory study of host polymorphisms in genes that clinically characterize breast cancer tumors and pretreatment cognitive performance in breast cancer survivors

Abstract

PurposeInspired by the hypothesis that heterogeneity in the biology of breast cancers at the cellular level may account for cognitive dysfunction symptom variability in survivors, the current study explored relationships between host single-nucleotide polymorphisms (SNPs) in 25 breast cancer-related candidate genes (AURKA, BAG1, BCL2, BIRC5, CCNB1, CD68, CENPA, CMC2, CTSL2, DIAPH3, ERBB2, ESR1, GRB7, GSTM1, MELK, MKI67, MMP11, MYBL2, NDC80, ORC6, PGR, RACGAP1, RFC4, RRM2, and SCUBE2), identified from clinically relevant prognostic multigene-expression profiles for breast cancer, and pretreatment cognitive performance.Patients and methodsThe sample (n=220) was comprised of 138 postmenopausal women newly diagnosed with early stage breast cancer and 82 postmenopausal age- and education-matched healthy controls without breast cancer. Cognitive performance was assessed after primary surgery but prior to initiation of adjuvant chemotherapy and/or hormonal therapy using a comprehensive battery of neuropsychological tests encompassing eight cognitive function composite domains: attention, concentration, executive function, mental flexibility, psychomotor speed, verbal memory, visual memory, and visual working memory. In total, 131 SNPs were included in the analysis. Standard and robust multiple linear regression modeling was used to examine relationships between each domain and the presence or absence of one or more minor alleles for each SNP. Genetic risk/protection scores (GRSs) were calculated for each domain to evaluate the collective effect of possession of multiple risk/protective alleles.ResultsWith the exception of CMC2, MMP11, and RACGAP1, significant (P<0.05) SNP main effect and/or SNP by future prescribed treatment group interactions were observed for every gene between at least one domain and one or more SNPs. All GRSs were found to be significantly (P<0.001) associated with each respective domain score.ConclusionAssociations between host SNPs and computed GRSs and variability in pretreatment cognitive function performance support the study hypothesis, and warrant further investigations to identify biomarkers for breast cancer-related cognitive dysfunction.

Genetic risk factors for cancer-related cognitive impairment: a systematic review

“…Six focused on breast cancer (BC) patients [19][20][21][22][23][24], one reported on both BC and lymphoma patients [25], and three reported on other patient groups [26][27][28]. The remaining seven studies reported results from studies investigating other genes than APOE, e.g., COMT [24,29] and BDNF [14,24], with five of these studies focusing on BC patients [14,[29][30][31][32], one on prostate cancer patients [33], and one on patients with mixed non-CNS cancers [34]. See Table 2 for overview of genotypes and patients.…”

“…Using the NIH Quality Assessment Tool [18], each study received a quality rating (range: 0-14). Eight studies [14,19,20,23,[25][26][27]33] were rated 'good quality' (>9 criteria met), and the remaining nine studies [21,22,24,[28][29][30][31][32]34] were rated 'fair quality' (5-9 criteria met). Study quality ratings are shown in Supplementary Table S3.…”

“…Two studies investigated other genes. A cross-sectional study of newly diagnosed BC patients revealed that all but three out of 25 genes related to BC phenotypes were significantly associated with at least one of eight cognitive factors by either a main effect and/or an interaction effect between genotype and prescribed treatment [31]. Another study investigated 353 SNPs previously found to be associated with cognitive impairment, depression, fatigue or circadian rhythm as possible moderators of prospectively assessed CRCI in prostate cancer patients [33].…”

“…Finally, G homozygous for the minor allele of rs873601 inERCC5 had increased odds of belonging to the low visual working memory trajectory subgroup (i.e., low and improving) (OR Continued. With the exception of CMC2, MMP11, and RACGAP1, all genes were associated with at least one cognitive factor by either a main effect and/or an interaction effect between genotype and prescribed treatment (see[31] for data) Continued.…”

Novel candidate biomarkers of origin recognition complex 1, 5 and 6 for survival surveillance in patients with hepatocellular carcinoma

“…The role of ORC3 has not yet been documented in tumors. However, a single nucleotide polymorphism of ORC6 was reported as a breast cancer-related candidate gene [66]. Xi et al found that ORC6 was highly expressed in tumors compared to paired normal tissues in colorectal cancer [67].…”