Polymorphisms in DNA repair and oxidative stress genes associated with pre-treatment cognitive function in breast cancer survivors: an exploratory study.

Theresa A Koleck,Priscilla F Mcauliffe,Shannon L Puhalla,Catherine M Bender,Priya Rastogi,Susan M Sereika,Barry C Lembersky,Adam M Brufsky,Yvette P Conley

doi:10.1186/s40064-016-2061-4

Abstract

PurposeThe purpose of this exploratory candidate gene association study was to examine relationships between polymorphisms in oxidative stress and DNA repair genes and pre-adjuvant therapy cognitive function (CF) in postmenopausal women diagnosed with early stage-breast cancer.MethodsUsing a neuropsychological test battery, CF was assessed in 138 women diagnosed with breast cancer prior to initiation of adjuvant therapy and 81 age- and education-matched controls and summarized across eight composites. Participants were genotyped for 39 functional or tagging single nucleotide polymorphisms (SNPs) of select oxidative stress (CAT, GPX1, SEPP1, SOD1, and SOD2) and DNA repair (ERCC2, ERCC3, ERCC5, and PARP1) genes. Multiple linear regression was used to determine if the presence or absence of one or more minor alleles account for variability in CF composite scores. Based on regression findings from the analysis of individual SNPs, weighted multi-gene, multi-polymorphism genetic risk scores (GRSs) were calculated to evaluate the collective effect of possession of multiple protective and/or risk alleles.ResultsEach CF composite was significantly (p < 0.05) associated with one or more oxidative stress and DNA repair gene polymorphisms evaluated either by SNP main effects and/or SNP-by-prescribed breast cancer treatment group interactions. Each computed GRS was found to be significantly (p < 0.001) related to its corresponding CF composite. All associations were positive suggesting that as overall genetic protection increases, CF composite score increases (indicating better performance).ConclusionsThese findings suggest that genetic variation in the oxidative stress and DNA repair pathways may play an important role in pre-adjuvant therapy CF in breast cancer survivors.Electronic supplementary materialThe online version of this article (doi:10.1186/s40064-016-2061-4) contains supplementary material, which is available to authorized users.

Highlights

Pretreatment cognitive dysfunction has been well documented in women diagnosed with breast cancer (Wefel et al 2008; Ahles et al 2012); the mechanismsKoleck et al SpringerPlus (2016) 5:422 underlying this phenomenon as well as the variability in the presence and severity of cognitive dysfunction experienced by breast cancer survivors remain largely unknown
Similar results were reported in a study of DNA damage and repair in peripheral blood leukocytes (PBL) in a heterogeneous sample of individuals with various cancer diagnoses compared to healthy controls with cells from cancer patients demonstrating higher levels of basal DNA damage
Group-wise comparisons of participant characteristics revealed that study groups differed statistically, but not clinically significantly by age and estimated verbal intelligence (Table 2)

Summary

Introduction

Pretreatment cognitive dysfunction has been well documented in women diagnosed with breast cancer (Wefel et al 2008; Ahles et al 2012); the mechanismsKoleck et al SpringerPlus (2016) 5:422 underlying this phenomenon as well as the variability in the presence and severity of cognitive dysfunction experienced by breast cancer survivors remain largely unknown. One biologically plausible mechanism that may at least partially account for pretreatment cognitive dysfunction and the observed variability is variation in response to oxidative stress and DNA damage (Janelsins et al 2012; Ahles and Saykin 2007; Vardy et al 2008). In one study of altered oxidative stress levels and breast cancer, Herrera et al (2014) found evidence to support enhanced oxidative stress and reduced antioxidant defenses in plasma of postmenopausal women with primary ductal carcinomas of the breast at diagnosis compared to women 6 months post tumor removal and to healthy controls. Similar results were reported in a study of DNA damage and repair in PBLs in a heterogeneous sample of individuals (ages 1–59 years) with various cancer diagnoses compared to healthy controls (ages 22–50 years) with cells from cancer patients demonstrating higher levels of basal DNA damage. Considerable individual variation was noted (Nadin et al 2006)

Methods

Results

Conclusion