Germline variants of base excision repair genes and breast cancer: A polymorphism in DNA polymerase gamma modifies gene expression and breast cancer risk

Abstract

Base excision repair (BER) removes DNA damage induced by endogenous reactive oxygen species or ionizing radiation, important breast cancer risk factors. Genetic variation associated with impaired BER might thus increase breast cancer risk. Therefore, we assessed risk associations of 123 common single nucleotide polymorphisms (SNPs) in 19 BER genes in 1,639 postmenopausal breast cancer cases and 1,967 controls from the German population-based case-control study MARIE. SNPs were tagging SNPs representing genetic variation across the gene together with potentially functional SNPs. Risk associations were assessed using conditional logistic regression, adjusted for potential breast cancer risk factors. Significant associations between polymorphisms and breast cancer risk were found for one SNP in PARP2 and three SNPs in the mitochondrial DNA polymerase gamma, POLG. A SNP in the promoter region of POLG (rs2856268, A>G) showed a protective effect for homozygous GG carriers (odds ratio 0.81, 95% confidence intervals 0.65-1.00). Joint analysis of an enlarged sample set and haplotype analysis supported the results for POLG. Quantification of POLG mRNA expression in lymphocytes of 148 breast cancer patients revealed higher mRNA levels for rs2856268 GG carriers (p value 5 0.038). A luciferase promoter assay showed significant differences between constructs harboring the respective alleles. Taken together, our results suggest that genetic variation in the POLG promoter region affects DNA polymerase gamma levels in mitochondria. This could contribute to the reported increase in mitochondrial mutation frequency resulting in dysfunction and altered breast cancer risk. Risk effects and the functional impact of the POLG promoter variant require further confirmation.Numerous risk factors like family history of the disease or hormone replacement therapy are known to contribute to breast cancer development, the most frequent cancer type in women. 1 In addition, oxidative stress is discussed to be involved. Reactive oxygen species (ROS) can originate from endogenous and exogenous processes, e.g., from cellular estrogen metabolism and exposure to tobacco smoke or ionizing radiation. [2][3][4] Normally, the amount of cellular ROS is well balanced between proteins producing and scavenging oxidative species, but this homeostasis can be disrupted under certain conditions. Then, oxidative DNA damage will occur, which, if not repaired, can cause mutations and genomic instability. 5 Insufficient DNA repair is one of the prominent risk factors for breast cancer. 6 The hereditary, high penetrance mutations in BRCA1 or 2 genes strongly increase the risk by disrupting DNA double strand break repair. But also, genetic variation by single nucleotide polymorphisms (SNPs) in further DNA repair genes has been suggested to play an important role. 7,8 Regarding the repair of oxidative damage, mainly base excision repair (BER) is involved. This pathway consists of about 11 damage specific DNA glycosylases and further proteins which tightly cooperate. 9-...

Rare missense mutations in RECQL and POLG associate with inherited predisposition to breast cancer

“…Of these, RECQL encodes a RecQ DNA helicase family member implicated in prevention of double-stranded DNA breaks by resolving stalled DNA replication forks. 19 Rare mutations in RECQL have also recently been associated with breast cancer susceptibility, [20][21][22][23][24][25] for which our results now provide further evidence. POLG encodes the catalytic subunit of DNA polymerase g responsible for the replication of mitochondrial DNA (mtDNA), 26 and our study proposes a novel link between POLG missense variants and inherited breast cancer predisposition.…”

BRCA1 and BRCA2 5′ noncoding region variants identified in breast cancer patients alter promoter activity and protein binding

“…Common and rare variations in regulatory elements upstream of genes have been shown to alter gene expression and be associated with disease risk (reviewed in Betts, French, Brown, & Edwards, 2013;Diederichs et al, 2016;Millot et al, 2012). We and others have described germline cancer-associated variants in the regulatory regions, including large deletions in the BRCA1 promoter (Brown et al, 2002), and single nucleotide variants in the promoter and/or 5 ′ UTR of BRCA1 and BRCA2 (Evans et al, 2018;Santana dos Santos et al, 2017), MLH1 promoter (Hitchins et al, 2011), POLG promoter (Popanda et al, 2013), PTEN promoter (Heikkinen et al, 2011), TERT promoter (Horn et al, 2013), KLHDC7A and PIDD1 promoters (Michailidou et al, 2017), BRCA1 3 ′ UTR (Brewster et al, 2012), and BC-associated Single Nucleotide Polymorphisms (SNPs) in long-range enhancers of CCND1 .…”

Germline Variations of Apurinic/Apyrimidinic Endonuclease 1 (APEX1) Detected in Female Breast Cancer Patients

“…Mutation frequency was found higher in patients with invasive ductal carcinoma, tumors grade II, family history of cancer, early menopause and negative ER, PR, HER-2/neu status which have been previously reported-contribute in breast cancer development in Pakistani populations (Naeem et al, 2008;Azizun-Nisa et al, 2008;Sharif et al, 2010;Ahmed et al, 2011) and worldwide (Dumitrescu et al, 2005;Ahmed et al, 2011;Popanda et al, 2013). Woman's breast cancer risk is two or more times greater if she has a family history of cancer (Ahmed et al, 2011).…”

“…Epidemiologic studies have linked single nucleotide polymorphisms (SNPs) in BER pathway genes-increased human cancer risk including breast cancer which have been evaluated in different populations in past by focusing on three key genes: X-ray repair cross-complementing protein 1 (XRCC1), 8-oxoguanine DNA glycosylase (OGG1) and apurinic/apyrimidinic endonuclease 1(APEX1) (Hu et al, 2001;Zhang et al, 2006;Lo et al, 2009;Lu et al, 2009;Li et al, 2011;Karahalil et al, 2012;Mahjabeen et al, 2013;Kim et al, 2013;Popanda et al, 2013 ). APEX1 is multifunctional protein playing an important role in DNA repair process through AP-endonucleolytic 3' phosphodiesterase, 3'-5' exonuclease and 3' phosphatase activities.…”