Abstract
Altered DNA repair capacity can result in increased susceptibility to cancer. The base excision repair (BER) pathway effectively removes DNA damage caused by ionizing radiation and reactive oxidative species (ROS). In the current study, we analyzed the possible relation of polymorphisms in BER genes, including 8-oxoguanine DNA glycosylase (OGG1), apurinic/apyrimidinic endonuclease 1 (APE1), and X-ray repair cross-complementing group 1 protein (XRCC1), with breast cancer risk in Chinese Han women. This case-control study examined 194 patients with breast cancer and 245 cancer-free hospitalized control subjects. Single nucleotide polymorphisms (SNPs) of OGG1 (Ser326Cys), XRCC1 (Arg399Gln), and APE1 (Asp148Glu and -141T/G) were genotyped and analyzed for their association with breast cancer risk using multivariate logistic regression models. We found that XRCC1 Arg399Gln was significantly associated with an increased risk of breast cancer. Similarly, the XRCC1 Gln allele was significantly associated with an elevated risk in postmenopausal women and women with a high BMI (≥ 24 kg/m2). The OGG1 Cys allele provided a significant protective effect against developing cancer in women with a low BMI (< 24 kg/m2). When analyzing the combined effects of these alleles on the risk of breast cancer, we found that individuals with ≥ 2 adverse genotypes (XRCC1 399Gln, APE1 148Asp, and OGG1 326Ser) were at a 2.18-fold increased risk of breast cancer (P = 0.027). In conclusion, our data indicate that Chinese women with the 399Gln allele of XRCC1 have an increased risk of breast cancer, and the combined effects of polymorphisms of BER genes may contribute to tumorigenesis.
Highlights
Breast cancer is the most frequently diagnosed cancer in women and the leading cause of cancer death in females worldwide (Jemal et al, 2011)
The base excision repair (BER) pathway consists of a series of coordinated sequential reactions to recognize and dispose of damage resulting from reactive oxygen species, hydroxylation reactions, and other cellular processes (Krokan et al, 2000; Hung et al, 2005; Hoeijmakers, 2007)
Single nucleotide polymorphisms (SNPs) in key repair genes of the BER pathway may impair DNA repair capacity, which may have a subsequent impact on cancer susceptibility and occurrence
Summary
Breast cancer is the most frequently diagnosed cancer in women and the leading cause of cancer death in females worldwide (Jemal et al, 2011). The efficient and potent base excision repair (BER) pathway plays a major role in maintaining integrity of the genome by correcting somatic mutations induced by endogenous free radicals produced during cellular metabolism or by exogenous exposure to chemicals and ionizing radiation (Nock et al, 2006). OGG1 recognizes and removes an oxidized 8-oxoguanine base by releasing the modified base, and creating an apurinic/apyrimidinic site This abasic site is excised by APE1, leaving behind a 5’-deoxiribose phosphate residue. The genetic variants OGG1 Ser326Cys, APE1 Asp148Glu, and XRCC1 Arg399Gln in the BER pathway play critical roles in repairing base damage, few studies have investigated the association between breast cancer risk and these genetic polymorphisms in Chinese women. To investigate potential differences in relative breast cancer risk by race, and the association between the genetic variants of these three BER genes and breast cancer risk, we conducted a hospital-based study of 194 patients with incident breast cancer and 245 cancer-free control subjects who were frequency-matched by age, age at menarche, age at menopause, menopausal status, pregnancy, body mass index, and family history of cancer
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