, 8-hydroxy-2′-deoxyguanine (8-OHdG), a typical product of oxidative stress-induced DNA damage, can cause a G–T transversion during DNA replication if it is not removed. Human 8-oxoguanine glycosylase 1 (hOGG1), a key DNA repair gene, recognizes and excises 8-OHdG from damaged DNA accurately; however, a c.977C>G (Ser326Cys) polymorphism in hOGG1 can inhibit the gene's ability to remove 8-OHdG. The aim of present study was to investigate the association between the c.977C>G polymorphism in hOGG1 and the risk of breast cancer in Chinese Han women. We used high-resolution melting and sequencing to analyze the genotypes of 630 patients with sporadic breast cancer patients and 777 healthy controls. We also performed risk-stratified subgroup analyses to determine the association between the c.977C>G polymorphism and other characteristics of breast cancer subgroups. Breast cancer patients and healthy controls did not have significantly different of c.977C/G genotypes (odds ratio [OR] = 1.10, 95% confidence interval [CI] = 0.82–1.49, p = 0.57) and c.977G/G genotypes (OR = 1.34, 95% CI = 0.97–1.84, p = 0.09). However, the c.977G/G genotype was especially prevalent in breast cancer patients who were younger than 55 years (OR = 1.58, 95% CI = 1.05–2.39, p = 0.04), were premenopausal status (OR = 1.87, 95% CI = 1.14–3.06, p = 0.02), had triple-negative disease (OR = 2.14, 95% CI = 1.06–4.29, p = 0.04), or p53-positive disease (OR = 1.56, 95% CI = 1.14–2.12, p = 0.005). These findings suggest that the c.977C>G polymorphism in hOGG1 is associated with an increased risk of breast cancer in Chinese Han women who are younger than 55 years, premenopausal, triple-negative, or p53-positive subgroups.
Breast cancer is one of the most common malignancies in women worldwide today, with an estimated 1.38 million new cases and 458,000 deaths in 2008, mostly in Europe and the United States.1 The morbidity and mortality of breast cancer have increased tremendously in many developing countries.2 Among women in China, breast cancer is the most prevalent cancer and the sixth leading cause of death.3 Known risk factors for breast cancer include family or personal history of cancer, nulliparous, and history of hormone replacement therapy.4 Many women are exposed to these risk factors, but only a portion of exposed individuals develop breast cancer, suggesting a variation in individual susceptibility to breast carcinogenesis.
Endogenous and exogenous factors, including ultraviolet light, ionizing radiation, and mutagenic chemicals, can induce reactive oxidative stress, which causes DNA damage.5 Cells containing damaged DNA, if not eliminated through apoptosis, will propagate with the mutations and develop disease, especially cancer. One typical product of oxidative DNA damage is 8-hydroxy-2′-deoxyguanosine (8-OHdG),6 increased levels of which have been detected in cancer patients.7, 8 and 9
Normally, efficient repair mechanisms prevent the harmful consequences of DNA damage.10 Oxidized DNA damage is repaired via the base excision repair (BER) pathway to excision oxidized DNA bases11; specifically, the BER pathway gene human 8-oxoguanine glycosylase 1 (hOGG1), a key enzyme to repair DNA oxidative damage, removes 8-OHdG from damaged DNA strands. hOGG1 located on chromosome 3p26.2 and generates a 345 amino acid OGG1 protein. In the absence of hOGG1, 8-OHdG persists and leads to the accumulation of G:C to T:A mutations. Functional single nucleotide polymorphisms (SNPs) in BER pathway genes such as hOGG1 may affect DNA repair capacity thus could be a risk factor for some cancers. 12, 13 and 14 Accumulating evidence suggests that variations of C.977C>G (also known as Ser326Cys and rs1502133) in exon 7 of the hOGG1 gene plays a potent role in the pathogenesis of many cancers, including breast cancer, colorectal cancer, childhood acute lymphoblastic leukemia, esophageal cancer and lung cancer. 13, 15, 16, 17, 18 and 19 Yet inconsistent results regarding the association between C.977C>G in hOGG1 and cancer have been reported. 20, 21 and 22 Some studies have suggested that this SNP is only associated with some subgroups of cancers in patients with a distinct genetic background, ethnicity, or lifestyle factor. 15, 23, 24 and 25
In our previous study, we found that functional variations in the 5′-untranslated region (5′-UTR) of hOGG1confer a risk of diabetes, gastric cancer, breast cancer, and type II ovarian cancer in subgroups of the Chinese population. 26, 27, 28 and 29 However, whether the C.977C>G polymorphism in hOGG1 is associated with an increased risk of breast cancer in Chinese Han women remains unknown.
In the current study, we performed a case–control study to determine the association between the C.977C>G polymorphism of hOGG1 and breast cancer risk in Chinese Han women and additional analyses to determine the association between this SNP and the clinicopathological features of breast cancer.
We recruited 630 unrelated Chinese Han breast cancer patients at Jiangsu Cancer Hospital between December 2007 and December 2010. All subjects were newly diagnosed and had been confirmed by one pathologist. Peripheral blood samples were collected before the patients underwent treatment.
We recruited 777 healthy controls for routine health examinations at Jiangsu Cancer Hospital that included a detailed interview, abdominal ultrasonography, cardiogram, chest X-ray, and hepatic function, fasting glucose, rheumatoid factor, α-fetoprotein, and carcinoembryonic antigen blood tests. Individuals with a disease diagnosed on the basis of examination results were excluded. All healthy controls were age- (±5 years), menopause status-, and body mass index-matched to cases. As sporadic cases, those patients and healthy controls that had first-degree relatives with breast or ovarian cancer were excluded from the study. All of the analysis in this study is restricted to Han due to small numbers of minority populations. This study was approved by the Local Ethic Committee of Jiangsu Cancer Hospital and each patient gave written consent.
We used the UltraPure blood kit (SBS Genetech Co. Ltd, Shanghai, China) to extract genomic DNA from peripheral blood samples. The extracted DNA was stored at −40 °C until further analysis. Polymerase chain reaction (PCR) was used to amplify DNA. We used the primer design software of the LightScanner high-resolution melting (HRM) system (BioFire Diagnostics, Salt Lake City, UT) to design primers for detecting variations in hOGG1. The primer sequences, as follows, were also synthesized by SBS to amplify the DNA fragment that included C.977C>G with flanking sequences in hOGG1: forward, 5′-ACTGTCACTAGTCTCACCAG-3′; reverse, 5′-GGAAGGTGCTTGGGGAAT-3′. The length of PCR product was 200bp.
The mixture for each reaction of 10-μL sample contains 25 ng of genomic DNA, 0.2 pmol of forward and reverse primers, 0.8 μL of 2.5-mM deoxynucleotide triphosphates, 1 μL of 25-mM MgCl2, 1 μL of 10× Taq buffer, 0.4 U of Taq DNA polymerase (Fermentas, St. Leon-Rot, Germany), and 0.4 μL of dimethyl sulfoxide. The samples were initially denatured at 95 °C for 5 min and then subjected to 35 cycles of 95 °C for 30 s, 55–60 °C for 10 s, and 72 °C for 30 s, extended for 10 min. The solutions plus 1 μL 1× LCGreen PLUS dye were added to 96-well plates and overlaid with 20 μL of mineral oil (Sigma, St. Louis, MO). The plates were then placed in the LightScanner HRM system for analysis. Fluorescence data were collected at 70–95 °C.
Although the HRM system could distinguish heterozygote genotypes from homozygote genotypes, it could not distinguish the wild-type genotype from homozygous variations. Therefore, the samples that HRM revealed to be homozygous were mixed with an equal amount of known homozygous DNA and then reanalyzed using the LightScanner system. Using this strategy, the homozygote of an allele could be converted to a heterozygote, the reanalysis of which would reveal two types of homozygote.
We used the BigDye Terminator v3.1 Cycle Sequencing Kit and ABI PRISM 3100 Genetic Analyzer (Applied Biosystems, Foster City, CA, USA) to directly sequence the PCR product. PCR products that could not be directly sequenced were cloned into the PMD-18-T vector (TaKaRa Bio, Inc, Tokyo, Japan), amplified using a recombinant vector in Escherichiacoli (TOP10), and sequenced as described above.
Breast cancer specimens were obtained during surgery and via biopsy in 617 and 13 breast cancer patients, respectively. The routine nuclear grading system was used to assign nuclear grade.30 We used the avidin–biotin peroxidase system for immunohistochemical staining. Primary antibodies against estrogen receptor (ER) (1:100, 6F11; Novocastra, Newcastle, UK), progesterone receptor (PR) (1:200, 1A6; Novocastra), human epidermal growth factor receptor 2 (HER-2) (1:200, CB11; Novocastra), p53 (1:100, DO-7; Novocastra), Ki67 (clone MIB-1, dilution 1:00; Dako, Denmark), vascular endothelium growth factor (VEGF) (1:100, A20; Santa Cruz, CA), and epidermal growth factor receptor (EGFR) (clone 3C6, 3 mg ml−1; Ventana Medical Systems, Tucson, AZ) were used. Negative and positive control slides were included in the assay.
The slides were reviewed and scored by one pathologist. For ER, PR, and p53 immunoassaying, nuclear staining in 10% of neoplastic cells was used as a positive cutoff. A Ki67-labelling index of >30% was considered positive. HER-2/neu results were determined according to the package insert and guidelines of the American Society of Clinical Oncology and College of American Pathologists.31
The statistical program SPSS version 13.0 (SPSS, Chicago, IL) was used for all statistical analyses. Means ± standard deviations were used to describe continuous data and percentages of categorical data. The relationship between the C.977C>G polymorphism genotypes in hOGG1 and breast cancer risk was estimated by an unconditional multivariate logistic regression to determine the adjusted odds ratio (aOR) along with corresponding 95% confidence interval (95% CI). The Student t-test was used to compare differences in continuous variables between groups. P values <0.05 were considered statistically significant.
A total of 630 patients diagnosed with breast cancer and 777 controls were included in this study. The mean ages (±SDs) of the breast cancer patients and healthy controls were 50.24 ± 12.84 years and 50.50 ± 12.84 years, respectively. The clinical characteristics of the patients included in the present study are summarized in Table 1. For the menopausal status, in breast cancer patients, 52.4% were postmenopausal, 47.6% were premenopausal. In healthy controls, 49.8% were postmenopausal, 50.2% were premenopausal. Of these patients, 74.3% had invasive ductal carcinoma, and 10.6% had invasive lobular carcinoma.
Table 1. Host and clinical characteristics of patients with breast cancer and controls.
SD: standard deviation; IDC, invasive ductal carcinoma; ILC, invasive lobular carcinoma.
Other including medullary carcinomas (25 patients), mucin-producing carcinomas (14 patients), neuroendocrine tumors (13 patients), invasive papillary carcinoma (8 patients), inflammatory carcinoma (4 patients), and cancer of unknown type (31 patients).
As defined in the AJCC Cancer Staging Manual (7th edition).
Nottingham combined histologic grade.
HRM analysis revealed a heterozygous curve indicating a variant allele of c.977C/G in hOGG1 in 310 of the 630 breast cancer patients (49.2%) (Fig. 1a). Heterozygous DNA was detected in 401 of 777 healthy controls (51.6%). A chi-square test revealed no significant difference between the proportions of breast cancer patients and healthy controls who had the heterozygous c.977C>G polymorphism in hOGG1 (p = 0.15). 10% of the samples for which HRM analysis revealed aberrant curves were tested for their nucleotide sequence in breast cancer patients and health controls to differentiate c.977G/G in hOGG1 (Fig. 1b) from wild-type c.977C/C (Fig. 1c) in hOGG1.
Fig. 1. The genotypes of the c.977C/G variations in the hOGG1 gene were determined using direct sequencing of the PCR product. (A), c.977C/G heterozygous variation genotype; (B), c.977G/G homozygous variation genotype; (C), c.977C/C wild genotype. The black arrows indicate the variation loci.
In Hardy–Weinberg equilibrium, the observed genotype frequency of the c.977C>G polymorphism in 630 breast cancer patients and 777 healthy controls were 0.51 and 0.16, respectively. A case–control analysis revealed no significant differences in the frequencies of c.977C/G (odds ratio [OR] = 1.10, 95% confidence interval [CI] = 0.82–1.49, p = 0.57) and c.977G/G (OR = 1.34, 95% CI = 0.97–1.84, p = 0.09) between breast cancer patients and healthy controls (Table 2).
Table 2. Association between the hOGG1 gene c.977C>G genotypes and breast cancer risk in cases and controls.
OR, odds ratio; CI, confidence interval.
Given that distinct subtypes of breast cancer have different mechanisms of carcinogenesis, we analyzed the association between c.977C>G polymorphism in hOGG1 and clinicopathologic characteristics of breast cancer patients (Tables 3 and 4). The c.977G/G polymorphism in hOGG1 was more prevalent in breast cancer patients who were younger than 55 years (OR = 1.58, 95% CI = 1.05–2.39, p = 0.04), were premenopausal (OR = 1.87, 95% CI = 1.14–3.06, p = 0.02), had triple-negative disease (OR = 2.14, 95% CI = 1.06–4.29, p = 0.04), or had p53-positive disease (OR = 1.56, 95% CI = 1.14–2.12, p = 0.005). The difference in the rate of the polymorphism in breast cancer patients stratified by other factors, including body mass index and Ki67, EGFR, and VEGF status, was not statistically significant (data not shown).
Table 3. Association between the hOGG1 gene c.977C>G polymorphism and breast cancer risk stratified by the clinical characteristics of cases and controls.
OR, odds ratio; CI, confidence interval; BMI, body mass index.P values < 0.05 were considered statistically significant.
Data available for 602 controls.
Data available for 560 patients and 688 controls.
Table 4. Association between the c.977C>G polymorphism and breast cancer risk stratified by clinicopathologic characteristics compared with controls.
OR, odds ratio; CI, confidence interval; EGFR, epidermal growth factor receptor; VEGF, vascular endothelial growth factor.P values < 0.05 were considered statistically significant.Notes: Triple-negative status, Ki67 status, p53 status, EGFR status, and VEGF status data were available for 550, 412, 410, 248, and 324 patients, respectively. All data are given as no. of patients (%) unless otherwise noted.
In this case–control study, we genotyped a functional SNP (c.977C>G) of hOGG1 gene in breast cancer in Chinese Han population. We found that the c.977C>G polymorphism in hOGG1 confers an increased risk of triple-negative, p53-positive breast cancer in premenopausal Han Chinese women younger than 55 years.
Five to ten percent of breast cancer cases are believed to be hereditary and associated with certain gene mutations, such as mutations in BRCA1 and BRCA2.32 Germline mutations in these genes, which are located on chromosome 17q12-21 and 13q12-13, respectively, predispose carriers to the development of hereditary breast and ovarian cancers. 33 and 34 Most germline mutations in breast cancer lead to a truncated protein that disrupts the function of the proteins encoded in the genes,35 and these mutations are probably responsible for the majority of familial breast cancers. 36 and 37 Somatic mutations in BRCA1 and BRCA2 are comparatively rare and do not seem to play a significant role in the etiology of sporadic breast cancer.35Other gene mutations can also lead to breast cancer. Variations in ATM, p53, CHEK2, PTEN, CDH1, andSTK11 genes have been reported to be associated with sporadic breast cancer.38 A considerable body of evidence suggests that defective or reduced DNA damage repairing ability in cells confers breast cancer susceptibility. 39 and 40
Age is the strongest demographic risk factor for most malignancies; 75% of malignancies occur in patients older than 55 years.41 Currently, most experts believe that oxidative stress plays an important role in age-related diseases including cancer.42, 43 and 44 Because the c.977C>G polymorphism inhibits the ability ofhOGG1 to repair damaged DNA, thus promoting the accumulation of oxidative damage over time, 45 and 46age-related diseases such as sporadic breast cancer could occur more frequently in young women who carry this variant of the gene.
In the present study, 16.2% of breast cancer patients had triple-negative breast cancer (TNBC), a rate similar to those reported in other large series (15–20%).47 and 48 TNBC, so named because of its negative expression of ER, PR, and HER-2/neu,49 is characterized by its aggressiveness and higher rates of recurrence and metastasis. Existing targeted therapies, which are effective in other subtypes of breast cancer, cannot be used to treat TNBC because of this type of cancer is lack of targeted sites. TNBC often occurs in young patients whose disease is associated with BRCA1 mutation and other hereditary factors.29 and 31 Accumulating evidence indicates that a defective repair capacity of the BER pathway is associated with TNBC carcinogenesis; in addition, TNBC has been found to have a reduced ability to repair oxidative DNA damage such as decreased hOGG1 expression. 50 and 51 Karihtala et al. found that TNBC rarely expresses hOGG1 and has relatively high levels of 8-OHdG.52 Also, in previous study, we found that c.−18G>T and c.−53G>C in the 5′-UTR of hOGG1 were prevalent in TNBC patients.27 The association between TNBC and lack of functional hOGG1 may provide important information to develop targeted therapy for this phenotype.
TP53 is one of the most common and important mutated genes in human neoplasms.53 The protein TP53encodes, p53, is involved in distinct cellular processes, including cell cycle control, apoptosis, DNA repair, and functions as a mediator of cellular response to DNA damage. Furthermore, p53 might interact with and affect the transcription of different BER proteins, such as hOGG1 and APE1, in response to cadmium treatment.54 The overexpression of p53, combined with morphologic features of a tumor, can be used to predict the risk of a germline mutation in BRCA1 and thus is a marker of aggressive disease. 55 and 56 In a previous study, we found that p53-positive disease is associated with a functional variation of c.−18G>T ofhOGG1 in breast cancer patients.27 In the present study, therefore, we sought to determine whether p53 expression is associated with the c.977C>G polymorphism.
Over the past decades, the value of genetic polymorphism in common diseases especially in cancer has been confirmed. Variations in the DNA sequences of humans can affect how humans develop diseases. Polymorphism test plays a rapidly growing role in the field of predict the risk of cancer. In our study, we demonstrated that the c.977C>G polymorphism in hOGG1 confers a risk of breast cancer in specific subgroups of Chinese Han women. The c.977C>G polymorphism may play an important role in the development of sporadic p53-positive TNBC in younger, premenopausal patients. Studies that explore the ways in which the molecular mechanism of variations in c.977C>G collaborates with other factors such as age, triple-negative and p53-positive status during breast cancer carcinogenesis are warranted.
The authors declare no conflicts of interests.
This work was partly supported by the Medical Science and Technology Development Foundation, Nanjing Department of Health (grant number: QYK11140); the Jiangsu Province Institute of Cancer Research Foundation (grant number: ZK201203), and the International Exchange Support Program of Jiangsu Health (2012).
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