Abstract
Single nucleotide polymorphisms (SNPs) may modify the risk of cancer. They may be then regarded as potential markers of carcinogenesis. The aim of this study was to analyze the frequency of genotypes and alleles of SNPs in DNA repair genes and to investigate the influence this genetic variation exerts on breast cancer in Polish females. The test group comprised 600 females with breast cancer and 600 healthy controls. Genomic DNA was isolated and the SNPs in DNA repair genes were determined by High-Resolution Melter (HRM) technique. Following polymorphisms were analysed: Arg399Gln (rs25487) of the XRCC1, Gly322Asp (rs4987188) of the hMSH2, Lys751Gln (rs13181) of the XPD, Arg188His (rs3218536) of the XRCC2, P871L (rs799917) of the BRCA1 and N372H (rs144848) of the BRCA2 gene. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each genotype and allele. Statistically significant correlations were identified between 4 single nucleotide polymorphisms and the breast cancer risk: rs25487 rs4987188 rs13181 and rs799917. The alleles XRCC1-Gln (OR 5.11; 95% CI 5.68–11.64, p < .0001), hMSH2-Asp (OR 4.66; 95% CI 3.90–5.56, p < .0001), XPD-Gln (OR 2.65; 95% CI 2.24–3.14, p < .0001) and BRCA1-L (OR 1.45; 95% CI 1.24–1.71, p < .0001) genes were strongly correlated with this malignancy. No correlation was found between the studied SNPs and tumor grading nor the lymph node status. Further research on larger groups is warranted to determine the influence of above-mentioned genetic variants on breast cancer risk.
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Introduction
Breast cancer is the most frequent malignancy in women, both in Poland and worldwide, and accounts for almost 1/4 of overall cancer cases in humans. Moreover, it is one of the most frequent death causes in women suffering from cancer [1, 2]. Annually almost 16,000 Polish women learn of such a diagnosis and the yearly death toll exceeds 5000. Furthermore, according to estimates, annual morbidity in Poland may rise up to 20,000 in 2020 [2]. According to the latest Eurocare-5 data, the breast cancer five-year survival rate in Polish females is 71.6% which is significantly lower than the mean European value: 82% [3]. In addition, the rate of successful 5-year treatment outcomes in Poland is by 10% lower then the EU average [3, 4].
Numerous genetic variations in various genes may be found in breast cancer patients [5]. However, one cannot be always sure whether the abovementioned are the cause or rather the very effect of cancerous transformation. Provided they are considered to be the former, research can easily benefit from investigation on how genetic variations – i.e. genetic polymorphism – influence carcinogenesis or cancer progression.
DNA repair is a vital tool that protects the cell from mutations that may result in its malignant transformation [6, 7]. According to literature, lion share of cancers is triggered by the impaired ability of DNA repair. Therefore, a specific set of repair protein genes’ alleles may define the individual ability of DNA damage repair, as well as the susceptibility to cancer development. It is then crucial to learn more of the polymorphic variants of DNA repair genes – including SNPs -, as well as of their distribution in population [8].
Although breast cancer displays a significant genetic component, it is also characterized by quite high cure rates provided the diagnosis was early [9, 10]. This may particularly justify the need for a better diagnostic/prophylactic pathway in subjects diagnosed with unfavorable genetic load which may then eventually result in reduced both morbidity and mortality.
The aim of this study was to investigate the association between SNPs in DNA repair genes and the risk of breast cancer in Polish females. Breast cancer patients were tested for polymorphisms in following genes:
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base excision repair (BER) system
XRCC1 gene - Arg399Gln, polymorphism (rs25487),
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nucleotide excision repair (NER) system
XPD gene - Lys751Gln polymorphism (rs13181),
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mismatch repair (MMR) system
hMSH2 gene - Gly322Asp, polymorphism rs4987188),
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repair by homologous recombination
XRCC2 gene - Arg188His polymorphism (rs3218536),
BRCA1 gene - P871L polymorphism (rs799917) and.
BRCA2 gene - N372H polymorphism (rs144848).
Materials and Methods
Patients
Six hundred blood samples were collected from female breast cancer patients treated in the Department of Oncological Surgery and Breast Diseases, Polish Mother’s Memorial Hospital, Lodz, Poland. Demographic data and pathological features of the cases are both summarized in Table 1. Breast cancer samples were graded according to Scarf-Bloom-Richardson criteria. 600 age-matched disease-free women were selected as controls (see Table 1). All analyzed subjects were Caucasians and constituted a homogenous population of the same ethnic and geographical origins. Blood samples were derived in EDTA-vacuum tubes and kept frozen in −20 °C until initial processing. All participants gave a written informed consent. A formal consent was also issued by the Bioethical Committee of the Institute of the Polish Mother’s Memorial Hospital in Lodz (Approval number: 10/2012).
Availability of Data and Material
Data will not be shared, because it is part of a clinical database.
DNA Isolation
DNA was extracted from blood samples by QIAamp DNA Kit (Qiagen GmbH, Hilden, Germany) according to manufacturer’s instruction.
High Resolution Melting Analyses
PCR products for the analyzed variants were tested by High-Resolution Melter (HRM) analysis. The HRM analysis was carried out in a LightCycler® 96 (Roche, Mannheim, Germany) Thermocycler. PCR amplification was performed with support of a Light Cycler® 480 High Resolution Melting Master Kit (Roche, Mannheim, Germany), according to the manufacturer’s recommendations. All control DNA samples were employed in each run of HRM analysis. The collected data was analyzed, using the LightCycler® 96 software version SW 1.1 (Roche, Mannheim, Germany). SNPs in DNA repair genes were selected using the public domain of the National Center for Biotechnology Information at http://www.ncbi.nlm.nih.gov/snp (Bethesda, MD, USA). Real-time PCR cycling and conditions for HRM analysis of the examined DNA repair SNPs are summarized in Table 2.
Statistical Analysis
Genotype and allele distributions were evaluated and their compatibility with the Hardy-Weinberg distribution (HWE) was assessed by the means of χ2 test. Differences between distributions in particular groups were evaluated also by χ2 test. The general risks were illustrated as odds ratios (ORs) with associated 95% intervals (CIs) by unconditional logistic regression. The wild type of genotype and allele acted as reference. P-values <0.05 were considered significant.
Results
Table 3 presents the total distribution of genotypes and alleles of SNPs in both breast cancer patients and in controls. Interestingly, statistically significant differences were demonstrated in genotype distribution in the test group and in controls (p < 0.05).
We have demonstrated that XRCC1-Gln/Gln genotype of Arg399Gln polymorphism was strongly correlated with breast cancer. The Gln/Gln homozygote increased the risk of cancer eight-fold (OR 8.13). The Gln allele in these patients may itself be a risk factor of breast cancer (OR 5.11; 95% CI 4.24–6.16, p < .0001).
This study demonstrated that hMSH2- Asp/Asp (OR 10.61; 95% CI 7.43–15.16, p < .0001), XPD-Gln/Gln (OR 3.81; 95% CI 2.82–5.13, p < .0001) and BRCA1-L/L genotypes (OR 1.95; 95% CI 1.42–2.68, p < .0001) were strongly associated with an increased risk of breast cancer. In addition, the alleles of hMSH2-Asp (OR 4.66; 95% CI 3.90–5.56, p < .0001), XPD-Gln (OR 2.65; 95% CI 2.24–3.14, p < .0001) and BRCA1-L genes (OR 1.45; 95% CI 1.24–1.71, p < .0001) are strongly correlated with this malignancy.
No statistically significant differences were observed in genotype frequencies of both XRCC2 Arg188His polymorphism and BRCA2 N372H polymorphism between breast cancer patients and healthy controls (p > 0.05) (Table 3).
The observed genotype frequency of XRCC1-Arg399Gln, XPD-Lys751Gln, hMSH2 - Gly322Asp, XRCC2-Arg188His, BRCA1 - P871L and BRCA2 - N372H in controls were in agreement with HWE (p > 0.05). In case of the Arg399Gln polymorphism of XRCC1 gene, Lys751Gln of XPD gene, Gly322Asp of hMSH2 gene and P871L of BRCA1 gene, the distribution of the genotypes in the test group differed significantly from one expected from the Hardy-Weinberg equilibrium (p < 0.05). It is caused by the very low abundance of the XRCC1 Arg/Arg genotype, hMSH2 Gly/Gly genotype, XPD Lys/Lys and BRCA1 L/L genotype in the examined Polish population.
We did not find any correlation between the repair genes polymorphic variants and tumor grade nor the lymph node status (p > 0.05). Nor was there any relationship between the analyzed polymorphisms and the status of the estrogen (ER), progesterone (PR) or HER2 receptors. DNA repair genes polymorphisms were also unrelated to the patients’ age, hormone replacement therapy (HRT), number of births, the date of menarche, nor menopause status (p > 0.05).
Discussion
In this project, we have focused on evaluating the role of single nucleotide polymorphisms of DNA repair genes in the pathogenesis of breast cancer. The primary objective of our study was to identify the SNPs associated with the risk of breast cancer in Polish females and to estimate the cancer risk in SNPs carriers. The results of our research may contribute to a better understanding of the molecular background of the disease development and enable to evaluate the probability of its occurrence in specific subjects in population. Regarding the abovementioned study, we focused on the polymorphisms with an already proven significance in carcinogenesis, but not yet analyzed in breast cancer patients. In our study, the analyzed individuals were ethnically homogenous: Polish females from Lodz Region.
Our results fit in the general commonly accepted trend in research based on the concept that assumes that an individual susceptibility to cancer – including breast cancer – is a cumulative outcome of multiple risk factors derived from numerous low-penetrating genetic variables.
Genes involved in MMR include: hMLH1, hMSH2, hPMS2 and hMSH6. We focused on analyzing of the relationship between Gly322Asp polymorphism of hMSH2 gene and breast cancer. We selected the gene for its well-proven role in the pathogenesis of cancer. According to the literature, Gly322Asp polymorphism of hMSH2 gene may enhance the risk of malignancy in both colon and stomach, as well as increase the incidence of lymphoma and anemia [11,12,13].
Our study demonstrated that Gly322Asp polymorphism was strongly associated with an increased risk of breast cancer in Polish women. The Asp allele may as such be a risk factor of breast cancer.
We tested 600 breast cancer females for polymorphisms of both BER system (XRCC1) and the NER system (XPD) genes. BER is mainly intended to remove uncomplicated but potentially dangerous DNA damages, such as oxidized and N-alkylated nitrogen bases [14]. NER enables the removal of various types of damages, including the more complex ones than those removed by BER, including - among others - the photoproducts, such as pyrimidine dimers, interstrand bonds, large adducts resulting from exposure to aflatoxin, benzo[a]pyrene, psolarens or polycyclic aromatic hydrocarbons [15]. A series of enzymes are involved in BER and NER, including XRCC1 and XPD which harbor polymorphisms associated with the risk of tumors [8, 16, 17].
We have demonstrated that the polymorphic form of XRCC1 and XPD contributes to an increased risk of breast cancer in Polish women: alleles of XRCC1-Gln and XPD -Gln are strongly correlated with this malignancy.
Literature proves DNA damages to be highly significant in the pathogenesis of breast cancer. This phenomenon is especially found in these damages, where repair by homologous recombination is required [18, 19].
The repair system via homologous recombination repairs DNA double-strand breaks (DSB), which carry the highest cell mortality risk of all known DNA damages. Non-repaired DSBs result in a loss of chromosome fragments and - in consequence – in cell’s death. Accumulated DSBs lead to genome destabilization and to its unfavorable rearrangement [20, 21]. Disorders in genomic DNA accumulate with age, causing deregulation of transcription process, which then leads to cancer development [22]. Genes that encode double-strand break repairing proteins are highly polymorphic and - taking into account the significance of the defects in cancer development - it seems crucial to expand the knowledge on the role of genetic polymorphisms in breast cancer [23].
We have demonstrated a possible correlation of rs799917 polymorphism of BRCA1 repair gene with breast cancer. Yet, it should be emphasized that this is the first paper on Polish breast cancer females that directly addresses this very polymorphism. Earlier reports of various researchers who were dealing with SNPs in RAD51 gene - with our co-authorship as well – focused mainly on G135C and G172 T polymorphisms at 5′ region, that is not a subject of translation [24,25,26,27,28].
Since RAD51 participates in DNA repair but also interacts with BRCA proteins (mutations of which are often identified in breast cancer), the above-mentioned polymorphisms may be associated with a higher risk of development this malignancy. It has been found, among others, that 135C variant may increase the risk of breast cancer in BRCA1 and BRCA2 genes mutations carriers, whereas no effects of 135C variant were observed on the morbidity in women without the mutations [29, 30]. G135C polymorphism can modify the way of mRNA splicing, what - in turn - affects the protein functions or the effectiveness of translation [31]. In spite of the abundance of results, there is still no unequivocal explanation of the role of RAD51 in cancer formation.
Our assumption was that another genetic variability factor could act either additively or independently of the above-mentioned polymorphisms in 5’UTR region, what may help to explain the role of RAD51 in breast cancer development. Our research was then oriented towards less investigated SNPs within BRCA1 and BRCA2 genes: P871L (rs799917) and N372H (rs144848).
In this study, significant correlations were identified between breast cancer and the new, not yet reported in literature, SNP-type polymorphism in BRCA1 (rs799917). No correlation was found between the studied SNP and tumor grade, nor tumor size, nor the lymph node status. Nor was there any relationship demonstrated between the analyzed polymorphism and the status of the estrogen, progesterone or HER2 receptors.
To conclude, this study contributes to a better knowledge of the molecular background of breast cancer. Our results point out the DNA repair genes and their polymorphisms, which can be involved in breast cancer formation in Polish women. They may find practical application in improvement in cancer diagnostics and may eventually result in decrease of morbidity and mortality in breast cancer patients.
Conclusions
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1.
We demonstrated a significant relationship between the single nucleotide polymorphism of hMSH2 (rs4987188) gene, participating in DNA repair via mismatch repair (MMR) and an increased risk of breast cancer.
-
2.
We demonstrated a significant relationship between the single nucleotide polymorphism of XPD (rs13181) gene, participating in DNA repair via nucleotide excision repair (NER) and an increased risk of breast cancer.
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3.
We demonstrated a significant relationship between the single nucleotide polymorphism of XRCC1 (rs25487) gene, participating in DNA repair via nitrogen base excision repair (BER) and an increased risk of breast cancer.
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4.
We presented a significant correlation between single nucleotide polymorphism of DNA double-strand break repair genes via homologous recombination (HRR) BRCA1 (rs799917), and breast cancer development.
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5.
The single nucleotide polymorphisms within the studied DNA repair genes may enrich the scope of new risk factors of breast cancer in Polish women.
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Acknowledgements
Authors acknowledge the financial support provided by the Institute of Polish Mother’s Memorial Hospital, Lodz, Poland, to conduct the study.
Funding
This work was supported by the Institute of Polish Mother’s Memorial Hospital, Lodz, Poland from the Statutory Development Fund.
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Contributions
Conceived and designed the experiments: MB, BS, HR. Performed the experiments – case group: BS, EF. Case group design and collect: MZ, HR. Performed the experiments – control group: BS, EF. Analysed data: BS, HR, MB. Contributed reagents/materials/analysis tools BS. Contributed to the writing of manuscript: BS, HR, JB. All authors approved the final manuscript.
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This work was supported by the Institute of Polish Mother’s Memorial Hospital, Lodz, Poland from the Statutory Development Fund. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Disclosure of Potential Conflicts of Interest
Author Beata Smolarz declares that she has no conflict of interest. Author Magdalena Bryś declares that she has no conflict of interest. Author Ewa Forma declares that she has no conflict of interest. Author Marek Zadrożny declares that he has no conflict of interest. Author Jan Bieńkiewicz declares that he has no conflict of interest. Author Hanna Romanowicz declares that she has no conflict of interest.
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Informed consent was obtained from all individual participants included in the study.
A formal consent was also issued by the Bioethical Committee of the Institute of the Polish Mother’s Memorial Hospital in Lodz (Approval number, 15.12.2010).
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Not applicable, the manuscript doesn’t contain any individual person’s data.
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Smolarz, B., Bryś, M., Forma, E. et al. Data on Single Nucleotide Polymorphism of DNA Repair Genes and Breast Cancer Risk from Poland. Pathol. Oncol. Res. 25, 1311–1317 (2019). https://doi.org/10.1007/s12253-017-0370-8
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DOI: https://doi.org/10.1007/s12253-017-0370-8