|Ahead of print publication
DNA base excision repair genes variants rs25487 (X-ray repair cross-complementing 1) and rs1052133 (human 8-oxoguanine glycosylase 1) with susceptibility to ovarian cancer in the population of the Jammu region, India
Sonali Verma1, Varun Sharma1, Ashna Nagpal1, Amrita Bhat1, GR Bhat1, Ruchi Shah1, Ajay Wakhloo2, Jyotsna Suri3, Deepak Abrol4, Sandeep Kaul5, Audesh Bhat6, Vijeshwar Verma1, Rakesh Kumar1
1 School of Biotechnology, Shri Mata Vaishno Devi University, Katra, Jammu and Kashmir, India
2 Department of Obstetrics and Gynecology, Government Medical College, Jammu, Jammu and Kashmir, India
3 Department of Pathology, Government Medical College, Jammu, Jammu and Kashmir, India
4 Department of Radiotherapy, Government Medical College, Jammu, Jammu and Kashmir, India
5 Shri Mata Vaishno Devi Narayana Superspeciality Hospital, Katra, Jammu and Kashmir, India
6 Centre for Molecular Biology, Central University, Jammu, Jammu and Kashmir, India
Department of Biotechnology, Shri Mata Vaishno Devi University, Katra, Jammu and Kashmir
Source of Support: None, Conflict of Interest: None
Background: Ovarian cancer is highly prevalent in the population of Jammu, in India; the ovarian cancer ranks third among other types of cancer prevalent in females. However, association studies on ovarian cancer are lacking in this region. We aimed to investigate the disease susceptible variants rs1052133 (human 8-oxoguanine glycosylase 1 [hOGG1]) and rs25487 (X-ray repair cross-complementing 1 [XRCC1]) with ovarian cancer in population of Jammu, India.
Materials and Methods: The study conducted in the Shri Mata Vaishno Devi University is a 3-year study which included a total of 280 well-characterized samples (130 ovarian cancer cases and 150 healthy controls). hOGG1 and XRCC1 polymorphisms were determined by polymerase chain reaction-based restriction fragment length polymorphism, and these genotyping results were confirmed by Sanger sequencing. Hardy–Weinberg equilibrium for both single-nucleotide polymorphisms (SNPs) was assessed using the Chi-square test. The allele and genotype-specific risks were estimated by odds ratios with 95% confidence intervals.
Results: In this preliminary study, SNP rs1052133 showed protection with ovarian cancer (P = 0.042). The SNP rs25487 was not found associated with ovarian cancer (P = 0.271).
Conclusion: Our results indicate that the G allele of rs1052133 imparts protection to the population whereas variant rs25487 was not associated with ovarian cancer in population from the Jammu region, indicating that larger sample size is needed for further statistical validation. Further, association of other SNPs in these genes should also be carried out as their role cannot be ruled out.
Keywords: Human 8-oxoguanine DNA N-glycosylase 1, restriction fragment length polymorphism, X-ray repair cross-complementing 1
|How to cite this URL:|
Verma S, Sharma V, Nagpal A, Bhat A, Bhat G R, Shah R, Wakhloo A, Suri J, Abrol D, Kaul S, Bhat A, Verma V, Kumar R. DNA base excision repair genes variants rs25487 (X-ray repair cross-complementing 1) and rs1052133 (human 8-oxoguanine glycosylase 1) with susceptibility to ovarian cancer in the population of the Jammu region, India. J Can Res Ther [Epub ahead of print] [cited 2019 Jul 17]. Available from: http://www.cancerjournal.net/preprintarticle.asp?id=261561
| > Introduction|| |
Ovarian cancer is a complex disease with different genetic and morphological characteristics. It is the most fatal gynecological malignancy in the females of the developing countries. As per the Indian Council of Medical Research 2006 assessment, females are more susceptible (0.428 million cases) to cancer than males (0.390 million cases). In India, ovarian cancer ranks third among other types of cancer prevalent in females. The rise in the ovarian cancer cases in the recent past among different female population groups of Jammu and Kashmir has made it necessary to identify the genetic factors that might be responsible for increase in incidence. In the Kashmir region, ovarian cancer is the third leading cause of cancer-related deaths in females from 2002 to 2012 (7.45% deaths) with breast cancer (16.83%) and esophagus cancer (12.85%) being the other two major malignancies. This incidence of ovarian cancer in the population of Jammu, which was confirmed through the unpublished data from Government Medical College, Jammu, is almost equal to that of Kashmir. No study was found in the public database about the prevalence of ovarian cancer in population of the Jammu region. There are various genetic factors which are critically associated with a higher risk of developing ovarian cancer. Germline BRCA1 and BRCA2 mutations are the most common and significant genomic risk factors for ovarian carcinoma, and these are found in 17% of women affected with ovarian cancer. In addition to BRCA1 and BRCA2, other germline mutations in genes involved in DNA damage and repair can also increase the risk of developing ovarian carcinoma. More than 130 genes are reported to be associated with DNA repair. Human 8-oxoguanine glycosylase 1 (hOGG1)and X-ray repair cross-complementing 1 (XRCC1) are two key DNA repair genes involved in the base excision repair (BER) pathway.,, The hOGG1 gene located on chromosome 3p26 encodes enzyme glycosylase that actively removes 8-hydroxy-2-deoxyguanosine and is highly mutagenic and plays a role in oxidative DNA damage. XRCC1 acts as a central scaffolding protein and interacts directly with enzymatic factors such as ligase III, DNA polymerase β, and poly(ADP-ribose) polymerase to expedite efficient single strands break and evoke BER,, by binding to the damaged DNA.,
The development of 8-OHdG in DNA is supposed to persuade deteriorating diseases, with cancer. 8-OHdG can couple with adenine and lead to G: C to T: A transversions. These alterations are broadly seen in altered oncogenes and tumor suppressor genes, and subsequently, 8-OHdG levels are strictly related to the amount and extent of cancerous tissues. Lifestyle factors, age, exposure to harmful environmental factors, such as ionizing radiation and chemical carcinogens are the main reasons behind the enhanced level of 8-OHdG.
Common variants of hOGG1 (rs1052133) Ser326Cys and XRCC1 (rs25487) Arg399Gln polymorphism, respectively, have been identified as potential cancer susceptibility loci and used as biomarkers in various recent studies., The potential role of these polymorphisms in cancer development lies in the fact that these polymorphic gene variations alter the level of DNA repair proteins and also act as biomarker for chemotherapeutic response., The XRCC1 and hOGG1 DNA repair genes were selected for this study because of their critical role in maintaining genomic integrity. The aim of this association study is to identify disease susceptible gene variants rs1052133 of hOGG1 and rs25487 of XRCC1 with ovarian cancer in the women of Jammu. To the best of my knowledge, this is the first documented study from Jammu.
| > Materials and Methods|| |
This is a case–control study which was carried out in Jammu from January 2015 to March 2017. A total of 130 histopathological confirmed ovarian cases and 150 controls were recruited for the study. All cases were collected from various hospitals and clinics of Jammu and adjoining areas. All clinical details are given in [Table 1]. Informed consent was obtained from cases and controls before blood collection. This study was approved by the Institutional Ethical Review Board of the Shri Mata Vaishno Devi University.
|Table 1: Clinical characteristics of the cases and controls belonging to women of the Jammu region, India|
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Blood samples and DNA isolation
After informed consent, 2 ml of venous blood was collected into ethylenediaminetetraacetic acid Vacutainer from patients and controls (age- and sex-matched immediate relative belonging to the same location and ethnicity). The genomic DNA was isolated from the blood samples using the Qiagen DNA isolation Kit (catalog No. 5126).
Genotyping of human 8-oxoguanine glycosylase 1 (Ser326Cys) rs1052133
hOGG1 genotypes were detected using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and later confirmed using DNA sequencing. A fragment of 200 bp was amplified using a previously published and validated set of primers [Table 2]. The total reaction volume of 25 μl contained 0.5 μl each of forward and reverse primers, 2.0 μl (50 ng/μl) of genomic DNA, 9.5 μl dH2O, and 12.5 μl master mix (MgCl2, dNTPs, Taq Polymerase). The PCR cycling conditions were predenaturing at 95°C for 10 min, denaturing at 95°C for 1 min, annealing at 64°C for 1 min, extension at 72°C for 1 min followed by a final extension at 72°C for 5 min with total 30 cycle. The amplification product of 200 bp was first confirmed on 2% agarose gel. The 5 ul of PCR product was followed by digestion with 5U of restriction enzyme SAT1 (Thermo Scientific Molecular Biology Pvt. Ltd). The restriction digestion profile was checked on 3% agarose gel.
|Table 2: Primers and restriction enzymes used for the detection of human 8-oxoguanine glycosylase 1 and X-ray repair cross-complementing 1 polymorphisms|
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Genotyping of X-ray repair cross-complementing 1 (Arg399Gln) rs25487
A previously published validated set of primers [Table 2] was used to amplify the product of 402 bp. The total reaction volume of 25 μl contained 0.5 μl each of forward and reverse primers, 2.0 μl (50 ng/μl) of genomic DNA, 9.5 μl dH2O, and 12.5 μl master mix (MgCl2, dNTPs, Taq Polymerase). The PCR cycling conditions were predenaturing at 95°C for 5 min, denaturing at 95°C for 1 min, annealing at 61°C for 45 s, extension at 72°C for 1 min followed by a final extension at 72°C for 2 min with total 30 cycles. PCR products were initially checked in 2% agarose gel. The PCR product was digested with 5U of restriction enzyme MSP1 (Thermo Scientific Molecular Biology Pvt. Ltd) and checked on 3% agarose gel.
Sanger sequencing for validation of genotypes
After PCR amplification, amplified products were repeatedly digested three times for confirmation with their respective restriction enzymes, and a part of purified PCR product was sent for Sanger sequencing to validate PCR-RFLP results. For sequencing, the purified PCR products were sent to AgriGenome Labs Pvt Ltd, Kochi, India. The sequencing results were then compared with original gene sequences for the expected results. The ChromasPro version 2.6.4 was used for comparing the gene sequences and the resulting chromatogram sequences. The concordance rate was 100%. The results are shown in [Figure 1]b and [Figure 2]b.
|Figure 1: (a) Polymerase chain reaction-restriction fragment length polymorphism gel image for variant rs1052133 of human 8-oxoguanine glycosylase 1 having genotypes GG with 100 bp, CG with 100/200 bp, and CC with 200 bp. (b) Chromatogram of hOGG rs1052133 showing transition Ser326Cys (C > G)|
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|Figure 2: (a) Polymerase chain reaction-restriction fragment length polymorphism gel image for variant rs25487 of X-ray repair cross-complementing 1 having genotype AA with 402 bp, AG with 402,269 and 133 bp, and GG with 269 and 133 bp. (b) Chromatogram of X-ray repair cross-complementing 1 rs25487 showing transition Arg399Gln (G > A)|
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Continuous clinical data (age and body mass index [BMI]) were shown as mean ± standard deviation, and clinical characteristics of ovarian cancer are shown in [Table 1]. The statistical analysis was mainly performed using the Statistical Package for the Social Science program (SPSS version 20.0; SPSS, Chicago, IL). Genotype frequencies were tested for Hardy–Weinberg equilibrium (HWE) by Chi-square analysis. Logistic regression analysis was used to estimate odds ratio (OR), its 95% confidence interval (CI), and respective level of significance as P value. The power of the study was calculated statistically by PS software version 3.1.2 (https://ps-power-and-sample-size-calculation.software.informer.com/download). The sample size included in this study has 75% power to detect the association with OR of 2.0 assuming minor allele frequency of 0.30.
| > Results|| |
Two variants rs1052133 and rs25487 were screened in a case–control study that included 130 cases and 150 healthy controls by RFLP and later confirmed by Sanger sequencing.
For rs1052133, in participants with Cys/Cys genotype, a 100 bp fragment was visualized and in participants with Ser/Cys genotype two bands, one 100 bp and another 200 bp were seen. Participants homozygous for the Ser/Ser genotypes, single 200 bp fragment was visualized [Figure 1]a.
For rs1052133, the allelic distribution in population was in accordance HWE with P = 0.54. The frequency of the allele C in cases was 0.808 and in controls was 0.725 whereas the frequency of allele G in cases was 0.192 and in controls was 0.275, respectively [Table 3].
|Table 3: Allelic frequency distribution and observed odds ratio for X-ray repair cross-complementing 1 and human 8-oxoguanine glycosylase 1 variants in females of the Jammu region, India|
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A significantly higher frequency of allele G was observed in controls. To observe the maximum effect of allele G, CG + GG genotypes were compared with CC. The OR observed was 0.63 (0.42–0.93 at 95% CI), P = 0.042.
For rs25487, single 402 bp fragment was observed in participants with Gln/Gln genotype. In participants with the Arg/Gln genotype, three bands of 402 bp, 269 bp, and 133 bp were observed, whereas in homozygous participants for Arg/Arg genotype, only two 269 bp and 133 bp fragments were observed [Figure 2]a.
For rs25487 variation, the allele frequency distribution in healthy controls and ovarian cancer patients of the Jammu region is summarized in [Table 3]. The allelic distribution of the rs25487 was in accordance with HWE (P = 0.65). For rs25487, the frequency of the allele G in cases was 0.619 and in controls was 0.703 and frequency of allele A in cases was 0.381 and in controls was 0.297, respectively. The analysis did not show any significant association for the SNP rs25487 with ovarian cancer (P = 0.271) [Table 3].
| > Discussion|| |
Endogenous and exogenous agents cause DNA damage, which leads to genomic instability, cell cycle arrest, and apoptosis. It is of great importance that cells recognize damage through cell cycle checkpoints during replication and rapidly and efficiently repair it by DNA repair pathway. The polymorphic variants of DNA repair genes may influence DNA repair capacity and in this way contribute to cancer development.
It has been reported that hOGG1 326 CC genotype of rs1052133 may be associated with better response to chemotherapy with longer progression-free survival. They demonstrate an association between the hOGG1 Ser326Cys single-nucleotide polymorphism (SNP) and progression-free survival and gastrointestinal toxicity in non-small cell lung cancer patients. The hOGG1 codon 326 polymorphism is characterized as C to G substitution and causes a Ser to Cys amino acid change at codon 326. It has been demonstrated that the hOGG1 Cys326 protein repairs 8-oxoG inefficiently, leading to the hypothesis that this variant may contribute to a higher DNA mutation rate in the cells. Kohno et al. showed that 326C-containing hOGG1 has a seven-fold higher activity for repairing 8-oxoguanine than 326G-containing hOGG1, but no association was found between hOGG1 genotypes and the enzyme activity of hOGG1 in some other studies.,
Chen et al. showed that XRCC1 genetic polymorphism affects chemotherapy (platinum-based drugs) and overall survival prognosis. The study showing association of XRCC1 Arg399Gln with cancer demonstrates that the participants with GG genotype were more responsive to chemotherapy and had higher survival capacity. Chemotherapeutic drugs which are based on platinum lead to the activation of apoptotic pathway in DNA damage repair process by forming platinum DNA adducts. Platinum agents remove DNA adducts and increase their DNA repair ability to make cancer cell resist against platinum-based chemotherapy., Therefore, it has been reported that genetic polymorphism of XRCC1 having variant rs25487 may reduce repairability of DNA damage and promote metastasis by affecting the sensitivity of tumor cell to chemotherapy drugs (platinum based). Hence, the allele GG and GA status show that XRCC1 Arg399 Gln variant rs25487 may act as an important prognostic factor in patients with cancer.
The XRCC1 and hOGG1 DNA repair genes were selected in this study because of their critical role in maintaining genome integrity and based on previous studies, suggesting that SNPs in these genes have protective or deleterious effects on cancers in different populations of the world. There are studies where variants associated with ovarian cancer show reduced risk in different populations. In the Chinese population, XRCC1 (rs25487) and hOGG1 (rs1052133) polymorphisms do not show any significant association with female reproductive cancers., Whereas, both SNPs show strong association with other cancers such as lung, breast, gastric, and prostate cancer in the Chinese population.,,,, In Serbian and Polish women, these two SNPs are used as biomarkers in screening of ovarian cancer patients., These SNPs are also reported in Indian population showing the same pattern of association or disassociation with different cancers., In the Kashmir region of J and K-India, studies have been done using these SNPs on colorectal cancer in which they have not found any significant association with these SNPs., Whereas, we observed that the XRCC1 Arg399Gln and hOGG Ser326Cys have allelic differences in our samples when compared with previous studies done in different population groups of the world., In this case–control association study, of two SNPs, rs1052133 shows reduced risk with ovarian cancer with an observed OR of 0.63 (0.42–0.93 at 95% of CI) after correction with age and BMI. The results from this study suggest that allele G of the SNP rs1052133 acts as an important ovarian cancer protective factor in females of the Jammu region. Whereas, the variant rs25487 shows risk with ovarian cancer with an observed OR of 1.5 (1.03–2.07, at 95% of CI). The variants show very weak or no association when corrected with age and BMI as shown in [Table 3].
The allelic distribution of both the SNPs in our population anticipates that a further large number of samples are required for confirmation of our findings. We found that population of the Jammu region has never been explored with perspective of genetics of ovarian cancer. Hence, it is very important to emphasize on such studies to understand the heterogeneity of ovarian cancer. The participants recruited in the present study are presently undergoing chemotherapy, and their response to drugs will be analyzed in another study. Keeping in mind, the extent of genetic heterogeneity in ovarian cancer and diversity of the Indian population groups, such candidate gene studies are very important in understanding the etiology of ovarian and other cancers.
| > Conclusion|| |
These results suggest that the variant rs1052133 of hOGG1 (Ser326Cys) shows protection with ovarian cancer whereas the obtained results from this study suggest that there is no strong relationship of XRCC1 Arg399Gln polymorphism with ovarian cancer women from the Jammu region (drugs metabolized through this pathway cannot be considered in these patients). Further characterization of the relationships between polymorphisms of other DNA repair genes may allow a better understanding of how the polymorphisms affect ovarian cancer development and progression in the studied population group.
Financial support and sponsorship
Funding for completion of this study was sanctioned by DST-SERB, GOI with sanctioned number: YSS/2014/000659.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]