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DNA repair genes hOGG1, XRCC1 and ERCC2 polymorphisms and their molecular mapping in breast cancer patients from India

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Abstract

Identification of modifier genes predisposing to breast cancer (BC) phenotype remains a significant challenge and varies with ethnicity. The genetic variability observed in DNA repair genes may modulate the cell’s ability to repair the damaged DNA and hence, evaluation of genetic variants in crucial DNA damage repair genes is of clinical importance. We performed the present study to evaluate the role of ERCC2-Lys751Gln, hOGG1-Ser326Cys, and XRCC1-Arg399Gln gene polymorphisms on the risk of BC development and its molecular profile in Indian women. Three non-synonymous variants (rs13181, rs1052133, and rs25487) were genotyped in 464 BC patients and 450 healthy controls. Logistic regression was employed to evaluate the association of genotypes with BC risk. Also, in silico analysis was carried out to map the Arg399Gln variant on the BRCT1 domain of XRCC1 protein. XRCC1 Gln/Gln genotype frequency was significantly elevated in BC patients [odd ratio (OR) = 1.73; 95% confidence interval (CI) = 1.13–2.65]. No significant association was observed between hOGG1-Ser326Cys and ERCC2-Lys751Gln variants and BC risk. Subgroup analysis revealed that ERCC2-Lys751Gln and XRCC1-Arg399Gln variants contributed towards tumor progression. A positive interaction between the investigated SNPs and BC was revealed by MDR analysis. Arg399Gln variant resulted in a change in the surface charge of XRCC1 protein. The rs25487 variant of XRCC1 might be associated with an elevated risk of BC. Furthermore, we demonstrated that high order gene–gene interaction plays a significant role in BC etiology. Hence, understanding the impact of low penetrant gene polymorphisms might enable a better understanding of the genetic background of breast cancer.

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References

  1. Momenimovahed Z, Salehiniya H (2019) Epidemiological characteristics of and risk factors for breast cancer in the world. Breast Cancer 11:151–164

    PubMed  Google Scholar 

  2. Hortobagyi GN, de la Garza SJ, Pritchard K, Amadori D, Haidinger R, Hudis CA et al (2005) The global breast cancer burden: variations in epidemiology and survival. Clin Breast Cancer 6:391–401

    PubMed  Google Scholar 

  3. Malvia S, Bagadi SA, Dubey US, Saxena S (2017) Epidemiology of breast cancer in Indian women. Asia Pac J Clin Oncol 13:289–295

    PubMed  Google Scholar 

  4. Lalloo F, Evans DG (2012) Familial breast cancer. Clin Genet 82:105–114

    CAS  PubMed  Google Scholar 

  5. Maxwell KN, Nathanson KL (2013) Common breast cancer risk variants in the post-COGS era: a comprehensive review. Breast Cancer Res 15:212

    PubMed  PubMed Central  Google Scholar 

  6. Rouse J, Jackson SP (2002) Interfaces between the detection, signalling and repair of DNA damage. Science 297:547–551

    CAS  PubMed  Google Scholar 

  7. Ochs K, Sobol RW, Wilson SH, Kaina B (1999) Cells deficient in DNA polymerase beta are hypersensitive to alkylating agent induced apoptosis and chromosomal breakage. Cancer Res 59:1544–1551

    CAS  PubMed  Google Scholar 

  8. Mohrenweiser HW, Jones IM (1998) Variation in DNA repair is a factor in cancer susceptibility: a paradigm for the promises and perils of individual and population risk estimation? Mutat Res 400:15–24

    CAS  PubMed  Google Scholar 

  9. Yauda MT, Sakakibara H, Shimoi K (2017) Estrogen- and stress-induced DNA damage in breast cancer and chemoprevention with dietary flavonoid. Genes Environ 39:10

    Google Scholar 

  10. Wilson DM, Bohr VA (2007) The mechanisms of base excision repair, and its relationship to aging and disease. DNA Repair 6:544–559

    CAS  PubMed  Google Scholar 

  11. Zhang H, Mizumachi T, Carcel-Trullos J, Li L, Naito A, Spencer HJ et al (2007) Targeting human 8-oxoguanine DNA glycosylase (hOGG1) to mitochondria enhances cisplatin cytotoxicity in hepatoma cells. Carcinogenesis 28:1629–1637

    CAS  PubMed  Google Scholar 

  12. Ide H, Kotera M (2004) Human DNA Glycosylases involved in the repair of oxidatively damaged DNA. Biol Pharm Bull 27:480–485

    CAS  PubMed  Google Scholar 

  13. Naylor SL, Johnson BE, Minna JD, Sakaguchi AY (1987) Loss of heterozygosity of chromosome 3p markers in small-cell lung cancer. Nature 329:451–454

    CAS  PubMed  Google Scholar 

  14. Kohn T, Shinmura K, Tosaka M, Tani M, Kim SR, Sugimura H et al (1998) Genetic polymorphisms and alternative splicing of the hOGG1 gene, that is involved in the repair of 8-hydroxyguanine in damaged DNA. Oncogene 16:3219–3226

    Google Scholar 

  15. Shinmura K, Kasai H, Sasaki A, Sugimura H, Yokota J (1997) 8-Hydroxyguanine (7,8-dihydro-8-oxoguanine) DNA glycosylase and AP lyase activities of hOGG1 protein and their substrate specificity. Mutat Res 385:75–82

    CAS  PubMed  Google Scholar 

  16. Ladiges WC (2006) Mouse models of XRCC1 DNA repair polymorphisms and cancer. Oncogene 25:1612–1619

    CAS  PubMed  Google Scholar 

  17. Zhou W, Liu G, Miller DP, Thurston SW, Xu LL, Wain JC et al (2003) Polymorphisms in the DNA repair genes XRCC1 and ERCC2, smoking, and lung cancer risk. Cancer Epidemiol Biomarkers Prev 12:359–365

    CAS  PubMed  Google Scholar 

  18. Figueiredo JC, Knight JA, Briollais L, Andrulis IL, Ozcelik H (2004) Polymorphisms XRCC1-R399Q and XRCC3-T241M and the risk of breast cancer at the Ontario site of the breast cancer family registry. Cancer Epidemiol Biomarkers Prev 13:583–591

    CAS  PubMed  Google Scholar 

  19. Ronen A, Glickman BW (2001) Human DNA repair genes. Environ Mol Mutagen 37:241–283

    CAS  PubMed  Google Scholar 

  20. Lehmann AR (2008) ERCC2 structure reveals its secrets. DNA Repair 7:1912–1915

    CAS  PubMed  Google Scholar 

  21. Tomescu D, Kavanagh G, Ha T, Campbell H, Melton DW (2001) Nucleotide excision repair gene ERCC2 polymorphisms and genetic predisposition to melanoma. Carcinogenesis 22:430–438

    Google Scholar 

  22. DeLano WL (2002) Pymol: an open-source molecular graphics tool. CCP4 Newslett Protein Crystallogr 40:82–92

    Google Scholar 

  23. Ritchie MD, Hahn LW, Roodi N, Bailey LR, Dupont WD, Parl FF et al (2001) Multifactor-dimenstionality reduction reveals high-order interactions among estrogen-metabolism genes in sporadic breast cancer. Am J Hum Genet 69:138–147

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Smolarz B, Michalska MM, Samulak D, Romanowicz H, Wójcik L (2019) Polymorphism of DNA repair genes in breast cancer. Oncotarget 10:527–535

    PubMed  PubMed Central  Google Scholar 

  25. Chacko P, Rajan B, Joseph T, Mathew BS, Pillai MR (2005) Polymorphisms in DNA repair gene XRCC1 and increased genetic susceptibility to breast cancer. Breast Cancer Res Treat 89:15–21

    CAS  PubMed  Google Scholar 

  26. Sanjari Moghaddam A, Nazarzadeh M, Sanjari Moghaddam H, Bidel Z, Keramatinia A, Darvish H et al (2016) XRCC1 gene polymorphisms and breast cancer risk: a systematic review and meta-analysis study. Asian Pac J Cancer Prev 17(S3):323–330

    PubMed  Google Scholar 

  27. Przybylowska-Sygut K, Stanczyk M, Kusinska R, Kordek R, Majsterek I (2013) Association of the Arg194Trp and the Arg399Gln polymorphisms of the XRCC1 gene with risk occurrence and the response to adjuvant therapy among Polish women with breast cancer. Clin Breast Cancer 13:61–68

    CAS  PubMed  Google Scholar 

  28. Sultana R, Abdel-Fatah T, Abbotts R, Hawkes C, Albarakati N, Seedhouse C et al (2013) Targeting XRCC1 deficiency in breast cancer for personalized therapy. Cancer Res 73:1621–1634

    CAS  PubMed  Google Scholar 

  29. Qiao Y, Spitz MR, Shen H, Guo Z, Shete S, Hedayati M et al (2002) Modulation of repair of ultraviolet damage in the host-cell reactivation assay by polymorphic XPC and ERCC2/ERCC2 genotypes. Carcinogenesis 23:295–299

    CAS  PubMed  Google Scholar 

  30. Kuschel B, Chenevix-Trench G, Spurdle AB, Chen X, Hopper JL, Giles GG et al (2005) Common polymorphisms in ERCC2 (Xeroderma pigmentosum D) are not associated with breast cancer risk. Cancer Epidemiol Biomarkers Prev 14:1828–1831

    CAS  PubMed  Google Scholar 

  31. Costa S, Pinto D, Pereira D, Rodrigues H, Cameselle-Teijerio J, Medeiros R et al (2007) DNA repair polymorphisms might contribute differentially on familial and sporadic breast cancer susceptibility: a study on a Portuguese population. Breast Cancer Res Treat 103:209–217

    CAS  PubMed  Google Scholar 

  32. Justenhoven C, Hamann U, Pesch B, Harth V, Rabstein S, Baisch C et al (2004) ERCC2 genotypes and a corresponding haplotype are linked with breast cancer risk in a German population. Cancer Epidemiol Biomarkers Prev 13:2059–2064

    CAS  PubMed  Google Scholar 

  33. Dufloth RM, Costa S, Schmitt F, Zeferino LC (2005) DNA repair gene polymorphisms and susceptibility to familial breast cancer in a group of patients from Campinas. Brazil Genet Mol Res 4:771–782

    CAS  PubMed  Google Scholar 

  34. Nissar B, Kadla SA, Khan NS, Shah IA, Majid M, Afshan FU et al (2018) DNA Repair gene XRCC1 and XPD polymorphisms and gastric cancer risk: a case-control study outcome from Kashmir, India. Anal Cell Pathol 2018:3806514

    Google Scholar 

  35. Terry MB, Gammon MD, Zhang FF, Eng SM, Sagiv SK, Paykin AB et al (2004) Polymorphism in the DNA repair gene ERCC2, polycyclic aromatic hydrocarbon DNA adducts, cigarette smoking, and breast cancer risk. Cancer Epidemiol Biomarkers Prev 13:2053–2058

    CAS  PubMed  Google Scholar 

  36. Srivastava A, Srivastava K, Pandey SN, Choudhuri G, Mittal B (2009) Single-nucleotide polymorphisms of DNA repair genes OGG1 and XRCC1: association with gallbladder cancer in North Indian population. Ann Surg Oncol 16:1695–1703

    PubMed  Google Scholar 

  37. Alanazi M, Pathan AAK, Shaik JP, Alhadheq A, Khan Z, Khan W et al (2017) The hOGG1 Ser326Cys gene polymorphism and breast cancer risk in Saudi population. Pathol Oncol Res 23:525–535

    CAS  PubMed  Google Scholar 

  38. Sliwinski T, Przybylowska K, Markiewicz L, Rusin P, Pietruszewska W, Zelinska-Blizniewska H et al (2011) MUTYH Tyr165Cys, OGG1 Ser326Cys and ERCC2 Lys751Gln polymorphisms and head neck cancer susceptibility: a case control study. Mol Biol Rep 38(2):1251–1261

    CAS  PubMed  Google Scholar 

  39. Verma S, Sharma V, Nagpal A, Bhat A, Bhat GR, Shah R et al (2019) 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 Cancer Res Ther 15:1270–1275

    CAS  PubMed  Google Scholar 

  40. Kamali M, Kargar S, Heiranizadeh N, Zare M, Kargar S, Shehneh MZ et al (2017) Lack of any association between the Hogg1 Ser326Cys polymorphism and breast cancer risk: a systematic review and meta-analysis of 18 studies. Asian Pac J Cancer Prev 18:245–251

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This study was supported by the Department of Science and Technology, SERB – Government of India (YSS/2015/001692). We would like to thank the study participants, the medical staff of Dr. G.V.N Cancer Institute and MMHRC, and SASTRA-Deemed University for their support.

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Authors and Affiliations

  1. Cancer Genomics Laboratory, Department of Biotechnology, School of Chemical and Biotechnology, SASTRA – Deemed University, Thanjavur, 613 401, India

    Taruna Rajagopal, Swarna Viswanathan & Nageswara Rao Dunna

  2. Department of Medical and Paediatric Oncology, Dr. G.V.N Cancer Institute, Singarathope, Tiruchchirappalli, 620 008, India

    Arun Seshachalam

  3. Department of Hemato Oncology – Medical Oncology and Bone Marrow Transplantation, Meenakshi Mission Hospital & Research Centre, Madurai, 625 107, India

    Krishna Kumar Rathnam

  4. Department of Bioinformatics, School of Chemical and Biotechnology, SASTRA – Deemed University, Thanjavur, 613 401, India

    Arunachalam Jothi

  5. Dana Farber Cancer Institute, Boston, MA, 02215, USA

    Srikanth Talluri

  6. Veterans Administration Boston Healthcare System, West Roxbury, MA, 02132, USA

    Srikanth Talluri

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  1. Taruna Rajagopal
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  2. Arun Seshachalam
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  7. Nageswara Rao Dunna
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Correspondence to Nageswara Rao Dunna.

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Ethical approval

Study proceeded with the approval of ethical committee Dr. GVN cancer Institute (GVNCI-IEC – ECR/436/INST/TN/2013 dated 04/01/2016) and MMRCH (MMRCH-IEC-ECR/398/INST/TN/2013/RR-16 dated 06/08/2018).

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Rajagopal, T., Seshachalam, A., Rathnam, K.K. et al. DNA repair genes hOGG1, XRCC1 and ERCC2 polymorphisms and their molecular mapping in breast cancer patients from India. Mol Biol Rep 47, 5081–5090 (2020). https://doi.org/10.1007/s11033-020-05577-2

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  • DOI: https://doi.org/10.1007/s11033-020-05577-2

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