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Homozygous T172T and Heterozygous G135C Variants of Homologous Recombination Repairing Protein RAD51 are Related to Sporadic Breast Cancer Susceptibility

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Abstract

Breast cancer (BC) is the most common cancer and the second leading cause of death among women worldwide. Only 10% of BC cases have been related to genetic predisposition. Rad51, a homologous recombination (HR) protein plays an important role in HR in meiosis and repairing DNA double-strand breaks. Expression of RAD51 may be a predictive biomarker in certain types of cancers. The exact mechanisms involved in the regulation of RAD51 expression are not fully understood, but certain transcription factors have been suggested to be the tuning mechanism of its expression. In this study, we propose that polymorphisms in the 5′-UTR promoter region of the RAD51 gene are prognostic factors for BC development. Direct sequencing of 106 samples from sporadic BC patients and 54 samples from a control group was performed. FFPE samples were the choice of sample collection, which might be a limitation of our study. Homologous variant T172T alone was found to be significantly associated with BC risk (OR 3.717, 95% CI 2.283–6.052, p < 0.0001). On the other hand, heterozygous G135C did not show any significant relationship with risk of sporadic BC (OR 1.598, 95% CI 0.5638–4.528, p > 0.05). Moreover, both variants; homozygous T172T and heterozygous G135C together; showed a significant relationship with sporadic BC susceptibility.

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References

  • Al Zoubi MS (2015) X-ray repair cross-complementing protein 1 and 3 polymorphisms and susceptibility of breast cancer in a Jordanian population. Saudi Med J 36(10):1163–1167

    Article  PubMed  Google Scholar 

  • Antoniou AC et al (2007) RAD51 135G–>C modifies breast cancer risk among BRCA2 mutation carriers: results from a combined analysis of 19 studies. Am J Hum Genet 81(6):1186–1200

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Arias-Lopez C et al (2006) p53 Modulates homologous recombination by transcriptional regulation of the RAD51 gene. EMBO Rep 7(2):219–224

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Arnaudeau C, Helleday T, Jenssen D (1999) The RAD51 protein supports homologous recombination by an exchange mechanism in mammalian cells. J Mol Biol 289(5):1231–1238

    Article  CAS  PubMed  Google Scholar 

  • Arnaudeau C et al (2001) RAD51 supports spontaneous non-homologous recombination in mammalian cells, but not the corresponding process induced by topoisomerase inhibitors. Nucleic Acids Res 29(3):662–667

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Auranen A et al (2005) Polymorphisms in DNA repair genes and epithelial ovarian cancer risk. Int J Cancer 117(4):611–618

    Article  CAS  PubMed  Google Scholar 

  • Bastos HN et al (2009) Association of polymorphisms in genes of the homologous recombination DNA repair pathway and thyroid cancer risk. Thyroid 19(10):1067–1075

    Article  CAS  PubMed  Google Scholar 

  • Baumann P, West SC (1998) Role of the human RAD51 protein in homologous recombination and double-stranded-break repair. Trends Biochem Sci 23(7):247–251

    Article  CAS  PubMed  Google Scholar 

  • Baumann P, Benson FE, West SC (1996) Human Rad51 protein promotes ATP-dependent homologous pairing and strand transfer reactions in vitro. Cell 87(4):757–766

    Article  CAS  PubMed  Google Scholar 

  • Blasiak J et al (2003) Analysis of the G/C polymorphism in the 5′-untranslated region of the RAD51 gene in breast cancer. Acta Biochim Pol 50(1):249–253

    CAS  PubMed  Google Scholar 

  • Brooks J et al (2008) Polymorphisms in RAD51, XRCC2, and XRCC3 are not related to breast cancer risk. Cancer Epidemiol Biomarkers Prev 17(4):1016–1019

    Article  CAS  PubMed  Google Scholar 

  • Ding SL et al (2009) Genetic variants of BLM interact with RAD51 to increase breast cancer susceptibility. Carcinogenesis 30(1):43–49

    Article  CAS  PubMed  Google Scholar 

  • Easton DF, Ford D, Bishop DT (1995) Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast cancer linkage consortium. Am J Hum Genet 56(1):265–271

    PubMed Central  CAS  PubMed  Google Scholar 

  • Ford D et al (1998) Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The breast cancer linkage consortium. Am J Hum Genet 62(3):676–689

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Gal I et al (2006) A specific RAD51 haplotype increases breast cancer risk in Jewish non-Ashkenazi high-risk women. Eur J Cancer 42(8):1129–1134

    Article  CAS  PubMed  Google Scholar 

  • Gao LB et al (2011) RAD51 135G/C polymorphism and breast cancer risk: a meta-analysis from 21 studies. Breast Cancer Res Treat 125(3):827–835

    Article  CAS  PubMed  Google Scholar 

  • Gaudet MM et al (2009) Five polymorphisms and breast cancer risk: results from the Breast Cancer Association Consortium. Cancer Epidemiol Biomarkers Prev 18(5):1610–1616

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hasselbach L et al (2005) Characterisation of the promoter region of the human DNA-repair gene Rad51. Eur J Gynaecol Oncol 26(6):589–598

    CAS  PubMed  Google Scholar 

  • Jara L et al (2007) RAD51 135G>C polymorphism and risk of familial breast cancer in a South American population. Cancer Genet Cytogenet 178(1):65–69

    Article  CAS  PubMed  Google Scholar 

  • Kadouri L et al (2004) A single-nucleotide polymorphism in the RAD51 gene modifies breast cancer risk in BRCA2 carriers, but not in BRCA1 carriers or noncarriers. Br J Cancer 90(10):2002–2005

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Klein HL (2008) The consequences of Rad51 overexpression for normal and tumor cells. DNA Repair (Amst) 7(5):686–693

    Article  CAS  Google Scholar 

  • Kuschel B et al (2002) Variants in DNA double-strand break repair genes and breast cancer susceptibility. Hum Mol Genet 11(12):1399–1407

    Article  CAS  PubMed  Google Scholar 

  • Lee KM et al (2005) Genetic polymorphisms of selected DNA repair genes, estrogen and progesterone receptor status, and breast cancer risk. Clin Cancer Res 11(12):4620–4626

    Article  CAS  PubMed  Google Scholar 

  • Linke SP et al (2003) p53 Interacts with hRAD51 and hRAD54, and directly modulates homologous recombination. Cancer Res 63(10):2596–2605

    CAS  PubMed  Google Scholar 

  • Lose F et al (2006) Variation in the RAD51 gene and familial breast cancer. Breast Cancer Res 8(3):R26

    Article  PubMed Central  PubMed  Google Scholar 

  • Lu J et al (2007) 172G>T variant in the 5′ untranslated region of DNA repair gene RAD51 reduces risk of squamous cell carcinoma of the head and neck and interacts with a P53 codon 72 variant. Carcinogenesis 28(5):988–994

    Article  CAS  PubMed  Google Scholar 

  • Lundin C et al (2003) RAD51 is involved in repair of damage associated with DNA replication in mammalian cells. J Mol Biol 328(3):521–535

    Article  CAS  PubMed  Google Scholar 

  • Maacke H et al (2000a) DNA repair and recombination factor Rad51 is over-expressed in human pancreatic adenocarcinoma. Oncogene 19(23):2791–2795

    Article  CAS  PubMed  Google Scholar 

  • Maacke H et al (2000b) Over-expression of wild-type Rad51 correlates with histological grading of invasive ductal breast cancer. Int J Cancer 88(6):907–913

    Article  CAS  PubMed  Google Scholar 

  • Martin RW et al (2007) RAD51 up-regulation bypasses BRCA1 function and is a common feature of BRCA1-deficient breast tumors. Cancer Res 67(20):9658–9665

    Article  CAS  PubMed  Google Scholar 

  • Masson JY, West SC (2001) The Rad51 and Dmc1 recombinases: a non-identical twin relationship. Trends Biochem Sci 26(2):131–136

    Article  CAS  PubMed  Google Scholar 

  • Michalska MM et al (2015) Single nucleotide polymorphisms (SNPs) of RAD51-G172T and XRCC2-41657C/T homologous recombination repair genes and the risk of triple-negative breast cancer in Polish women. Pathol Oncol Res 21(4):935–940

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Mitra A et al (2009) Overexpression of RAD51 occurs in aggressive prostatic cancer. Histopathology 55(6):696–704

    Article  PubMed Central  PubMed  Google Scholar 

  • Piscitelli P et al (2009) Incidence of breast cancer in Italy: mastectomies and quadrantectomies performed between 2000 and 2005. J Exp Clin Cancer Res 28:86

    Article  PubMed Central  PubMed  Google Scholar 

  • Pooley KA et al (2008) Common single-nucleotide polymorphisms in DNA double-strand break repair genes and breast cancer risk. Cancer Epidemiol Biomarkers Prev 17(12):3482–3489

    Article  CAS  PubMed  Google Scholar 

  • Raderschall E et al (2002) Elevated levels of Rad51 recombination protein in tumor cells. Cancer Res 62(1):219–225

    CAS  PubMed  Google Scholar 

  • Richardson C (2005) RAD51, genomic stability, and tumorigenesis. Cancer Lett 218(2):127–139

    Article  CAS  PubMed  Google Scholar 

  • Richardson C et al (2004) Rad51 overexpression promotes alternative double-strand break repair pathways and genome instability. Oncogene 23(2):546–553

    Article  CAS  PubMed  Google Scholar 

  • Rollinson S et al (2007) RAD51 homologous recombination repair gene haplotypes and risk of acute myeloid leukaemia. Leuk Res 31(2):169–174

    Article  CAS  PubMed  Google Scholar 

  • Schmutte C et al (1999) Characterization of the human Rad51 genomic locus and examination of tumors with 15q14-15 loss of heterozygosity (LOH). Cancer Res 59(18):4564–4569

    CAS  PubMed  Google Scholar 

  • Schneider J, Classen V, Helmig S (2008) XRCC1 polymorphism and lung cancer risk. Expert Rev Mol Diagn 8(6):761–780

    Article  CAS  PubMed  Google Scholar 

  • Shinohara A, Ogawa T (1995) Homologous recombination and the roles of double-strand breaks. Trends Biochem Sci 20(10):387–391

    Article  CAS  PubMed  Google Scholar 

  • Siegel R, Naishadham D, Jemal A (2012) Cancer statistics, 2012. CA Cancer J Clin 62(1):10–29

    Article  PubMed  Google Scholar 

  • Silva SN et al (2010) Breast cancer risk and common single nucleotide polymorphisms in homologous recombination DNA repair pathway genes XRCC2, XRCC3, NBS1 and RAD51. Cancer Epidemiol 34(1):85–92

    Article  CAS  PubMed  Google Scholar 

  • Struewing JP et al (1997) The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med 336(20):1401–1408

    Article  CAS  PubMed  Google Scholar 

  • Sun H et al (2011) RAD51 G135C polymorphism is associated with breast cancer susceptibility: a meta-analysis involving 22,399 subjects. Breast Cancer Res Treat 125(1):157–161

    Article  PubMed  Google Scholar 

  • Thacker J (2005) The RAD51 gene family, genetic instability and cancer. Cancer Lett 219(2):125–135

    Article  CAS  PubMed  Google Scholar 

  • Thorlacius S et al (1998) Population-based study of risk of breast cancer in carriers of BRCA2 mutation. Lancet 352(9137):1337–1339

    Article  CAS  PubMed  Google Scholar 

  • Vispe S et al (1998) Overexpression of Rad51 protein stimulates homologous recombination and increases resistance of mammalian cells to ionizing radiation. Nucleic Acids Res 26(12):2859–2864

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wang WW et al (2001) A single nucleotide polymorphism in the 5′ untranslated region of RAD51 and risk of cancer among BRCA1/2 mutation carriers. Cancer Epidemiol Biomarkers Prev 10(9):955–960

    CAS  PubMed  Google Scholar 

  • Winsey SL et al (2000) A variant within the DNA repair gene XRCC3 is associated with the development of melanoma skin cancer. Cancer Res 60(20):5612–5616

    CAS  PubMed  Google Scholar 

  • Xia SJ, Shammas MA, Reis RJS (1997) Elevated recombination in immortal human cells is mediated by HsRAD51 recombinase. Mol Cell Biol 17(12):7151–7158

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Yu KD et al (2011) RAD51 135G>C does not modify breast cancer risk in non-BRCA1/2 mutation carriers: evidence from a meta-analysis of 12 studies. Breast Cancer Res Treat 126(2):365–371

    Article  CAS  PubMed  Google Scholar 

  • Zhou GW et al (2011) RAD51 135G>C polymorphism and breast cancer risk: a meta-analysis. Breast Cancer Res Treat 125(2):529–535

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We would like to thank Dr. Ahmed F. Salem for his help.

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Authors and Affiliations

  1. Division of Surgical, Molecular, and Ultrastructural Pathology, Pisa University Hospital, University of Pisa, Pisa, Italy

    Mazhar Salim Al-Zoubi, Chiara Maria Mazzanti, Katia Zavaglia, Mohammad Al Hamad, Ivana Armogida & Generoso Bevilacqua

  2. Department of Biological Sciences, Faculty of Science, Yarmouk University, Irbid, 211-63, Jordan

    Mazhar Salim Al-Zoubi

  3. Manchester Breast Centre & Breakthrough Breast Cancer Research Unit, Paterson Institute for Cancer Research, Manchester Academic Health Science Centre, School of Cancer, Enabling Sciences and Technology, University of Manchester, Manchester, UK

    Michael P. Lisanti

  4. Department of Pathology and Laboratory Medicine, University of Dammam, Dammam, Saudi Arabia

    Mohammad Al Hamad

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  1. Mazhar Salim Al-Zoubi
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Correspondence to Mazhar Salim Al-Zoubi.

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Al-Zoubi, M.S., Mazzanti, C.M., Zavaglia, K. et al. Homozygous T172T and Heterozygous G135C Variants of Homologous Recombination Repairing Protein RAD51 are Related to Sporadic Breast Cancer Susceptibility. Biochem Genet 54, 83–94 (2016). https://doi.org/10.1007/s10528-015-9703-z

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  • DOI: https://doi.org/10.1007/s10528-015-9703-z

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