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Variants in DNA double-strand break repair genes and risk of familial breast cancer in a South American population

  • Epidemiology
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Abstract

The double-strand break (DSB) DNA repair pathway has been implicated in breast cancer (BC). RAD51 and its paralogs XRCC3 and RAD51D play an important role in the repair of DSB through homologous recombination (HR). Some polymorphisms including XRCC3-Thr241Met, RAD51-135G>C, and RAD51D-E233G have been found to confer increased BC susceptibility. In order to detect novel mutations that may contribute to BC susceptibility, 150 patients belonging to 150 Chilean BRCA1/2-negative families were screened for mutations in XRCC3. No mutations were detected in the XRCC3 gene. In addition, using a case–control design we studied the XRCC3-Thr241Met, and RAD51D-E233G polymorphisms in 267 BC cases and 500 controls to evaluate their possible association with BC susceptibility. The XRCC3 Met/Met genotype was associated with an increased BC risk (P = 0.003, OR = 2.44 [95%CI 1.34–4.43]). We did not find an association between E233G polymorphism and BC risk. We also analyzed the effect of combined genotypes among RAD51-135G>C, Thr241Met, and E233G polymorphisms on BC risk. No interaction was observed between Thr241Met and 135G>C. The combined genotype Thr/Met–E/G was associated with an increased BC risk among women who (a) have a family history of BC, (b) are BRCA1/2-negative, and (c) were <50 years at onset (n = 195) (P = 0.037, OR = 10.5 [95%CI 1.16–94.5]). Our results suggested that the variability of the DNA HR repair genes XRCC3 and RAD51D may play a role in BC risk, but this role may be underlined by a mutual interaction between these genes. These findings should be confirmed in other populations.

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References

  1. Jemal A, Siegel R, Ward E et al (2009) Cancer statistics, 2009. CA Cancer J Clin 59(4):225–249. doi:10.3322/caac.20006

    Article  PubMed  Google Scholar 

  2. Peralta O, Jorquera A, Rencoret C et al (1995) Cáncer de mama: resultados del programa de pesquisa y tratamiento del Servicio de Salud Central. Rev Chil Obstet Ginecol 60(6):417. doi:10.4067/S0717-75262002000600002

    Google Scholar 

  3. Departamento de Estadísticas e Información en Salud (2009) Mortalidad en mujeres, Chile, 2006. Ministerio de Salud de Chile. http://deis.minsal.cl/deis/salidas06/causas06.asp?temp=TODAS_EDADES_MUJ.htm. Accessed 04 Jan 2010

  4. Prieto M (2006) Situación epidemiológica del cáncer de mama en Chile 1994–2003. Rev Med Clin Condes 17(4):142–148

    Google Scholar 

  5. Easton D (2002) Familial risks of breast cancer. Breast Cancer Res 4(5):179–181. doi:10.1186/bcr448

    Article  PubMed  Google Scholar 

  6. Wooster R, Weber BL (2003) Breast and ovarian cancer. N Engl J Med 348(23):2339–2347. doi:10.1056/NEJMra012284

    Article  CAS  PubMed  Google Scholar 

  7. Thacker J (2005) The RAD51 gene family, genetic instability and cancer. Cancer Lett 219(2):125–135. doi:10.1016/j.canlet.2004.08.018

    Article  CAS  PubMed  Google Scholar 

  8. San Filippo J, Sung P, Klein H (2008) Mechanism of eukaryotic homologous recombination. Annu Rev Biochem 77:229–257. doi:10.1146/annurev.biochem.77.061306.125255

    Article  CAS  PubMed  Google Scholar 

  9. Kuschel B, Auranen A, McBride S 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 

  10. Levy-Lahad E, Lahad A, Eisenberg S et al (2001) A single nucleotide polymorphism in the RAD51 gene modifies cancer risk in BRCA2 but not BRCA1 carriers. Proc Natl Acad Sci USA 98(6):3232–3236

    Article  CAS  PubMed  Google Scholar 

  11. Wang WW, Spurdle AB, Kolachana P 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 Biomark Prev 10(9):955–960

    CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  13. Costa S, Pinto D, Pereira D 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(2):209–217. doi:10.1007/s10549-006-9364-z

    Article  CAS  PubMed  Google Scholar 

  14. Jacobsen NR, Nexo BA, Olsen A et al (2003) No association between the DNA repair gene XRCC3 T241M polymorphism and risk of skin cancer and breast cancer. Cancer Epidemiol Biomark Prev 12(6):584–585

    CAS  Google Scholar 

  15. Smith TR, Levine EA, Perrier ND et al (2003) DNA-repair genetic polymorphisms and breast cancer risk. Cancer Epidemiol Biomark Prev 12(11 Pt 1):1200–1204

    CAS  Google Scholar 

  16. Smith TR, Miller MS, Lohman K et al (2003) Polymorphisms of XRCC1 and XRCC3 genes and susceptibility to breast cancer. Cancer Lett 190(2):183–190. doi:10.1016/S0304-3835(02)00595-5

    Article  CAS  PubMed  Google Scholar 

  17. Figueiredo JC, Knight JA, Briollais L et al (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 Biomark Prev 13(4):583–591

    CAS  Google Scholar 

  18. Han J, Hankinson SE, Hunter DJ et al (2004) Genetic variations in XRCC2 and XRCC3 are not associated with endometrial cancer risk. Cancer Epidemiol Biomark Prev 13(2):330–331

    Article  CAS  Google Scholar 

  19. Forsti A, Angelini S, Festa F et al (2004) Single nucleotide polymorphisms in breast cancer. Oncol Rep 11(4):917–922

    PubMed  Google Scholar 

  20. Webb PM, Hopper JL, Newman B et al (2005) Double-strand break repair gene polymorphisms and risk of breast or ovarian cancer. Cancer Epidemiol Biomark Prev 14(2):319–323

    Article  CAS  Google Scholar 

  21. Rodriguez-Lopez R, Osorio A, Ribas G et al (2004) The variant E233G of the RAD51D gene could be a low-penetrance allele in high-risk breast cancer families without BRCA1/2 mutations. Int J Cancer 110(6):845–849. doi:10.1002/ijc.20169

    Article  CAS  PubMed  Google Scholar 

  22. Dowty JG, Lose F, Jenkins MA et al (2008) The RAD51D E233G variant and breast cancer risk: population-based and clinic-based family studies of Australian women. Breast Cancer Res Treat 112(1):35–39. doi:10.1007/s10549-007-9832-0

    Article  CAS  PubMed  Google Scholar 

  23. Jara L, Acevedo ML, Blanco R 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. doi:10.1016/j.cancergencyto.2007.05.024

    Article  CAS  PubMed  Google Scholar 

  24. Han S, Zhang HT, Wang Z et al (2006) DNA repair gene XRCC3 polymorphisms and cancer risk: a meta-analysis of 48 case-control studies. Eur J Hum Genet 14(10):1136–1144. doi:10.1038/sj.ejhg.5201681

    Article  CAS  PubMed  Google Scholar 

  25. Jara L, Ampuero S, Santibanez E et al (2006) BRCA1 and BRCA2 mutations in a South American population. Cancer Genet Cytogenet 166(1):36–45. doi:10.1016/j.cancergencyto.2005.08.019

    Article  CAS  PubMed  Google Scholar 

  26. Chomczynski P, Sacchi N (2006) The single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction: twenty-something years on. Nat Protoc 1(2):581–585. doi:10.1038/nprot.2006.83

    Article  CAS  PubMed  Google Scholar 

  27. Korkko J, Annunen S, Pihlajamaa TPD, Ala-Kokko L (1998) Conformation sensitive gel electrophoresis for simple and accurate detection of mutations: comparison with denaturing gradient gel electrophoresis and nucleotide sequencing. Proc Natl Acad Sci USA 95(4):1681–1685

    Article  CAS  PubMed  Google Scholar 

  28. Nataraj AJ, Olivos-Glander I, Kusukawa N et al (1999) Single-strand conformation polymorphism and heteroduplex analysis for gel-based mutation detection. Electrophoresis 20(6):1177–1185

    Article  CAS  PubMed  Google Scholar 

  29. Ganguly A (2002) An update on conformation sensitive gel electrophoresis. Hum Mutat 19(4):334–342. doi:10.1002/humu.10059

    Article  CAS  PubMed  Google Scholar 

  30. Perry DJ, Carrell RW (1992) Hydrolink gels—a rapid and simple approach to the detection of DNA mutations in thromboembolic disease. J Clin Pathol 45(2):158–160

    Article  CAS  PubMed  Google Scholar 

  31. Soto D, Sukumar S (1992) Improved detection of mutations in the p53 gene in human tumors as single-stranded conformation polymorphs and double-stranded heteroduplex DNA. Genome Res 2(1):96–98. doi:10.1101/gr.2.1.96

    Article  CAS  Google Scholar 

  32. Perkins EJ, Nair A, Cowley DO et al (2002) Sensing of intermediates in V(D)J recombination by ATM. Genes Dev 16(2):159–164

    Article  CAS  PubMed  Google Scholar 

  33. Araujo FD, Pierce AJ, Stark JM et al (2002) Variant XRCC3 implicated in cancer is functional in homology-directed repair of double-strand breaks. Oncogene 21(26):4176–4180. doi:10.1038/sj.onc.1205539

    Article  CAS  PubMed  Google Scholar 

  34. Garcia-Closas M, Egan KM, Newcomb PA et al (2006) Polymorphisms in DNA double-strand break repair genes and risk of breast cancer: two population-based studies in USA and Poland, and meta-analyses. Hum Genet 119(4):376–388. doi:10.1007/s00439-006-0135-z

    Article  CAS  PubMed  Google Scholar 

  35. Breast Cancer Association Consortium (2006) Commonly studied single-nucleotide polymorphisms and breast cancer: results from the Breast Cancer Association Consortium. J Natl Cancer Inst 98(19):1382–1396. doi:10.1093/jnci/djj374

    Article  Google Scholar 

  36. Cruz-Coke R (1976) Origen y evolución étnica de la población chilena. Rev Med Chile 101:365–368

    Google Scholar 

  37. Valenzuela CY, Harb Z (1977) Socioeconomic assortative mating in Santiago, Chile: as demonstrated using stochastic matrices of mother-child relationships applied to ABO blood groups. Soc Biol 24:225–233

    CAS  PubMed  Google Scholar 

  38. Valenzuela CY, Acuña M, Harb Z (1987) Gradiente sociogenético en la población chilena. Rev Med Chile 115:295–299

    CAS  PubMed  Google Scholar 

  39. Valenzuela CY (1988) On sociogenetic clines. Ethol Sociobiol 9(5):259–268

    Article  Google Scholar 

  40. Wang Y, Liang D, Spitz MR et al (2003) XRCC3 genetic polymorphism, smoking, and lung carcinoma risk in minority populations. Cancer 98(8):1701–1706. doi:10.1002/cncr.11692

    Article  CAS  PubMed  Google Scholar 

  41. Schwartz GF, Hughes KS, Lynch HT et al (2008) Proceedings of the international consensus conference on breast cancer risk, genetics, & risk management, April, 2007. Cancer 113(10):2627–2637. doi:10.1002/cncr.23903

    Article  PubMed  Google Scholar 

  42. Krupa R, Synowiec E, Pawlowska E et al (2009) Polymorphism of the homologous recombination repair genes RAD51 and XRCC3 in breast cancer. Exp Mol Pathol 87(1):32–35. doi:10.1016/j.yexmp.2009.04.005

    Article  CAS  PubMed  Google Scholar 

  43. Manuguerra M, Saletta F, Karagas MR et al (2006) XRCC3 and XPD/ERCC2 single nucleotide polymorphisms and the risk of cancer: a HuGE review. Am J Epidemiol 164(4):297–302. doi:10.1093/aje/kwj189

    Article  PubMed  Google Scholar 

  44. Nadkarni A, Furda A, Rajesh C et al (2009) Functional characterization of the RAD51D E233G genetic variant. Pharmacogenet Genomics 19(2):153–160. doi:10.1097/FPC.0b013e32831db2fd

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

Grant support: FONDECYT 1060094, Corporación Nacional del Cáncer (CONAC).

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Authors and Affiliations

  1. Human Genetics Program, Institute of Biomedical Sciences (ICBM), School of Medicine, University of Chile, Av. Independencia 1027, P.O. Box 70061, Santiago, Chile

    Lilian Jara, Karen Dubois, Daniel Gaete, Tomas de Mayo, Nikalai Ratkevicius, Rafael Blanco & Patricio González-Hormazábal

  2. National Cancer Society (Corporación Nacional del Cáncer—CONAC), Capellan Abarzua 027, Santiago, Chile

    Teresa Bravo

  3. School of Medicine and Clínica Alemana, Universidad del Desarrollo, Av. Las Condes 12438, Santiago, Chile

    Sonia Margarit

  4. Clínica Santa María, Santiago, Chile

    Fernando Gómez & Enrique Waugh

  5. Department of Gynaecology and Obstetrics, School of Medicine, University of Chile, Av Santa Rosa 1234, Santiago, Chile

    Octavio Peralta

  6. Clínica Las Condes, Lo Fontecilla 441, Santiago, Chile

    Octavio Peralta & Jose M. Reyes

  7. Clínica Dávila, Av. Recoleta 464, Santiago, Chile

    Gladys Ibáñez

  8. Hospital San José, San José 1196, Santiago, Chile

    Gladys Ibáñez

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  1. Lilian Jara
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Correspondence to Lilian Jara.

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Jara, L., Dubois, K., Gaete, D. et al. Variants in DNA double-strand break repair genes and risk of familial breast cancer in a South American population. Breast Cancer Res Treat 122, 813–822 (2010). https://doi.org/10.1007/s10549-009-0709-2

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  • DOI: https://doi.org/10.1007/s10549-009-0709-2

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