Abstract
Purpose
RAD51, a central player in the response to DNA damage, has been suspected to contribute to tumour resistance to therapy. A single-nucleotide polymorphism, RAD51 135G>C, in the untranslated region of the RAD51 gene elevates breast cancer risk among BRCA2 carriers. In this study, it was investigated whether this polymorphism is related to prognosis of breast cancer and RAD51 protein expression and whether it is indicative of resistance to radiotherapy or cyclophosphamide/methotrexate/5-fluorouracil (CMF) chemotherapy.
Patients and methods
We genotyped 306 patients with early breast cancer, who were randomised to receive post-operative radiotherapy or CMF chemotherapy, for the RAD51 135G>C polymorphism. RAD51 protein expression was evaluated with immunohistochemistry.
Results
15.4 % of the patients had at least one C-allele (three were C homozygotes). There was no correlation between genotype and protein expression. Patients who were G homozygotes benefitted from radiotherapy with decreased risk of local recurrences (RR = 0.32, 95 % C.I. 0.16–0.64, p = 0.001). CMF chemotherapy reduced the risk of distant recurrence for patients carrying at least one C-allele (RR = 0.29, 95 % C.I. 0.10–0.88, p = 0.03), whereas G homozygotes had no benefit from chemotherapy. There was a significant interaction between chemotherapy and genotype (p = 0.02).
Conclusion
The results suggest that the RAD51 135G>C polymorphism predicts CMF chemotherapy effect in early breast cancer.
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References
Antoniou AC, Sinilnikova OM, Simard J 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 81:1186–1200
Clarke M, Collins R, Darby S et al (2005) Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet 366:2087–2106
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 103:209–217
Graeser M, McCarthy A, Lord CJ et al (2010) A marker of homologous recombination predicts pathologic complete response to neoadjuvant chemotherapy in primary breast cancer. Clin Cancer Res 16:6159–6168
Hannay JA, Liu J, Zhu QS et al (2007) Rad51 overexpression contributes to chemoresistance in human soft tissue sarcoma cells: a role for p53/activator protein 2 transcriptional regulation. Mol Cancer Ther 6:1650–1660
Hansen LT, Lundin C, Spang-Thomsen M et al (2003) The role of RAD51 in etoposide (VP16) resistance in small cell lung cancer. Int J Cancer 105:472–479
Hasselbach L, Haase S, Fischer D et al (2005) Characterisation of the promoter region of the human DNA-repair gene Rad51. Eur J Gynaecol Oncol 26:589–598
Henning W, Sturzbecher HW (2003) Homologous recombination and cell cycle checkpoints: Rad51 in tumour progression and therapy resistance. Toxicology 193:91–109
Huang F, Mazin AV (2014) A small inhibitor of human RAD51 potentiates breast cancer cell killing by therapeutic agents in mouse xenografts. PLoS One 9:e100993. doi:10.1371/journal.pone.0100993
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 178:65–69
Kadouri L, Kote-Jarai Z, Hubert A 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 90:2002–2005
Lee KM, Choi JY, Kang C et al (2005) Genetic polymorphisms of selected DNA repair genes, estrogen and progesterone receptor status, and breast cancer risk. Clin Cancer Res 11:4620–4626
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 98:3232–3236
Maacke H, Opitz S, Jost K et al (2000) Over-expression of wild-type Rad51 correlates with histological grading of invasive ductal breast cancer. Int J Cancer 88:907–913
Nogueira A, Catarino R, Coelho A et al (2010) Influence of DNA repair RAD51 gene variants in overall survival of non-small cell lung cancer patients treated with first line chemotherapy. Cancer Chemother Pharmacol 66:501–506
Ohnishi T, Taki T, Hiraga S et al (1998) In vitro and in vivo potentiation of radiosensitivity of malignant gliomas by antisense inhibition of the RAD51 gene. Biochem Biophys Res Commun 245:319–324
Raderschall E, Stout K, Freier S et al (2002) Elevated levels of Rad51 recombination protein in tumor cells. Cancer Res 62:219–225
Rutqvist LE, Johansson H (2006) Long-term follow-up of the Stockholm randomized trials of postoperative radiation therapy versus adjuvant chemotherapy among ‘high risk’ pre- and postmenopausal breast cancer patients. Acta Oncol 45:517–527
Shin A, Lee K-M, Ahn B et al (2008) Genotype-phenotype relationship between DNA repair gene genetic polymorphisms and DNA repair capacity. Asian Pac J Cancer Prev 9:501–505
Slupianek A, Hoser G, Majsterek I et al (2002) Fusion tyrosine kinases induce drug resistance by stimulation of homology-dependent recombination repair, prolongation of G(2)/M phase, and protection from apoptosis. Mol Cell Biol 22:4189–4201
Soderlund K, Skoog L, Fornander T, Askmalm MS (2007) The BRCA1/BRCA2/Rad51 complex is a prognostic and predictive factor in early breast cancer. Radiother Oncol 84:242–251
Vispe S, Cazaux C, Lesca C, Defais M (1998) Overexpression of Rad51 protein stimulates homologous recombination and increases resistance of mammalian cells to ionizing radiation. Nucl Acids Res 26:2859–2864
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 Biomarkers Prev 10:955–960
Yang Z, Waldman A, Wyatt MD (2012) Expression and regulation of RAD51 mediate cellular responses to chemotherapeutics. Biochem Pharmacol 83(6):741–746
Yu KD, Yang C, Fan L 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 126:365–371
Zhou GW, Hu J, Peng XD et al (2011) RAD51 135G>C polymorphism and breast cancer risk: a meta-analysis. Breast Cancer Res Treat 125:529–535
Acknowledgments
We are thankful to Birgit Olsson for valuable advice and skilful technical assistance. We also thank Najme Wall and Jan Olofsson for classifying the tumours according to the Nottingham grading system and Lambert Skoog for sharing his knowledge on breast tumour pathology. This work was supported by grants from the Swedish Cancer Society to M.S.A.
Conflict of interest
We declare that we have no conflict of interest.
Informed consent
Patients have given their informed consent regarding participation in the randomised study. The use of human tissue for retrospective analysis of prognostic and predictive factors was approved by the Local Ethics Committee.
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Söderlund Leifler, K., Asklid, A., Fornander, T. et al. The RAD51 135G>C polymorphism is related to the effect of adjuvant therapy in early breast cancer. J Cancer Res Clin Oncol 141, 797–804 (2015). https://doi.org/10.1007/s00432-014-1859-0
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DOI: https://doi.org/10.1007/s00432-014-1859-0