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Clinical and Translational Oncology

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01-02-2014 | Research Article

Role of XRCC3, XRCC1 and XPD single-nucleotide polymorphisms in survival outcomes following adjuvant chemotherapy in early stage breast cancer patients

Authors: E. Castro, D. Olmos, A. Garcia, J. J. Cruz, R. González-Sarmiento

Published in: Clinical and Translational Oncology | Issue 2/2014

Abstract

Introduction

Anthracyclines have various mechanisms of action that in the end lead to DNA double-strand breaks. Single-nucleotide polymorphisms (SNPs) in DNA repair genes may alter the protein function, affecting DNA repair proficiency and, therefore, the efficiency of DNA damaging chemotherapy. We have analysed whether SNPs in DNA repair genes (XRCC1, XRCC3 and XPD) could be useful to predict the response to anthracyclines in patients with early-stage breast cancer (EBC).

Methods

Peripheral blood samples from 150 patients with EBC were used for genotyping XRCC3Thr241Met, XRCC1Arg399Gln and XPDLys751Gln. Genotypes were correlated with survival outcomes.

Results

Eighty-four patients received treatment with chemotherapy regimens containing anthracyclines. In this group, patients with XRCC1Arg399Arg had a significant improvement in 5-year Disease Free Survival (DFS) compared with those with the Arg/Gln and Gln/Gln variants (84 vs 46 %, p = 0.026). In the multivariate analysis, XRCC1Arg399Arg was reported as an independent prognostic factor for DFS (HR 0.4, CI-95 % 0.2–0.9, p = 0.035). Patients with the XRCC3 Met241Met genotype presented better 5-year OS than those carrying the Thr/Thr and Met/Thr variants (100 vs 70 %, p = 0.030). A multivariate analysis for OS confirmed the independent prognostic value of XRCC3 Met241Met (HR 0.15, CI-95 % 0.02–0.90, p = 0.048). These differences were not significant when patients receiving other chemotherapy treatments, different from anthracyclines, were also considered (n = 150). XPDLys751Lys was associated with older age at diagnosis than the Lys/Gln and Gln/Gln genotypes (65 vs 58 years, p < 0.0001).

Conclusions

XRCC3Thr241Met and XRCC1Arg399Gln may be predictive of survival outcome in EBC patients treated with anthracycline-based chemotherapy regimens.

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Ferlay J, Autier P, Boniol M, Heanue M, Colombet M, Boyle P. Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol. 2007;18(3):581–92.PubMedCrossRef

Autier P, Boniol M, La Vecchia C, Vatten L, Gavin A, Hery C, et al. Disparities in breast cancer mortality trends between 30 European countries: retrospective trend analysis of WHO mortality database. BMJ. 2010;341:c3620.PubMedCentralPubMedCrossRef

Siegel R, DeSantis C, Virgo K, Stein K, Mariotto A, Smith T, et al. Cancer treatment and survivorship statistics. CA Cancer J Clin. 2010;62(4):220–41.CrossRef

Di Marco A, Silvestrini R, Di Marco S, Dasdia T. Inhibiting effect of the new cytotoxic antibiotic daunomycin on nucleic acids and mitotic activity of HeLa cells. J Cell Biol. 1965;27(3):545–50.PubMedCrossRef

Feinstein E, Canaani E, Weiner LM. Dependence of nucleic acid degradation on in situ free-radical production by Adriamycin. Biochemistry. 1993;32(48):13156–61.PubMedCrossRef

Skladanowski A, Konopa J. Interstrand DNA crosslinking induced by anthracyclines in tumour cells. Biochem Pharmacol. 1994;47(12):2269–78.PubMedCrossRef

Swift LP, Rephaeli A, Nudelman A, Phillips DR, Cutts SM. Doxorubicin-DNA adducts induce a non-topoisomerase II-mediated form of cell death. Cancer Res. 2006;66(9):4863–71.PubMedCrossRef

Sinha BK, Mimnaugh EG, Rajagopalan S, Myers CE. Adriamycin activation and oxygen free radical formation in human breast tumor cells: protective role of glutathione peroxidase in Adriamycin resistance. Cancer Res. 1989;49(14):3844–8.PubMed

Tewey KM, Rowe TC, Yang L, Halligan BD, Liu LF. Adriamycin-induced DNA damage mediated by mammalian DNA topoisomerase II. Science. 1984;226(4673):466–8.PubMedCrossRef

10.

Zunino F, Gambetta R, Di Marco A, Zaccara A, Luoni G. A comparison of the effects of daunomycin and Adriamycin on various DNA polymerases. Cancer Res. 1975;35(3):754–60.PubMed

11.

Hoeijmakers JH. Genome maintenance mechanisms for preventing cancer. Nature. 2001;411(6835):366–74.PubMedCrossRef

12.

Munro AF, Cameron DA, Bartlett JM. Targeting anthracyclines in early breast cancer: new candidate predictive biomarkers emerge. Oncogene. 2010;29(38):5231–40.PubMedCrossRef

13.

Saffi J, Agnoletto MH, Guecheva TN, Batista LF, Carvalho H, Henriques JA, et al. Effect of the anti-neoplastic drug doxorubicin on XPD-mutated DNA repair-deficient human cells. DNA Repair (Amst). 2010;9(1):40–7.PubMedCrossRef

14.

Spencer DM, Bilardi RA, Koch TH, Post GC, Nafie JW, Kimura K, et al. DNA repair in response to anthracycline-DNA adducts: a role for both homologous recombination and nucleotide excision repair. Mutat Res. 2008;638(1–2):110–21.PubMedCrossRef

15.

Au WW, Salama SA, Sierra-Torres CH. Functional characterization of polymorphisms in DNA repair genes using cytogenetic challenge assays. Environ Health Perspect. 2003;111(15):1843–50.PubMedCentralPubMedCrossRef

16.

Vodicka P, Kumar R, Stetina R, Sanyal S, Soucek P, Haufroid V, et al. Genetic polymorphisms in DNA repair genes and possible links with DNA repair rates, chromosomal aberrations and single-strand breaks in DNA. Carcinogenesis. 2004;25(5):757–63.PubMedCrossRef

17.

Vodicka P, Stetina R, Polakova V, Tulupova E, Naccarati A, Vodickova L, et al. Association of DNA repair polymorphisms with DNA repair functional outcomes in healthy human subjects. Carcinogenesis. 2007;28(3):657–64.PubMedCrossRef

18.

Synowiec E, Stefanska J, Morawiec Z, Blasiak J, Wozniak K. Association between DNA damage, DNA repair genes variability and clinical characteristics in breast cancer patients. Mutat Res. 2008;648(1–2):65–72.PubMedCrossRef

19.

Bewick MA, Conlon MS, Lafrenie RM. Polymorphisms in XRCC1, XRCC3, and CCND1 and survival after treatment for metastatic breast cancer. J Clin Oncol. 2006;24(36):5645–51.PubMedCrossRef

20.

Han S, Zhang HT, Wang Z, Xie Y, Tang R, Mao Y, et al. DNA repair gene XRCC3 polymorphisms and cancer risk: a meta-analysis of 48 case-control studies. Eur J Hum Genet. 2006;14(10):1136–44.PubMedCrossRef

21.

Li H, Ha TC, Tai BC. XRCC1 gene polymorphisms and breast cancer risk in different populations: a meta-analysis. Breast. 2009;18(3):183–91.PubMedCrossRef

22.

Clarkson SG, Wood RD. Polymorphisms in the human XPD (ERCC2) gene, DNA repair capacity and cancer susceptibility: an appraisal. DNA Repair (Amst). 2005;4(10):1068–74.PubMedCrossRef

23.

Li C, Jiang Z, Liu X. XPD Lys(751)Gln and Asp (312)Asn polymorphisms and bladder cancer risk: a meta-analysis. Mol Biol Rep. 2010;37(1):301–9.PubMedCrossRef

24.

Ye W, Kumar R, Bacova G, Lagergren J, Hemminki K, Nyren O. The XPD 751Gln allele is associated with an increased risk for esophageal adenocarcinoma: a population-based case-control study in Sweden. Carcinogenesis. 2006;27(9):1835–41.PubMedCrossRef

25.

Manuguerra M, Saletta F, Karagas MR, Berwick M, Veglia F, Vineis P, et al. XRCC3 and XPD/ERCC2 single nucleotide polymorphisms and the risk of cancer: a HuGE review. Am J Epidemiol. 2006;164(4):297–302.PubMedCrossRef

26.

Sun H, Qiao Y, Zhang X, Xu L, Jia X, Sun D, et al. XRCC3 Thr241Met polymorphism with lung cancer and bladder cancer: a meta-analysis. Cancer Sci. 2010;101(8):1777–82.PubMedCrossRef

27.

Nowosielska A, Marinus MG. Cisplatin induces DNA double-strand break formation in Escherichia coli dam mutants. DNA Repair (Amst). 2005;4(7):773–81.PubMedCrossRef

28.

de las Penas R, Sanchez-Ronco M, Alberola V, Taron M, Camps C, Garcia-Carbonero R, et al. Polymorphisms in DNA repair genes modulate survival in cisplatin/gemcitabine-treated non-small-cell lung cancer patients. Ann Oncol. 2006;17(4):668–75.CrossRef

29.

Krupa R, Synowiec E, Pawlowska E, Morawiec Z, Sobczuk A, Zadrozny M, et al. Polymorphism of the homologous recombination repair genes RAD51 and XRCC3 in breast cancer. Exp Mol Pathol. 2009;87(1):32–5.PubMedCrossRef

30.

Rodriguez AA, Makris A, Wu MF, Rimawi M, Froehlich A, Dave B, et al. DNA repair signature is associated with anthracycline response in triple negative breast cancer patients. Breast Cancer Res Treat. 2010;123(1):189–96.PubMedCrossRef

Title: Role of XRCC3, XRCC1 and XPD single-nucleotide polymorphisms in survival outcomes following adjuvant chemotherapy in early stage breast cancer patients
Authors: E. Castro
D. Olmos
A. Garcia
J. J. Cruz
R. González-Sarmiento
Publication date: 01-02-2014
Publisher: Springer Milan
Published in: Clinical and Translational Oncology / Issue 2/2014
Print ISSN: 1699-048X
Electronic ISSN: 1699-3055
DOI: https://doi.org/10.1007/s12094-013-1055-8

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Abstract

Introduction

Methods

Results

Conclusions

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