Menopausal age and XRCC1 gene polymorphisms: Role in breast cancer risk
Introduction
Breast cancer is the most prevalent common malignancy among women. For a substantial fraction of breast cancer cases, the age at the first child's birth, nulliparity, and family history are well-established risk factors, but in the majority of cases the cause of the disease is still obscure [1]. Several studies using functional measurements of DNA repair activity suggest that DNA repair capability is variable within human populations, leading to the hypothesis that this variation in the general population is a consequence of combinations of multiple alleles that show subtle variations in biological function [2]. The possible role for DNA repair deficiencies in cancer development, namely in breast cancer, has been the subject of increasing interest since it has been reported that breast cancer patients might be deficient in the repair of radiation-induced DNA damage [2].
Several recent studies aiming to identify polymorphic variants in DNA repair genes potentially associated with breast cancer suggest that variants in XRCC1, XRCC2, XRCC4, LIG4, RAD52, ERCC1, and BRCA2 genes [3], [4], [5], [6], [7] may be associated with individual susceptibility towards breast cancer. However, concerning the role of XRCC1 polymorphisms on breast cancer, the data published until now have not been conclusive [1], [2], [4], [8], [9], [10], [11], [12].
The XRCC1, one of the 20 genes that participate in the base excision repair pathway, has multiple roles in repairing DNA base damage and single-strand DNA breaks, related with the wide variety of non-bulky exogenous and endogenous base damage and single strand breaks [2], [13], [14], [15]. Although XRCC1 has no known enzymatic activity, it has three distinct domains that are sites for interaction with DNA polymerase β, poly(ADP-ribose) polymerase, and DNA ligase III, suggesting that XRCC1 may act as a nucleating factor in BER by bringing different components together at the site of action to promote the efficiency of the repair machinery. A number of single nucleotide polymorphisms (SNPs) in XRCC1 have been identified [2], [16]. These polymorphisms may alter BER proficiency and, in turn, confer genetic predisposition to breast cancer.
Since the data available concerning the role of XRCC1 polymorphisms on breast cancer risk has been contradictory [1], [2], [4], [8], [9], [10], [11], [12], we carried out an hospital based case–control study in a Caucasian Portuguese population in order to evaluate the potential modifying role of the XRCC1 polymorphisms R194W and R399Q on the individual susceptibility to breast cancer.
Section snippets
Study subjects
Healthcare services in Portugal are mainly public and generally assists the whole population, and breast cancer treatment units are located in all the major hospitals.
This study includes 241 Caucasian breast cancer female patients, recruited at São Francisco Xavier Hospital (Department of Laboratorial Medicine) between 2001 and 2005, without previous history of neoplastic disease, thyroid pathology, and blood transfusions. Histological diagnosis was confirmed in all the cases and includes 213
Results
The main characteristics of the case–control populations are listed in Table 2. There were no significant differences between cases and controls concerning age and frequencies of the XRCC1 polymorphisms. However, smokers and alcohol drinkers are more prevalent in the study population (the cases) than in control population. The results obtained concerning the frequency of the XRCC1 polymorphisms showed that the allelic frequencies of the wild-type Arg194Trp alleles are 0.94 and 0.91 for controls
Discussion
Since XRCC1 gene is involved in the repair of a wide variety of non-bulky exogenous, endogenous DNA base damage and single strand breaks, the role of the Arg194Trp and Arg399Gln XRCC1 gene polymorphisms have been studied concerning the effect of allelic variants in the levels of DNA lesion induced by environmental genotoxicants/carcinogens and also in the individual susceptibility for different kinds of cancer (for review, see [3], [19], [20]). The results previously reported concerning the
Conflict of interest
None.
Acknowledgements
We wish to thank Luísa Manso Oliveira, Lylliane Luz, Maria Catarina Soveral and Maria do Carmo Alves for technical support. Center for Research in Human Molecular Genetics (CIGMH), Projects POCTI/BIO/38922/2000 and POCTI/QUI/57110/2004 from Fundação da Ciência e Tecnologia (FCT), and Fundação Calouste Gulbenkian (Grant 69405) support our current research. The Ph.D. grant SFRH/BD/17828/2004 from FCT is also acknowledged.
References (33)
- et al.
XRCC1 genetic polymorphism and breast cancer risk
Pharmacogenetics
(2002) - et al.
Gene SNPs and mutations in clinical genetic testing: haplotype-based testing and analysis
Mutat Res
(2005) - et al.
Polymorphisms of XRCC1 and XRCC3 genes and susceptibility to breast cancer
Cancer Lett
(2003) - et al.
Micronuclei in humans induced by exposure to low level of ionizing radiation: influence of polymorphisms in DNA repair genes
Mutat Res
(2005) - et al.
Effects on sister chromatid exchange frequency of polymorphisms in DNA repair gene XRCC1 in smokers
Mutat Res
(2002) - et al.
From genotype to phenotype: correlating XRCC1 polymorphisms with mutagen sensitivity
DNA Repair (Amst)
(2003) - et al.
Micronuclei in EM9 cells expressing polymorphic forms of human XRCC1
Cancer Lett
(2005) XRCC1 and DNA strand break repair
DNA Repair (Amst)
(2003)- et al.
Association of the XRCC1 gene polymorphisms with cancer risk in Turkish breast cancer patients
Exp Mol Med
(2004) - et al.
Polymorphisms in the DNA repair gene XRCC1 and breast cancer
Cancer Epidemiol Biomarkers Prev
(2001)
Polymorphisms in DNA repair genes and associations with cancer risk
Cancer Epidemiol Biomarkers Prev
Variants in DNA double-strand break repair genes and breast cancer susceptibility
Hum Mol Genet
A potential role for the XRCC2 R188H polymorphic site in DNA-damage repair and breast cancer
Hum Mol Genet
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
Polymorphisms in the DNA repair gene XRCC1, breast cancer risk, and response to radiotherapy
Cancer Epidemiol Biomarkers Prev
Polymorphisms in XRCC1 modify the association between polycyclic aromatic hydrocarbon–DNA adducts, cigarette smoking, dietary antioxidants, and breast cancer risk
Cancer Epidemiol Biomarkers Prev
Cited by (42)
Association of damaging nsSNPs of XRCC1 with breast cancer
2017, Meta GeneIs organic farming safer to farmers' health? A comparison between organic and traditional farming
2014, Toxicology LettersCitation Excerpt :The GSTP1 codon 105 polymorphism was determined by PCR and RFLP according to the method of Harries et al. (1997), with minor modifications in Teixeira et al. (2004). XRCC1 codon 194 and 399 polymorphisms were genotyped by PCR followed by RFLP according to Silva et al. (2007). The genotyping of XRCC2 188Arg/His was also determined by PCR-RFLP as described by Bastos et al. (2009).
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
2013, Clinical Breast CancerCitation Excerpt :Additionally, the 194Trp variant was found to be significantly associated with benign breast disease, which is a risk factor for breast cancer and may have a heritable component.27 The analysis of the Arg194Trp polymorphism of the XRCC1 gene after stratification by menopausal status elucidated that heterozygous menopausal women with the 194Trp allele who were between 45 and 54 years of age were at increased risk for breast cancer.28 Several studies showed no association between the 194Trp allele and cancer risk.29-31
Genotoxic effects of occupational exposure to lead and influence of polymorphisms in genes involved in lead toxicokinetics and in DNA repair
2012, Environment InternationalCitation Excerpt :The genetic polymorphisms of ALAD (c.177 G > C, p.N59K, rs1800435) and vitamin D receptor (VDR) (c.1024 + 283 G > A, rs1544410) were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods described in García-Lestón et al. (2011). The XRCC1 (c.580 C > T, p.R194W, rs1799782; c.1196 G > A, p.R399Q, rs25487), XRCC2 (c.563 G > A, p.R188H, rs3218536) and XRCC3 (c.722 C > T, p.T241M, rs861539) genetic polymorphisms were analysed by PCR-RFLP as described in Silva et al. (2007) for XRCC1 polymorphisms, and in Bastos et al. (2009) for XRCC2 and XRCC3 polymorphisms. The following polymorphisms were genotyped by real-time PCR using TaqMan® SNP Genotyping Assays from Applied Biosystems (ABI Assays references are indicated for each polymorphism) following Gomes et al. (2010), Conde et al. (2009) and Silva et al. (2010): XRCC4 (c.894-7 G > A, rs1805377, C_11685997_10; c.401 T > C, p.I134T, rs28360135, C_25618660_10), LIG4 (c.26 C > T, p.T9I, rs1805388, C_11427969_20), XRCC5 (c.2199*841 G > A, rs2440, C_3231046_20; c.2199*323 T > C, rs1051677, C_8838367_1; c.2199*451 A > G, rs1051685, C_8838368_1), APE1 (c.444 T > G, p.D148E, rs1130409, C_8921503_10), MUTYH (c.1005 C > G, p.Q335H, rs3219489, C_27504565_10), PARP1 (c.2285 T > C, p.V762A, rs1136410, C_1515368_1), PARP4 (c.3982 C > A, p.P1328T, rs1050112, C_8700142_10), MPG (c.49 A > C, p.K17Q, rs3176383, C_32323403_10), OGG1 (c.977 C > G, p.S326C, rs1052133, C_3095552_1), RAD51 (c.1-61 G > T, rs1801321, C_7482700_10) and NBS1 (c.553 G > C, p.E185Q, rs1805794, C_26470398_10).