Menopausal age and XRCC1 gene polymorphisms: Role in breast cancer risk

https://doi.org/10.1016/j.cdp.2007.07.001Get rights and content

Abstract

Background: Recent evidence that some DNA-repair functions are haploinsufficient adds weight to the notion that variants in DNA-repair genes constitute part of the spectrum of defects contributing to cancer risk. X-ray repair cross-complementing group 1 gene (XRCC1) is involved in base excision repair (BER) pathway, acting on spontaneous and induced DNA damage. This gene encodes for a scaffolding protein that brings together different proteins involved in the repair process. Among the non-synonymous polymorphisms in XRCC1 gene, codons 194 and 399 lead to amino acid changes at evolutionary conserved regions, and seem to alter the efficiency of the protein. Methods: A hospital based case–control study was carried out in a Caucasian Portuguese population (241 cancer patients and 457 controls matched for sex and age) in order to evaluate the potential modifying role of the XRCC1 polymorphisms on the individual susceptibility to breast cancer. Results: Our data did not reveal a positive association between the polymorphisms individually and breast cancer, or with the combination of the different genotypic associations. However, after stratification to the menopausal status, it was observed that carriers of the Gln/Gln genotype of the R399Q polymorphism with a menopausal age above 55 years are at increased risk for breast cancer (OR = 4.074; CI = 1.562–10.626; P = 0.004). Concerning the Arg194Trp polymorphism, after stratification by menopausal status, it was observed that heterozygous individuals (Arg/Trp) with a menopausal age between 45 and 54 are at increased risk for breast cancer (adjusted OR = 1.964; CI = 1.174–3.288; P = 0.01) as well as carriers of the variant allele (Arg/Trp + Trp/Trp) (adjusted OR = 1.932; CI = 1.156–3.228; P = 0.012). Conclusions: Our results suggest that menopausal age together with Arg194Trp and Arg399Gln XRCC1 gene polymorphisms might be involved in individual susceptibility to breast cancer.

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.

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