XRCC1 Arg399Gln and RAD51 5′UTR G135C polymorphisms and their outcome in tumor aggressiveness and survival of Portuguese breast cancer patients

Abstract

Breast cancer (BC) is the most common type of cancer in female, including Portugal, where this disease presents the highest incidence and mortality rates [1]. BC risk factors, like prolonged exposure to estrogen and/or ionizing radiation, BRCA1, BRCA2, TP53, ATM and CHEK2 mutations [2, 3], are related with an increased chance of DNA damage, acting as initiators of cellular alterations. DNA repair pathways are critical processes in order to maintain genome integrity. Therefore, genetic polymorphisms in DNA repair genes are common events [4]. We previously showed correlations of some of these genetic variations, as XRCC1 Arg399Gln, RAD51 5’UTR G135C and XRCC3 Thr241Met, with changeable BC susceptibility [5]. In the present study, we aimed to investigate the possible correlations between DNA repair polymorphisms with BC clinico-pathological phenotypes, identifying subgroups of patients according to their genetic background. We analysed DNA from 165 BC patients, including 33 unrelated family history (FH) and 132 sporadic BC cases from Surgical Departments of S. Joao Hospital and the Oncology Portuguese Institute, at Porto. All participants provided informed consent. Patients presented a mean age of 51.01 years (standard deviation (SD) ± 12.68). We determined XRCC1 Arg399Gln, RAD51 5’0UTR G135C and XRCC3 Thr241Met genotypes by PCR-RFLP technique, as previously described [5]. Chi-square (v test) analysis was used to compare different variables. Logistic regression analysis was applied to calculate the adjusted p value for age and FH in identification of subgroups of patients according to genotypes. The Kaplan-Meier method was used to estimate overall survival (OS). OS was defined as minimal 60 months follow-up, from clinical diagnosis until death or censorship (were alive at the end of the follow-up time period). Differences on OS were obtained by Log Rank test. The correlation of the analysed DNA repair polymorphisms with some clinical-pathological features is presented in Table 1. According to our results, XRCC1 Gln/Gln genotype seems to be associated with less aggressive tumors, since this genotype was correlated with well differentiated tumors (p = 0.022 adjusted for age and BC FH, using logistic regression analysis). Deficient efficiency of the XRCC1 protein has been described in XRCC1 Gln399 variant [6, 7]. Furthermore, repair of more complex base lesions [8, 9, 10] by base excision repair (BER) pathway can potentially convert S. Costa ICVS, Life and Health Sciences Research Institute, Health Science School, Minho University, 4710-057, Braga, Portugal