Genetic polymorphisms in APE1 Asp148Glu(rs3136820) as a modifier of the background levels of abasic sites in human leukocytes derived from breast cancer patients and controls.

Abstract

Apurinic/apyrimidinic (abasic/AP) sites are among the most common endogenous DNA lesions. AP sites, if not repaired, could result in genomic instability as well as chromosome aberrations. Information regarding the direct assay of the number of abasic sites in human leukocytes and its association with risk of breast cancer has not been reported. In this study, we investigated the association between certain risk factors for breast cancer and the background levels of AP sites in leukocytes derived from 148 Taiwanese women with breast cancer and 140 cancer-free controls. The risk factors studied include age, body mass index (BMI), and polymorphisms of apurinic/apyrimidinic endonuclease (APE1) [APE1 Asp148Glu(rs3136820)]. Mean levels of AP sites were estimated to be 23.3 and 50.3 per 106 nucleotides in controls and breast cancer patients, respectively (~twofold, p<0.001). In subjects with age<50 or BMI<27 (kg/m2), the levels of AP sites in breast cancer patients were~2-3-fold greater than those of controls (p<0.05). Additionally, results from the AP site 3'-cleavage assay indicated that the AP sites detected in both controls and patients were likely to be oxidant-mediated 5'-cleaved AP sites (~61-64%). The number of AP sites in breast cancer patients was~twofold greater in subjects with Asp/Glu+Glu/Glugenotypes than those with Asp/Asp genotype (p<0.001). We confirmed that cumulative body burden of AP sites is a significant predictor of the risk of developing breast cancer and that genetic predisposition and environment factors may modulate the induction of oxidative DNA lesions in breast cancer patients.