The Value Study Of Genes Of Base Excision Repair In Diagnosis And Prognosis Of Breast Cancer

ObjectivesAs a commonly exist process, base excision repair pathway is responsible for thousands of DNA damages in cells from bacteria to human beings. It is one of the major repair pathways for DNA basic damages caused by reactive oxygen species(ROS), alkylating agents and ionizing radiation. Researches found the deficiency of BER would induce the accumulation of DNA damages, thus leading to gene deletion or mutation. The association between key repair gene polymorphisms and human diseases were also widely reported. This research studied the relationships of key genes in BER with carcinogenesis as well as development from protein and gene aspects, to reveal its expression patterns and sensitive population characteristics. This research hoped to provide experimental evidences for sensitive population screening and anti-cancer therapy optimization.MethodsThis program consisted of two parts. In the first part, the peripheral blood samples from 194 breast cancer patients and 245 cancer-free controls were collected, and the whole blood DNA was extracted. The PCR-CTPP(Polymerase chain reaction with confronting two-pair primers) was conducted to analyze the associations of breast cancer susceptibility with four single nucleotide polymorphisms in three BER genes(OGG1Ser326Cys, APE1Asp148 Glu,-141T/G in the promoter region and XRCC1Arg399Gln). In the second part, APE1, PARP1 and BRCA1 expression in 60 triple-negative breast cancer tissues were evaluated by IHC. The expression patterns of these 3 proteins were observed and the relationship between their expression levels and the clinical characteristics was analyzed.ResultsThe subjects carrying the XRCC1 Arg/Gln genotype or Gln/Gln genotype showed a higher risk than subjects carrying the Arg/Arg genotype(Adjusted OR: 1.529, 95% CI:1.012~2.310,P=0.044 for Arg/Gln; Adjusted OR: 2.189, 95% CI:1.063~4.507,P=0.033 for Gln/Gln). Among subjects with a BMI lower than the 24 kg/m2, carriers of OGG1 Cys allele showed a significantly decrease of breast cancer risk(Adjusted OR: 0.426, 95% CI:0.2~0.905,P=0.027 for Ser/Cys; Adjusted OR: 0.323, 95% CI:0.146~0.715,P=0.005 for Cys/Cys). Among the post-menopause population, carriers of XRCC1 Arg/Glu genotype showed a significant increase on breast cancer susceptibility(Adjusted OR: 1.848, 95% CI:1.084~3.153,P=0.024 for Arg/Gln). The multi-variant analysis suggested that compared with zero risk allele subjects, subjects with more than 2 risk alleles had a higher risk of breast cancer(Adjusted OR: 2.183, 95% CI:1.095~4.353,P=0.027). In the second part of our research, PARP1 expression was an apparent difference in axillary lymph node metastasis. Compared with no ALMN metastasis, PARP1 showed a higher expression in patients with ALMN metastasis(P=0.009). APE1 and BRCA1 expression were different along with differentiation. The tissues with poor differentiation had a higher expression of APE1(P=0.027) but a less expression of BRCA1(P=0.017). The correlation analysis indicated a positive relationship between APE1 and PARP1(r=0.489, P < 0.001). The survival analysis revealed a significantly shorter survival time in APE1 positive expression patients, compared with negative expression patients(P=0.038), especially when they were also positive in PAPR1. The cox regression suggested that age, ALMN metastasis, poor differentiation and APE1 expression were the independent prognostic factors in triple-negative breast cancer, which would result in a remarkably decrease in patient survival.ConclusionsXRCC1 Arg399 Gln polymorphisms were related with breast cancer susceptibility, and OGG1 Ser326 Cys polymorphisms would decrease the risk of breast cancer among population with a BMI lower than 24 kg/m2. In triple-negative breast cancer tissues, APE1 was positively correlated with PARP1. Combination detection may help on the diagnosis and prognosis evaluation to triple-negative breast cancer. The survival analysis showed that patients with high expression of APE1 had a shorter survival time and APE1 was one of the independent risk factor for TP breast cancer prognosis.