Association Of BRCA1/TopBP1 Expression And Efficacy Of Platinum-based Chemotherapy In Non-small Cell Lung Cancer

Background:Lung cancer is a malignant tumor with high incidence and mortality. Approximately 85% of all cases present with non-small cell lung cancer (NSCLC), most of which have already been at an advanced stage when diagnosed, thus cannot benefit from surgery. Although the widely used first-line chemotherapeutic regimens, which consist of a third-generation cytotoxic compound (eg, gemcitabine, docetaxel or vinorelbine) and a platinum agent (eg, cisplatin or carboplatin), can improve clinical outcomes of advanced NSCLC patients, only 20%-40% patients have response to it, and the overall 5-year survival rate is below 15%. Furthermore,this therapeutic regimen has entered a plateau.Thus,drug resistance is the important cause of the failure of the chemotherapy.DNA repair genes present in cells have specific repair capacities for particular types of DNA damage. In tumor therapy, abnormal high capacity of DNA damage repair is closely related with the formation of anti-tumor drug resistance. Platinum is an indispensable drug for the standard treatment of non-small cell lung cancer (NSCLC). Platinum binds to nucleophilic DNA of cells, leading to cross-linking of interstrand or intrastrand DNA and thereby resulting in cell death. Tumor cells with high repair capacity are more prone to chemotherapy resistance, suggesting that the expression of DNA repair genes may serve as a relatively ideal predictor of chemotherapeutic resistance.Breast cancer susceptibility gene 1 (BRCA1) is located in chromosome 17q12-21 and is a tumor suppressor gene, which arrests the cell cycle at the G/M phase and induces apoptosis. BRAC1 regulates DNA repair by directly interacting with other repair genes or by regulating the expression of genes in the DNA regulatory pathway. Therefore, BRCA1 is an important negative regulator of the cell cycle. A previous study showed that the upregulated expression of BRCA1 increases resistance to cisplatin, suggesting that high BRCA1 expression enhances cell repair capacity, thereby preventing cancer cells from being killed by chemotherapy, ultimately resulting in drug resistance. Cancer cells with low BRCA1 expression are less likely to develop platinum-resistance, thereby increasing the chances of effective chemotherapy.Topoisomerase Ⅱβ binding protein 1 (TopBP1) and BRCA1 are structurally homologous, both presenting eight BRCA1 carboxyl terminus (BRCT) functional domains within the TopBPl protein. The functional domain of BRCT can combine with other BRCT functional domains, non-BRCT functional domains, and DNA fragments that regulate DNA damage repair and cell cycle progression. TopBPl interacts with a variety of proteins and specific binding domains, thus conferring multiple functions for the maintenance of genomic stability.Detection and screening of gene and protein biomarkers in patients or populations who have received the highest benefit from clinical treatments has helped in the design of effective individual therapies for NSCLC patients. To further assess the association between expression of BRCA1 and TopBP1 and clinical outcome of NSCLC patients, we conducted a prospective study involving a series of NSCLC cases treated with platinum-based chemotherapy.Objective: To explore BRCA1 and TopBPl expressions are associated with clinical outcome of non-small cell lung cancer treated with platinum-based chemotherapy.Methods:Clinical data of non-small cell lung cancer treated with platinum-based chemotherapy admitted to our hospital from January 2008 to December 2012 were collected and reviewed. Expression levels of BRCA1 and TopBPl were detected by method of immunohistochemistry, evaluation of BRCA1 and TopBPl expression and NSCLC the correlation of clinical features, With Kaplan Meier survival curve and Cox proportion hazards regression was conducted to assess the effects of BRCA1 and TopBP1 proteins expression on PFS and OS of NSCLC.Results:Analysis revealed that BRCA1 expression was significantly associated with that of TopBPl in this set of Chinese patients with NSCLC (P<0.001, r=0.326). There was no significant correlation of BRCA1 and TopBP1 gene expression with gender, age, smoking status, clinical stages and histological types of patients (P>0.05). Negative of BRCA1 were associated with longer OS time when compared with Positive (Median OS 34 vs.21 months, P=0.011), and the adjusted HRs (95%CI) for OS were 1.913(1.161-3.150), respectively. Moreover, patients with Negative of TopBP1 were correlated with longer OS time when compared with Positive (Median OS 36 vs.23 months, P=0.012), and the adjusted HRs (95%CI) for OS were 1.931 (1.157-3.224), respectively. There was no significant correlation of BRCA1 and TopBP1 expression with disease progression (P>0.05).Conclusion:In summary, the present study showed that protein expression of BRCA1 and TopBP1 in NSCLC tumors showed an apparent correlation with each other. These were also associated with the efficacy of platinum-based chemotherapy and prognosis of NSCLC patients. Protein expression of BRCA1 and TopBPl in NSCLC tumor tissues did not impart a significant impact on disease progression. However, NSCLC patients with negative expression of both proteins showed better prognosis and longer survival compared to NSCLC patients presenting positive BRCA1 and TopBPl expression. The results obtained in the present study were derived from a single observation. Further studies, particularly those involving larger clinical randomized controlled trials, are therefore necessary to confirm the correlation between BRCA and TopBP1 protein expression and chemotherapeutic efficacy and NSCLC prognosis.