Abstract
The mechanisms of radiation-induced effects in cancer mainly involve double-strand breaks (DSBs) which are important in maintaining the stability of genes. The DNA repair genes breast cancer 1 (BRCA1) and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) are capable of maintaining genetic stability through two distinct and complementary repair mechanisms for DNA DSBs, known as repair-homologous recombination (HR) and non-homologous end joining (NHEJ). DNA-PKcs is a member of the phosphatidylinositol 3-kinase (PI3K) family. The PI3K/AKT cell signaling pathway is implicated in cell migration and invasion. The BRCA1 protein is implicated in multiple complex cellular processes that are related to chromosome sensitivity to mutagens. To determine the protein expression and clinical implications of DNA-PKcs and BRCA1 in nasopharyngeal carcinoma (NPC) and cancer progression, we evaluated its expression status by immunohistochemistry in 87 patients who received intensity-modulated radiation therapy (IMRT). In NPC, negative expression of DNA-PKcs was detected in 35 of the 87 (40.2%) cancer types and was significantly associated with poor patient survival (P<0.05). The overexpression of DNA-PKcs and BRCA1 also led to significantly improved distant metastasis-free survival compared with patients who did not overexpress both genes, although the expression level of BRCA1 and distant metastasis-free survival were not closely correlated. In addition, multivariate analysis indicated that DNA-PKcs status is a predictive marker of distant metastasis-free survival. In conclusion, lower expression of DNA-PKcs may be correlated with higher distant metastasis in patients with NPC. DNA-PKcs may be a predictive marker of distant metastasis after IMRT, independent of the classical prognostic marker. BRCA1 may additionally exert a synergistic effect to predict distant metastasis-free survival.
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