5591

PRKDC

protein kinase, DNA-activated, catalytic polypeptide;PRKDC;protein kinase, DNA-activated, catalytic polypeptide

DNA-PK catalytic subunit|DNA-dependent protein kinase catalytic subunit|hyper-radiosensitivity of murine scid mutation, complementing 1|p460

8q11

protein-coding

DNA double-strand break (DSB) is one of the most deleterious lesions induced by DNA damaging agents. DSB repair pathway is implicated in maintaining genomic integrity via suppression of genetic instability and neoplastic transformation. DNA-dependent protein kinase (DNA-PK) has a pivotal role in DNA DSB repair. The Nijmegen breakage syndrome protein (NBS1), essential for DSB repair, re-localizes into subnuclear structures upon induction of DNA damage by ionizing radiation, forming so-called ionizing radiation-induced foci (IRIF), which is visualized by immunostaining. We measured DNA-PK activity and the number of persistent NBS1 IRIF per nucleus 24 h after irradiation of peripheral blood lymphocytes (PBL) from patients with sporadic breast cancer. Chromosomal aberrations were examined by cytogenetic methods. We examined the relationship between these measurements and clinical characteristics of patients such as tumor size, lymph node metastasis and nuclear grade of cancer cells. A higher number of NBS1 IRIF or lower DNA-PK activity correlated with higher chromosome instability. Patients whose PBL had lower DNA-PK or higher NBS1 IRIF had aggressive cancer phenotypes such as a larger tumor, higher nuclear grade and positive axillary lymph node metastasis. The combination of DNA-PK activity and NBS1 IRIF were useful for predicting lymph node metastasis. The ability of DSB repair in PBL is related to aggressive breast cancer phenotypes. Axillary lymph node dissection can be avoided by examining DNA-PK activity and NBS1 IRIF of PBL, which can contribute to improving the quality of life of breast cancer patients.

BACKGROUND: Repair of various types of DNA damages is critical for genomic stability. DNA-dependent protein kinase (DNA-PK) has an important role in DNA double-strand break repair. We examined whether there may be a correlation between DNA-PK activity in peripheral blood lymphocytes (PBLs) and survival percentages in various cancer patients. We also investigated the changes of DNA-PK activity in PBLs after radiotherapy. METHODS: A total of 167 of untreated cancer patients participated in this study. Peripheral blood was collected, separated, and centrifuged. DNA-PK activity was measured by DNA-pull-down assay. Chromosomal aberrations were examined by cytogenetic methods. RESULTS: DNA-PK activity of PBLs in advanced cancer patients was significantly lower than that in early stage. The patients with lower DNA-PK activity in PBLs tended to have the lower disease-specific survivals and distant metastasis-free survivals than those with higher DNA-PK activity in advanced stages. There was also a tendency of inverse correlation between DNA-PK activity and excess fragments. The DNA-PK activity of PBLs in most patients decreased in response to radiation as the equivalent whole-body dose increased. CONCLUSION: cancer patients in advanced stage, with lower DNA-PK activity of PBLs might have higher distant metastasis and exhibit poorer prognosis. Therefore, DNA-PK activity in PBLs could be used as a marker to predict the chromosomal instability and poorer prognosis.