Abstract
BackgroundAtaxia-telangiectasia mutated (ATM), ataxia-telangiectasia mutated and rad3 related (ATR) and DNA-dependent protein kinase catalytic sub-unit (DNA-PKcs) play critical roles in DNA damage response (DDR) by linking DNA damage sensing to DDR effectors that regulate cell cycle progression and DNA repair. Our objective was to evaluate if ATM, ATR and DNA-PKcs expressions could predict response to therapy and clinical outcome in epithelial ovarian cancers. MethodsWe investigated ATM, ATR, and DNA-PKcs expressions in ovarian epithelial cancers [protein expression (n=194 patients), mRNA expression (n=156 patients)] and correlated to clinicopathological outcomes as well as expression of X-ray repair cross-complementing protein 1 (XRCC1), cell division cycle-45 (CDC45), cyclin-dependent kinase 1(CDK1) and Ki-67 in tumours. ResultsHigh ATM protein expression was associated with serous cystadenocarcinomas (p=0.021) and platinum resistance (p=0.017). High DNA-PKcs protein expression was associated with serous cystadenocarcinomas (p=0.006) and advanced stage tumours (p=0.018). High ATM protein (p=0.001), high ATM mRNA (p=0.018), high DNA-PKcs protein (p=0.002), high DNA-PKcs mRNA (p=0.044) and high ATR protein (p=0.001) expressions are correlated with poor ovarian cancer specific survival (OCSS). In multivariate Cox model, high DNA-PKcs (p=0.006) and high ATR (p=0.043) protein expressions remain independently associated with poor OCSS. ConclusionsATM, ATR and DNA-PKcs expressions may have prognostic and predictive significances in epithelial ovarian cancer. General significanceThe data presented here provides evidence that ATM, ATR and DNA-PKcs involved in DDR are not only promising biomarkers but are also rational targets for personalized therapy in ovarian cancer.
Highlights
Despite the efficacy of platinum based chemotherapy, the overall prognosis for patients with advanced ovarian cancer remains poor [1,2,3]
Ataxia-telangiectasia mutated (ATM), ATR kinases and DNA-PKcs (DNA-dependent protein kinase catalytic sub-unit) play critical roles in the DNA damage response (DDR) and link DNA damage sensing to DDR effectors that regulate cell cycle
High ATM expression was significantly associated with serous cystadenocarcinomas (p = 0.021), CA-125 response to chemotherapy (p = 0.017) and platinum resistance (p = 0.017)
Summary
Despite the efficacy of platinum based chemotherapy, the overall prognosis for patients with advanced ovarian cancer remains poor [1,2,3]. ATM (ataxiatelangiectasia mutated), ATR (ataxia-telangiectasia mutated and Rad related) kinases and DNA-PKcs (DNA-dependent protein kinase catalytic sub-unit) play critical roles in the DNA damage response (DDR) and link DNA damage sensing to DDR effectors that regulate cell cycle. Activated ATR and ATM phosphorylate Chk or Chk respectively This in turn modulates a number of other proteins involved in DNA repair, cell cycle control and apoptosis [6,7,8,9,10,11,12,13,14]. Ataxia-telangiectasia mutated (ATM), ataxia-telangiectasia mutated and rad related (ATR) and DNA-dependent protein kinase catalytic sub-unit (DNA-PKcs) play critical roles in DNA damage response (DDR) by linking DNA damage sensing to DDR effectors that regulate cell cycle progression and DNA repair. General significance: The data presented here provides evidence that ATM, ATR and DNA-PKcs involved in DDR are promising biomarkers but are rational targets for personalized therapy in ovarian cancer
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