ATM, {ATR} and DNA-PKcs expressions correlate to adverse clinical outcomes in epithelial ovarian cancers

摘要

Background Ataxia-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. Methods We 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. Results High {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. Conclusions ATM, {ATR} and DNA-PKcs expressions may have prognostic and predictive significances in epithelial ovarian cancer. General significance The 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.