PURPOSE: Double-strand breaks, the most lethal DNA lesions induced by ionizing radiation, are mainly repaired by the nonhomologous end-joining system. The expression of the nonhomologous end-joining pathway has never been studied in prostate cancer, and its prognostic value for patients undergoing radiotherapy remains unknown. METHODS: Pretreatment biopsies from 238 patients treated with exclusive external beam radiotherapy for localized prostate cancer with ≥ 2 years of follow-up were reviewed to reassess the Gleason score. Of these 238 cases, 179 were suitable for in situ analysis and were included in the tissue microarrays. Expression of the nonhomologous end-joining proteins Ku70, Ku80, DNA-dependent protein kinase, catalytic subunits (DNA-PKcs), and X-ray repair cross complementing 4-like factor was studied by immunohistochemistry, together with the proliferation marker Ki67. RESULTS: The predictive value of the Gleason score for biochemical relapse (using the Phoenix criteria) was markedly improved after review (P<.0001) compared with the initial score (P=.003). The clinical stage, pretreatment prostate-specific antigen level, and perineural invasion status were also associated with progression-free survival (P=.005, P<.0001, and P=.03, respectively). High proliferation (>4%) tends to be associated with biochemical recurrence; however, the difference did not reach statistical significance (P=.06). Although the expression of Ku70, Ku80, and X-ray repair cross complementing 4-like factor was not predictive of relapse, positive DNA-PKcs nuclear staining was closely associated with biochemical recurrence (P=.0002). On multivariate analysis, only the Gleason score, prostate-specific antigen level, and DNA-PKcs status remained predictive of recurrence (P=.003, P=.002, and P=.01, respectively). CONCLUSIONS: The results of the present study highly suggest that DNA-PKcs could be a predictive marker of recurrence after radiotherapy, independently of the classic prognostic markers, including the Gleason score modified after review.
PURPOSE: Double-strand breaks, the most lethal DNA lesions induced by ionizing radiation, are mainly repaired by the nonhomologous end-joining system. The expression of the nonhomologous end-joining pathway has never been studied in prostate cancer, and its prognostic value for patients undergoing radiotherapy remains unknown. METHODS: Pretreatment biopsies from 238 patients treated with exclusive external beam radiotherapy for localized prostate cancer with ≥ 2 years of follow-up were reviewed to reassess the Gleason score. Of these 238 cases, 179 were suitable for in situ analysis and were included in the tissue microarrays. Expression of the nonhomologous end-joining proteins Ku70, Ku80, DNA-dependent protein kinase, catalytic subunits (DNA-PKcs), and X-ray repair cross complementing 4-like factor was studied by immunohistochemistry, together with the proliferation marker Ki67. RESULTS: The predictive value of the Gleason score for biochemical relapse (using the Phoenix criteria) was markedly improved after review (P<.0001) compared with the initial score (P=.003). The clinical stage, pretreatment prostate-specific antigen level, and perineural invasion status were also associated with progression-free survival (P=.005, P<.0001, and P=.03, respectively). High proliferation (>4%) tends to be associated with biochemical recurrence; however, the difference did not reach statistical significance (P=.06). Although the expression of Ku70, Ku80, and X-ray repair cross complementing 4-like factor was not predictive of relapse, positive DNA-PKcs nuclear staining was closely associated with biochemical recurrence (P=.0002). On multivariate analysis, only the Gleason score, prostate-specific antigen level, and DNA-PKcs status remained predictive of recurrence (P=.003, P=.002, and P=.01, respectively). CONCLUSIONS: The results of the present study highly suggest that DNA-PKcs could be a predictive marker of recurrence after radiotherapy, independently of the classic prognostic markers, including the Gleason score modified after review.
Authors: Jonathan F Goodwin; Matthew J Schiewer; Jeffry L Dean; Randy S Schrecengost; Renée de Leeuw; Sumin Han; Teng Ma; Robert B Den; Adam P Dicker; Felix Y Feng; Karen E Knudsen Journal: Cancer Discov Date: 2013-09-11 Impact factor: 39.397
Authors: Jonathan F Goodwin; Vishal Kothari; Justin M Drake; Shuang Zhao; Emanuela Dylgjeri; Jeffry L Dean; Matthew J Schiewer; Christopher McNair; Jennifer K Jones; Alvaro Aytes; Michael S Magee; Adam E Snook; Ziqi Zhu; Robert B Den; Ruth C Birbe; Leonard G Gomella; Nicholas A Graham; Ajay A Vashisht; James A Wohlschlegel; Thomas G Graeber; R Jeffrey Karnes; Mandeep Takhar; Elai Davicioni; Scott A Tomlins; Cory Abate-Shen; Nima Sharifi; Owen N Witte; Felix Y Feng; Karen E Knudsen Journal: Cancer Cell Date: 2015-07-13 Impact factor: 31.743
Authors: Cindy R Timme; Barbara H Rath; John W O'Neill; Kevin Camphausen; Philip J Tofilon Journal: Mol Cancer Ther Date: 2018-03-16 Impact factor: 6.261
Authors: Dermot O'Sullivan; Michael Henry; Helena Joyce; Naomi Walsh; Edel Mc Auley; Paul Dowling; Niall Swan; Michael Moriarty; Paul Barnham; Martin Clynes; Annemarie Larkin Journal: Tumour Biol Date: 2014-04-18