title: Prognostic significance of human apurinic/apyrimidinic endonuclease (APE/Ref-1) expression in rectal cancer treated with preoperative radiochemotherapy.
abstract: OBJECTIVE
  Human apurinic endonuclease/redox factor 1 (APE/Ref-1) mediates repair of radiation-induced DNA lesions and regulates transcription via redox-based activation. We investigated the predictive and prognostic significance of APE/Ref-1 expression in pretreatment biopsy specimens in locally advanced rectal cancer (LARC) (cT3-T4 or N+).
  
  
  METHODS
  APE/Ref-1 expression was analyzed by immunohistochemistry in pretreatment biopsy specimens obtained from 83 patients with LARC. Patients received preoperative radiotherapy of 50.4 Gy in 28 fractions, combined with oral capecitabine and leucovorin chemotherapy, followed by curative surgery. The prognostic significance of various clinicopathologic characteristics, including APE/Ref-1 protein expression, was evaluated.
  
  
  RESULTS
  APE/Ref-1 was expressed in 97% of patient samples. Exclusive APE/Ref-1 nuclear staining was observed in 49 of 83 samples (59%), and mixed nuclear and cytoplasmic staining was observed in 31 samples (37%). APE/Ref-1 nuclear expression levels were low in 49 patients (59%) and high in 34 patients (41%). The level of APE/Ref-1 nuclear expression was not a prognostic factor for overall and disease-free survival. Cytoplasmic expression of APE/Ref-1 was a borderline-significant predictive factor for pathologic tumor response (p = 0.08) and a significant prognostic factor for disease-free survival, as shown by univariate analysis (p = 0.037). Multivariate analysis confirmed that cytoplasmic localization of APE/Ref-1 is a significant predictor of disease-free survival (hazard ratio, 0.45; p = 0.046).
  
  
  CONCLUSIONS
  APE/Ref-1 was expressed in a majority of pretreatment biopsy specimens from patients with LARC. The level of APE/Ref-1 nuclear expression was not a significant predictive and prognostic factor; however, cytoplasmic localization of the protein was negatively associated with disease-free survival. These results indicate that cytoplasmic expression of APE/Ref-1 represents an adverse prognostic factor for LARC patients who receive preoperative radiochemotherapy.
authors.affiliation: Department of Radiation Oncology, College of Medicine, Chungnam National University, Daejeon, Republic of Korea. k423j@cnu.ac.kr
authors.forename: Jun-Sang
authors.initials: JS
authors.lastname: Kim
authors.forename: Jin-Man
authors.initials: JM
authors.lastname: Kim
authors.forename: Zhe Long
authors.initials: ZL
authors.lastname: Liang
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Jang
authors.forename: Sup
authors.initials: S
authors.lastname: Kim
authors.forename: Gil Ja
authors.initials: GJ
authors.lastname: Huh
authors.forename: Ki-Hwan
authors.initials: KH
authors.lastname: Kim
authors.forename: Moon-June
authors.initials: MJ
authors.lastname: Cho
mesh_terms: D000368:Aged; D000704:Analysis of Variance; D001706:Biopsy; D059248:Chemoradiotherapy / Q000379:methods*; D003593:Cytoplasm / Q000201:enzymology; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000378:metabolism*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000378:metabolism; D011300:Preoperative Care / Q000379:methods; D011879:Radiotherapy Dosage; D012004:Rectal Neoplasms / Q000201:enzymology* / Q000473:pathology / Q000628:therapy*; D012007:Rectum / Q000201:enzymology / Q000473:pathology; D012737:Sex Factors
chemical_list: D009687:Nuclear Proteins; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase