title: Clinico-epigenetic combination including quantitative methylation value of DKK3 augments survival prediction of the patient with cervical cancer.
abstract: OBJECTIVE
  DKK3 is a target of methylation in various cancers and has been studied by a non-quantitative method. We assessed the quantitative methylation levels of DKK3 in cervical carcinoma, determined the potential clinical correlations, and tested whether the combination of clinical and epigenetic factors augmented the prediction power of prognosis.
  
  
  METHODS
  Sixty-two patients with cervical squamous cell carcinoma were included in this study. Quantitative methylation levels were evaluated by pyrosequencing. Clinical and pathologic findings were obtained from medical records. Survival data were analyzed using Kaplan-Meier estimates and compared with the log-rank test. The best clinico-epigenetic combinations were found using the Cox proportional hazard model.
  
  
  RESULTS
  Four of five CpG positions of DKK3 were strongly methylated in cervical carcinoma compared to normal controls (p = 0.0048). The methylation in positions 1 and/or 2 were stronger in patients with higher serum levels of the SCC tumor marker and/or larger tumors (p = 0.01). The patients with a methylation level ≥26.3 % at position 1 had a lower survival rate than the patients with methylation levels at position 1 that were <26.3 % (p = 0.03). The combination of methylation level of position 1, position 3, age, parametrial invasion, and lymphovascular space invasion (LVSI) have a significant correlation with survival (p = 0.0006). Recurrence was significantly related to the combination of methylation level of position 2, position 3, age, parametrium, and LVSI (p = 0.0041).
  
  
  CONCLUSIONS
  DKK3 methylation is unfavorable to prognosis. This study defined a threshold level of methylation associated with recurrence-free survival and, furthermore, identified novel clinico-epigenetic combinations predicting disease survival or recurrence.
authors.affiliation: Seoul Women's Hospital, Seoul, Korea.
authors.forename: Woong-Sun
authors.initials: WS
authors.lastname: Kang
authors.forename: Sung Bum
authors.initials: SB
authors.lastname: Cho
authors.forename: Jun-Soo
authors.initials: JS
authors.lastname: Park
authors.forename: Moo-Yul
authors.initials: MY
authors.lastname: Lee
authors.forename: Soon-Chul
authors.initials: SC
authors.lastname: Myung
authors.forename: Won Yong
authors.initials: WY
authors.lastname: Kim
authors.forename: Sang-Hoon
authors.initials: SH
authors.lastname: Lee
authors.forename: Dong-Ho
authors.initials: DH
authors.lastname: Kim
authors.forename: Eun-Ju
authors.initials: EJ
authors.lastname: Lee
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D018925:Chemokines; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D018572:Disease-Free Survival; D057890:Epigenomics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D015999:Multivariate Analysis; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000401:mortality; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D056910:Republic of Korea / Q000453:epidemiology; D017422:Sequence Analysis, DNA / Q000379:methods; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D018925:Chemokines; C498624:DKK3 protein, human; D036341:Intercellular Signaling Peptides and Proteins