title: ZNF695 methylation predicts a response of esophageal squamous cell carcinoma to definitive chemoradiotherapy.
abstract: OBJECTIVE
  Definitive chemoradiotherapy (dCRT) is one of the standard treatments for esophageal squamous cell carcinoma. Patients with a response to dCRT have a better prognosis than those resistant to dCRT while survival benefits for patients with residual tumors are limited. Nevertheless, few molecular markers to predict the response to dCRT are currently available. Here, we aimed to establish a DNA methylation marker to predict the response to dCRT.
  
  
  METHODS
  A total of 104 patients were divided into screening (n = 43) and validation (n = 61) sets. A genome-wide DNA methylation analysis was performed using an Infinium HumanMethylation450 BeadChip array. Methylation levels were measured by quantitative methylation-specific PCR and normalized by the fraction of cancer cells in a sample.
  
  
  RESULTS
  The genome-wide methylation analysis of seven responders and eight non-responders identified 18 genomic regions specifically (un)methylated in the responders. Among these, methylation of the promoter CpG island of ZNF695 was significantly associated with the response to dCRT in the screening set (P = 0.004), and a cutoff value was determined. In the validation set, the association was successfully validated (P = 0.021), and a high specificity (90 %) for the prediction of responders was obtained using the prefixed cutoff value. In addition, a multivariate analysis showed that ZNF695 methylation was an independent predictive factor for the response to dCRT (OR 7.55, 95 % CI 2.12-26.9, P = 0.002).
  
  
  CONCLUSIONS
  ZNF695 methylation was significantly associated with the response to dCRT and is a promising predictive marker for the response to dCRT.
authors.affiliation: Division of Epigenomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Takamasa
authors.initials: T
authors.lastname: Takahashi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamahsita
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Matsuda
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Kishino
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nakajima
authors.forename: Ryoji
authors.initials: R
authors.lastname: Kushima
authors.forename: Ken
authors.initials: K
authors.lastname: Kato
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Igaki
authors.forename: Yuji
authors.initials: Y
authors.lastname: Tachimori
authors.forename: Harushi
authors.initials: H
authors.lastname: Osugi
authors.forename: Masato
authors.initials: M
authors.lastname: Nagino
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Ushijima
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy; D016022:Case-Control Studies; D059248:Chemoradiotherapy; D002945:Cisplatin / Q000008:administration & dosage; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics*; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D015996:Survival Rate; D016335:Zinc Fingers / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D002945:Cisplatin; D005472:Fluorouracil