title: Prognostication of patients with clear cell renal cell carcinomas based on quantification of DNA methylation levels of CpG island methylator phenotype marker genes.
abstract: BACKGROUND
  The CpG island methylator phenotype (CIMP) of clear cell renal cell carcinomas (ccRCCs) is characterized by accumulation of DNA methylation at CpG islands and poorer patient outcome. The aim of this study was to establish criteria for prognostication of patients with ccRCCs using the ccRCC-specific CIMP marker genes.
  
  
  METHODS
  DNA methylation levels at 299 CpG sites in the 14 CIMP marker genes were evaluated quantitatively in tissue specimens of 88 CIMP-negative and 14 CIMP-positive ccRCCs in a learning cohort using the MassARRAY system. An additional 100 ccRCCs were also analyzed as a validation cohort.
  
  
  RESULTS
  Receiver operating characteristic curve analysis showed that area under the curve values for the 23 CpG units including the 32 CpG sites in the 7 CIMP-marker genes, i.e. FAM150A, ZNF540, ZNF671, ZNF154, PRAC, TRH and SLC13A5, for discrimination of CIMP-positive from CIMP-negative ccRCCs were larger than 0.95. Criteria combining the 23 CpG units discriminated CIMP-positive from CIMP-negative ccRCCs with 100% sensitivity and specificity in the learning cohort. Cancer-free and overall survival rates of patients with CIMP-positive ccRCCs diagnosed using the criteria combining the 23 CpG units in a validation cohort were significantly lower than those of patients with CIMP-negative ccRCCs (P = 1.41 × 10-5 and 2.43 × 10-13, respectively). Patients with CIMP-positive ccRCCs in the validation cohort had a higher likelihood of disease-related death (hazard ratio, 75.8; 95% confidence interval, 7.81 to 735; P = 1.89 × 10-4) than those with CIMP-negative ccRCCs.
  
  
  CONCLUSIONS
  The established criteria are able to reproducibly diagnose CIMP-positive ccRCCs and may be useful for personalized medicine for patients with ccRCCs.
authors.forename: Ying
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Division of Molecular Pathology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. earai@ncc.go.jp.
authors.forename: Eri
authors.initials: E
authors.lastname: Arai
authors.forename: Masahiro
authors.initials: M
authors.lastname: Gotoh
authors.forename: Motokiyo
authors.initials: M
authors.lastname: Komiyama
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Fujimoto
authors.forename: Yae
authors.initials: Y
authors.lastname: Kanai
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D015415:Biomarkers; D002292:Carcinoma, Renal Cell / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D005819:Genetic Markers; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011379:Prognosis; D011401:Promoter Regions, Genetic; D027981:Symporters / Q000235:genetics
chemical_list: D015415:Biomarkers; D005819:Genetic Markers; C470492:SLC13A5 protein, human; D027981:Symporters