title: Promoter hypermethylation of the tumor-suppressor genes ITIH5, DKK3, and RASSF1A as novel biomarkers for blood-based breast cancer screening.
abstract: BACKGROUND
  For early detection of breast cancer, the development of robust blood-based biomarkers that accurately reflect the host tumor is mandatory. We investigated DNA methylation in circulating free DNA (cfDNA) from blood of breast cancer patients and matched controls to establish a biomarker panel potentially useful for early detection of breast cancer.
  
  
  METHODS
  We examined promoter methylation of seven putative tumor-suppressor genes (SFRP1, SFRP2, SFRP5, ITIH5, WIF1, DKK3, and RASSF1A) in cfDNA extracted from serum. Clinical performance was first determined in a test set (n = 261 sera). In an independent validation set (n = 343 sera), we validated the most promising genes for further use in early breast cancer detection. Sera from 59 benign breast disease and 58 colon cancer patients were included for additional specificity testing.
  
  
  RESULTS
  Based on the test set, we determined ITIH5 and DKK3 promoter methylation as candidate biomarkers with the best sensitivity and specificity. In both the test and validation set combined, ITIH5 and DKK3 methylation achieved 41% sensitivity with a specificity of 93% and 100% in healthy and benign disease controls, respectively. Combination of these genes with RASSF1A methylation increased the sensitivity to 67% with a specificity of 69% and 82% in healthy controls and benign disease controls, respectively.
  
  
  CONCLUSIONS
  Tumor-specific methylation of the three-gene panel (ITIH5, DKK3, and RASSF1A) might be a valuable biomarker for the early detection of breast cancer.
authors: Vera
authors: V
authors: Kloten
authors: Birte
authors: B
authors: Becker
authors: Kirsten
authors: K
authors: Winner
authors: Michael G
authors: MG
authors: Schrauder
authors: Peter A
authors: PA
authors: Fasching
authors: Tobias
authors: T
authors: Anzeneder
authors: Jürgen
authors: J
authors: Veeck
authors: Arndt
authors: A
authors: Hartmann
authors: Ruth
authors: R
authors: Knüchel
authors: Edgar
authors: E
authors: Dahl
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000097:blood; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D018925:Chemokines; D019175:DNA Methylation / Q000235:genetics; D055088:Early Detection of Cancer; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood*; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D053491:Proteinase Inhibitory Proteins, Secretory / Q000097:blood*; D025521:Tumor Suppressor Proteins / Q000097:blood*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D018925:Chemokines; C498624:DKK3 protein, human; C482680:ITIH5 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D053491:Proteinase Inhibitory Proteins, Secretory; C411762:RASSF1 protein, human; D025521:Tumor Suppressor Proteins