title: Validation of DNA promoter hypermethylation biomarkers in breast cancer--a short report.
abstract: OBJECTIVE
  DNA promoter hypermethylation of tumor suppressor genes is known to occur early in cancer development, including breast cancer. To improve early breast cancer detection, we aimed to investigate whether the identification of DNA promoter hypermethylation might be of added value.
  
  
  METHODS
  The methylation status of a panel of 19 candidate genes (AKR1B1, ALX1, ARHGEF7, FZD10, GHSR, GPX7, GREM1, GSTP1, HOXD1, KL, LHX2, MAL, MGMT, NDRG2, RASGRF2, SFRP1, SFRP2, TM6SF1 and TMEFF2) was determined in formalin-fixed paraffin-embedded normal breast and breast cancer tissue samples using gel-based methylation-specific PCR (MSP).
  
  
  RESULTS
  The promoters of the AKR1B1, ALX1, GHSR, GREM1, RASGRF2, SFRP2, TM6SF1 and TMEFF2 genes were found to be significantly differentially methylated in normal versus malignant breast tissues. Based on sensitivity, specificity and logistic regression analyses the best performing genes for detecting breast cancer were identified. Through multivariate analyses, we found that AKR1B1 and TM6SF1 could detect breast cancer with an area under the curve (AUC) of 0.986 in a receiver operating characteristic (ROC) assessment.
  
  
  CONCLUSIONS
  Based on our data, we conclude that AKR1B1 and TM6SF1 may serve as candidate methylation biomarkers for early breast cancer detection. Further studies are underway to evaluate the methylation status of these genes in body fluids, including nipple aspirates and blood.
authors.affiliation: Department of Pathology, University Medical Center Utrecht, H04.312, PO Box 85500, 3508, GA, Utrecht, the Netherlands.
authors.forename: Jolien S
authors.initials: JS
authors.lastname: de Groot
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Pan
authors.forename: Jan
authors.initials: J
authors.lastname: Meeldijk
authors.forename: Elsken
authors.initials: E
authors.lastname: van der Wall
authors.forename: Paul J
authors.initials: PJ
authors.lastname: van Diest
authors.forename: Cathy B
authors.initials: CB
authors.lastname: Moelans
mesh_terms: D000449:Aldehyde Reductase / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics* / Q000502:physiology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005979:Glutathione Peroxidase; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics; D010544:Peroxidases / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics*; D054440:Receptors, Ghrelin / Q000235:genetics; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D000449:Aldehyde Reductase; D014408:Biomarkers, Tumor; D005979:Glutathione Peroxidase; D018398:Homeodomain Proteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D010544:Peroxidases; D054440:Receptors, Ghrelin; C489985:ALX1 protein, human; C109618:SFRP2 protein, human; D000094742:Secreted Frizzled-Related Proteins; C419194:TM6SF1 protein, human; C423567:TMEFF2 protein, human; C484670:AKR1B1 protein, human; C558641:GPX7 protein, human