title: GATA4 and GATA5 are potential tumor suppressors and biomarkers in colorectal cancer.
abstract: OBJECTIVE
  The transcription factors GATA4 and GATA5 are involved in gastrointestinal development and are inactivated by promoter hypermethylation in colorectal cancer. Here, we evaluated GATA4/5 promoter methylation as potential biomarkers for noninvasive colorectal cancer detection, and investigated the role of GATA4/5 in colorectal cancer.
  
  
  METHODS
  Promoter methylation of GATA4/5 was analyzed in colorectal tissue and fecal DNA from colorectal cancer patients and healthy controls using methylation-specific PCR. The potential function of GATA4/5 as tumor suppressors was studied by inducing GATA4/5 overexpression in human colorectal cancer cell lines.
  
  
  RESULTS
  GATA4/5 methylation was observed in 70% (63/90) and 79% (61/77) of colorectal carcinomas, respectively, and was independent of clinicopathologic features. Methylation frequencies in normal colon tissues from noncancerous controls were 6% (5 of 88, GATA4; P < 0.001) and 13% (13 of 100, GATA5; P < 0.001). GATA4/5 overexpression suppressed colony formation (P < 0.005), proliferation (P < 0.001), migration (P < 0.05), invasion (P < 0.05), and anchorage-independent growth (P < 0.0001) of colorectal cancer cells. Examination of GATA4 methylation in fecal DNA from two independent series of colorectal cancer patients and controls yielded a sensitivity of 71% [95% confidence interval (95% CI), 55-88%] and specificity of 84% (95% CI, 74-95%) for colorectal cancer detection in the training set, and a sensitivity of 51% (95% CI, 37-65%) and specificity of 93% (95% CI, 84-100%) in the validation set.
  
  
  CONCLUSIONS
  Methylation of GATA4/5 is a common and specific event in colorectal carcinomas, and GATA4/5 exhibit tumor suppressive effects in colorectal cancer cells in vitro. GATA4 methylation in fecal DNA may be of interest for colorectal cancer detection.
authors.affiliation: Departments of Pathology and Epidemiology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands.
authors.forename: Debby M E I
authors.initials: DM
authors.lastname: Hellebrekers
authors.forename: Marjolein H F M
authors.initials: MH
authors.lastname: Lentjes
authors.forename: Sandra M
authors.initials: SM
authors.lastname: van den Bosch
authors.forename: Veerle
authors.initials: V
authors.lastname: Melotte
authors.forename: Kim A D
authors.initials: KA
authors.lastname: Wouters
authors.forename: Kathleen L J
authors.initials: KL
authors.lastname: Daenen
authors.forename: Kim M
authors.initials: KM
authors.lastname: Smits
authors.forename: Yoshimitsu
authors.initials: Y
authors.lastname: Akiyama
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Yuasa
authors.forename: Silvia
authors.initials: S
authors.lastname: Sanduleanu
authors.forename: Carolina A J
authors.initials: CA
authors.lastname: Khalid-de Bakker
authors.forename: Daisy
authors.initials: D
authors.lastname: Jonkers
authors.forename: Matty P
authors.initials: MP
authors.lastname: Weijenberg
authors.forename: Joost
authors.initials: J
authors.lastname: Louwagie
authors.forename: Wim
authors.initials: W
authors.lastname: van Criekinge
authors.forename: Beatriz
authors.initials: B
authors.lastname: Carvalho
authors.forename: Gerrit A
authors.initials: GA
authors.lastname: Meijer
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Baylin
authors.forename: James G
authors.initials: JG
authors.lastname: Herman
authors.forename: Adriaan P
authors.initials: AP
authors.lastname: de Bruïne
authors.forename: Manon
authors.initials: M
authors.lastname: van Engeland
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D002277:Carcinoma / Q000175:diagnosis* / Q000235:genetics; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000235:genetics; D018899:CpG Islands / Q000235:genetics / Q000502:physiology; D019175:DNA Methylation; D005243:Feces / Q000737:chemistry; D005260:Female; D050991:GATA4 Transcription Factor / Q000235:genetics*; D050992:GATA5 Transcription Factor / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000502:physiology; D012189:Retrospective Studies
chemical_list: D014408:Biomarkers, Tumor; D050991:GATA4 Transcription Factor; D050992:GATA5 Transcription Factor