GATA4 and GATA5 are potential tumor suppressors and biomarkers in colorectal cancer.
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.
Hellebrekers
Debby M E I
DM
Departments of Pathology and Epidemiology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands.
Lentjes
Marjolein H F M
MH
van den Bosch
Sandra M
SM
Melotte
Veerle
V
Wouters
Kim A D
KA
Daenen
Kathleen L J
KL
Smits
Kim M
KM
Akiyama
Yoshimitsu
Y
Yuasa
Yasuhito
Y
Sanduleanu
Silvia
S
Khalid-de Bakker
Carolina A J
CA
Jonkers
Daisy
D
Weijenberg
Matty P
MP
Louwagie
Joost
J
van Criekinge
Wim
W
Carvalho
Beatriz
B
Meijer
Gerrit A
GA
Baylin
Stephen B
SB
Herman
James G
JG
de Bruïne
Adriaan P
AP
van Engeland
Manon
M
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
D014408:Biomarkers, Tumor; D050991:GATA4 Transcription Factor; D050992:GATA5 Transcription Factor