PURPOSE: 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. EXPERIMENTAL DESIGN: 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, D. M., Lentjes, M. H., van den Bosch, S. M., Melotte, V., Wouters, K. A.
, Daenen, K. L., Smits, K. M.
, Akiyama, Y., Yuasa, Y., Sanduleanu, S., Khalid - de Bakker, C. A., Jonkers, D., Weijenberg, M. P.
, Louwagie, J., van Criekinge, W., Carvalho, B., Meijer, G. A., Baylin, S. B., Herman, J. G., ... van Engeland, M.
(2009). GATA4 and GATA5 are potential tumor suppressors and biomarkers in colorectal cancer
. Clinical Cancer Research
(12), 3990-7. https://doi.org/10.1158/1078-0432.CCR-09-0055