Data from GATA4 and GATA5 are Potential Tumor Suppressors and Biomarkers in Colorectal Cancer

Abstract

<div>Abstract<p><b>Purpose:</b> The transcription factors GATA4 and GATA5 are involved in gastrointestinal development and are inactivated by promoter hypermethylation in colorectal cancer. Here, we evaluated <i>GATA4/5</i> promoter methylation as potential biomarkers for noninvasive colorectal cancer detection, and investigated the role of GATA4/5 in colorectal cancer.</p><p><b>Experimental Design:</b> Promoter methylation of <i>GATA4/5</i> 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.</p><p><b>Results:</b><i>GATA4/5</i> 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, <i>GATA4</i>; <i>P</i> < 0.001) and 13% (13 of 100, <i>GATA5</i>; <i>P</i> < 0.001). GATA4/5 overexpression suppressed colony formation (<i>P</i> < 0.005), proliferation (<i>P</i> < 0.001), migration (<i>P</i> < 0.05), invasion (<i>P</i> < 0.05), and anchorage-independent growth (<i>P</i> < 0.0001) of colorectal cancer cells. Examination of <i>GATA4</i> 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.</p><p><b>Conclusions:</b> Methylation of <i>GATA4/5</i> is a common and specific event in colorectal carcinomas, and GATA4/5 exhibit tumor suppressive effects in colorectal cancer cells <i>in vitro</i>. <i>GATA4</i> methylation in fecal DNA may be of interest for colorectal cancer detection.</p></div>