Data from Mechanisms of Inactivation of the Receptor Tyrosine Kinase EPHB2 in Colorectal Tumors

Abstract

<div>Abstract<p>The receptor tyrosine kinase <i>EPHB2</i> has recently been shown to be a direct transcriptional target of TCF/β-catenin. Premalignant lesions of the colon express high levels of EPHB2 but the expression of this kinase is reduced or lost in most colorectal carcinomas. In addition, inactivation of <i>EPHB2</i> has been shown to accelerate tumorigenesis initiated by <i>APC</i> mutation in the colon and rectum. In this study, we investigated the molecular mechanisms responsible for the inactivation of <i>EPHB2</i> in colorectal tumors. We show here the presence of mutations in repetitive sequences in exon 17 of <i>EPHB2</i> in 6 of 29 adenomas with microsatellite instability (MSI), and 101 of 246 MSI carcinomas (21% and 41%, respectively). Moreover, we found <i>EPHB2</i> promoter hypermethylation in 54 of the 101 colorectal tumors studied (53%). Importantly, EPHB2 expression was restored after treatment of <i>EPHB2</i>-methylated colon cancer cells with the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine. In conclusion, in this study, we elucidate the molecular mechanisms of inactivation of <i>EPHB2</i> and show for the first time the high incidence of frameshift mutations in MSI colorectal tumors and aberrant methylation of the regulatory sequences of this important tumor suppressor gene.</p></div>