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

Abstract

The receptor tyrosine kinase EPHB2 has recently been shown to be a direct transcriptional target of TCF/B-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 EPHB2 has been shown to accelerate tumorigenesis initiated by APC mutation in the colon and rectum. In this study, we investigated the molecular mechanisms responsible for the inactivation of EPHB2 in colorectal tumors. We show here the presence of mutations in repetitive sequences in exon 17 of EPHB2 in 6 of 29 adenomas with microsatellite instability (MSI), and 101 of 246 MSI carcinomas (21% and 41%, respectively). Moreover, we found EPHB2 promoter hypermethylation in 54 of the 101 colorectal tumors studied (53%). Importantly, EPHB2 expression was restored after treatment of EPHB2-methylated colon cancer cells with the DNA methyltransferase inhibitor 5-aza-2V-deoxycytidine. In conclusion, in this study, we elucidate the molecular mechanisms of inactivation of EPHB2 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. (Cancer Res 2005; 65(22): 10170-3)

Serrated carcinomas form a subclass of colorectal cancer with distinct molecular basis

“…We observed EPHB2 LOH in 25% (3/12) and promoter hypermethylation in 63% (5/8) of serrated tumors. Our study on EPHB2 inactivation in CRC (Alazzouzi et al, 2005) has showed that EPHB2 promotor methylation indeed is causally related to the reduced expression of EPHB2 protein in a cell line and we found frequent frameshift mutations in EPHB2 in MSI adenomas and carcinomas (21 and 41%, respectively). This finding is interesting and well compatible with our present data on serrated CRCs; indeed, previous literature (Hawkins and Ward, 2001;Ma¨kinen et al, 2001) has connected MSI phenotype and serrated morphology, and early loss of EPHB2 may play a role in this association.…”

Colorectal cancer and genetic alterations in the Wnt pathway

“…c-Myc may be amplified in some cases, and cyclinD1 in a very few. EPHB2 undergoes slippage in a short repeat tract in about half of microsatellite-unstable colon cancers (Alazzouzi et al, 2005), although biallelic changes are apparently uncommon; other tumours show transcriptional silencing. The functional consequences, if any, of these EPHB2 changes are currently unknown.…”

Overexpression of the receptor tyrosine kinase EphA4 in human gastric cancers

“…Overexpression of EphB2, ephrinB1, EphA2, and ephrinA1 has been reported in gastric cancer [11][12][13] . On the other hand, the concept that Eph receptors are oncogenes needs a new look on the basis of recent findings of downregulation of Eph receptors in certain types of cancer [14][15][16][17] . However, because functions of Eph receptors can overlap, loss of one receptor can be partially compensated for by other Eph receptors that have similar ligand-binding specificities and expression patterns [7] .…”