Mechanisms of inactivation of the receptor tyrosine kinase EPHB2 in colorectal tumors

Hafid Alazzouzi, Veronica Davalos, Antti Kokko, Enric Domingo, Stefan M Woerner, Andrew J Wilson, Lars Konrad, Päivi Laiho, Eloi Espin, Manel Armengol, Kohzoh Imai, Hiroyuki Yamamoto, John M Mariadason, Johannes F Gebert, Lauri A Aaltonen, Simo Schwartz, Diego Arango

    Research output: Contribution to journalArticleScientificpeer-review

    Abstract

    The receptor tyrosine kinase EPHB2 has recently been shown to be a direct transcriptional target of TCF/beta-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 (NISI), 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-2'-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.
    Original languageEnglish
    JournalCancer Research
    Volume65
    Issue number22
    Pages (from-to)10170-10173
    Number of pages4
    ISSN0008-5472
    DOIs
    Publication statusPublished - 2005
    MoE publication typeA1 Journal article-refereed

    Fields of Science

    • 311 Basic medicine

    Cite this

    Alazzouzi, H., Davalos, V., Kokko, A., Domingo, E., Woerner, S. M., Wilson, A. J., ... Arango, D. (2005). Mechanisms of inactivation of the receptor tyrosine kinase EPHB2 in colorectal tumors. Cancer Research, 65(22), 10170-10173. https://doi.org/10.1158/0008-5472.CAN-05-2580
    Alazzouzi, Hafid ; Davalos, Veronica ; Kokko, Antti ; Domingo, Enric ; Woerner, Stefan M ; Wilson, Andrew J ; Konrad, Lars ; Laiho, Päivi ; Espin, Eloi ; Armengol, Manel ; Imai, Kohzoh ; Yamamoto, Hiroyuki ; Mariadason, John M ; Gebert, Johannes F ; Aaltonen, Lauri A ; Schwartz, Simo ; Arango, Diego. / Mechanisms of inactivation of the receptor tyrosine kinase EPHB2 in colorectal tumors. In: Cancer Research. 2005 ; Vol. 65, No. 22. pp. 10170-10173.
    @article{1f060b1389234937ab9275769d0a7a40,
    title = "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/beta-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 (NISI), 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-2'-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.",
    keywords = "311 Basic medicine",
    author = "Hafid Alazzouzi and Veronica Davalos and Antti Kokko and Enric Domingo and Woerner, {Stefan M} and Wilson, {Andrew J} and Lars Konrad and P{\"a}ivi Laiho and Eloi Espin and Manel Armengol and Kohzoh Imai and Hiroyuki Yamamoto and Mariadason, {John M} and Gebert, {Johannes F} and Aaltonen, {Lauri A} and Simo Schwartz and Diego Arango",
    year = "2005",
    doi = "10.1158/0008-5472.CAN-05-2580",
    language = "English",
    volume = "65",
    pages = "10170--10173",
    journal = "Cancer Research",
    issn = "0008-5472",
    publisher = "American Association for Cancer Research",
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    Alazzouzi, H, Davalos, V, Kokko, A, Domingo, E, Woerner, SM, Wilson, AJ, Konrad, L, Laiho, P, Espin, E, Armengol, M, Imai, K, Yamamoto, H, Mariadason, JM, Gebert, JF, Aaltonen, LA, Schwartz, S & Arango, D 2005, 'Mechanisms of inactivation of the receptor tyrosine kinase EPHB2 in colorectal tumors', Cancer Research, vol. 65, no. 22, pp. 10170-10173. https://doi.org/10.1158/0008-5472.CAN-05-2580

    Mechanisms of inactivation of the receptor tyrosine kinase EPHB2 in colorectal tumors. / Alazzouzi, Hafid; Davalos, Veronica; Kokko, Antti; Domingo, Enric; Woerner, Stefan M; Wilson, Andrew J; Konrad, Lars; Laiho, Päivi; Espin, Eloi; Armengol, Manel; Imai, Kohzoh; Yamamoto, Hiroyuki; Mariadason, John M; Gebert, Johannes F; Aaltonen, Lauri A; Schwartz, Simo; Arango, Diego.

    In: Cancer Research, Vol. 65, No. 22, 2005, p. 10170-10173.

    Research output: Contribution to journalArticleScientificpeer-review

    TY - JOUR

    T1 - Mechanisms of inactivation of the receptor tyrosine kinase EPHB2 in colorectal tumors

    AU - Alazzouzi, Hafid

    AU - Davalos, Veronica

    AU - Kokko, Antti

    AU - Domingo, Enric

    AU - Woerner, Stefan M

    AU - Wilson, Andrew J

    AU - Konrad, Lars

    AU - Laiho, Päivi

    AU - Espin, Eloi

    AU - Armengol, Manel

    AU - Imai, Kohzoh

    AU - Yamamoto, Hiroyuki

    AU - Mariadason, John M

    AU - Gebert, Johannes F

    AU - Aaltonen, Lauri A

    AU - Schwartz, Simo

    AU - Arango, Diego

    PY - 2005

    Y1 - 2005

    N2 - The receptor tyrosine kinase EPHB2 has recently been shown to be a direct transcriptional target of TCF/beta-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 (NISI), 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-2'-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.

    AB - The receptor tyrosine kinase EPHB2 has recently been shown to be a direct transcriptional target of TCF/beta-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 (NISI), 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-2'-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.

    KW - 311 Basic medicine

    U2 - 10.1158/0008-5472.CAN-05-2580

    DO - 10.1158/0008-5472.CAN-05-2580

    M3 - Article

    VL - 65

    SP - 10170

    EP - 10173

    JO - Cancer Research

    JF - Cancer Research

    SN - 0008-5472

    IS - 22

    ER -

    Alazzouzi H, Davalos V, Kokko A, Domingo E, Woerner SM, Wilson AJ et al. Mechanisms of inactivation of the receptor tyrosine kinase EPHB2 in colorectal tumors. Cancer Research. 2005;65(22):10170-10173. https://doi.org/10.1158/0008-5472.CAN-05-2580