Epigenetic regulation of Amphiregulin and Epiregulin in colorectal cancer

Felix Bormann; Sebastian Stinzing; Sascha Tierling; Markus Morkel; Maria Rivera Markelova; Jörn Walter; Wilko Weichert; Florian Roßner; Natalia Kuhn; Juliane Perner; Johanna Dietz; Sylvia Ispasanie; Manfred Dietel; Reinhold Schäfer; Volker Heinemann; Christine Sers

doi:10.1002/ijc.31892

Epigenetic regulation of Amphiregulin and Epiregulin in colorectal cancer

Felix Bormann, Sebastian Stinzing, Sascha Tierling, Markus Morkel, Maria Rivera Markelova, Jörn Walter, Wilko Weichert, Florian Roßner, Natalia Kuhn, Juliane Perner, Johanna Dietz, Sylvia Ispasanie, Manfred Dietel, Reinhold Schäfer, Volker Heinemann, Christine Sers

Chair of Pathology

Research output: Contribution to journal › Article › peer-review

20 Scopus citations

Abstract

Expression of the epidermal growth factor ligands amphiregulin (AREG) and epiregulin (EREG) is positively correlated with a response to EGFR-targeted therapies in colorectal cancer. Gene-body methylation sites, which show a strong inverse correlation with AREG and EREG gene expression, were identified in cell lines using targeted 454 FLX-bisulfite sequencing and SIRPH analyses for AREG/EREG promoters and intragenic CpGs. Upon treatment of colorectal cancer cells with 5-aza-2′-desoxycytidine, methylation decreases at specific intragenic CpGs accompanied by upregulation of AREG and EREG gene expression. The same AREG gene-body methylation was also found in human colorectal cancer samples and is independent of KRAS and NRAS mutations. Methylation is specifically decreased in the tumor epithelial compartment as compared to stromal tissue and normal epithelium. Investigation of a promoter/enhancer function of the AREG exon 2 region revealed a potential promoter function in reverse orientation. Retrospective comparison of the predictive power of AREG gene-body methylation versus AREG gene expression using samples from colorectal cancer patients treated with anti-EGFR inhibitors with complete clinical follow-up revealed that AREG expression is superior to AREG gene methylation. AREG and EREG genes undergo a complex regulation involving both intragenic methylation and promoter-dependent control.

Original language	English
Pages (from-to)	569-581
Number of pages	13
Journal	International Journal of Cancer
Volume	144
Issue number	3
DOIs	https://doi.org/10.1002/ijc.31892
State	Published - 1 Feb 2019

Keywords

DNA methylation
amphiregulin
expression
prediction

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/ijc.31892

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Bormann, F., Stinzing, S., Tierling, S., Morkel, M., Markelova, M. R., Walter, J., Weichert, W., Roßner, F., Kuhn, N., Perner, J., Dietz, J., Ispasanie, S., Dietel, M., Schäfer, R., Heinemann, V., & Sers, C. (2019). Epigenetic regulation of Amphiregulin and Epiregulin in colorectal cancer. International Journal of Cancer, 144(3), 569-581. https://doi.org/10.1002/ijc.31892

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title = "Epigenetic regulation of Amphiregulin and Epiregulin in colorectal cancer",

abstract = "Expression of the epidermal growth factor ligands amphiregulin (AREG) and epiregulin (EREG) is positively correlated with a response to EGFR-targeted therapies in colorectal cancer. Gene-body methylation sites, which show a strong inverse correlation with AREG and EREG gene expression, were identified in cell lines using targeted 454 FLX-bisulfite sequencing and SIRPH analyses for AREG/EREG promoters and intragenic CpGs. Upon treatment of colorectal cancer cells with 5-aza-2′-desoxycytidine, methylation decreases at specific intragenic CpGs accompanied by upregulation of AREG and EREG gene expression. The same AREG gene-body methylation was also found in human colorectal cancer samples and is independent of KRAS and NRAS mutations. Methylation is specifically decreased in the tumor epithelial compartment as compared to stromal tissue and normal epithelium. Investigation of a promoter/enhancer function of the AREG exon 2 region revealed a potential promoter function in reverse orientation. Retrospective comparison of the predictive power of AREG gene-body methylation versus AREG gene expression using samples from colorectal cancer patients treated with anti-EGFR inhibitors with complete clinical follow-up revealed that AREG expression is superior to AREG gene methylation. AREG and EREG genes undergo a complex regulation involving both intragenic methylation and promoter-dependent control.",

keywords = "DNA methylation, amphiregulin, expression, prediction",

author = "Felix Bormann and Sebastian Stinzing and Sascha Tierling and Markus Morkel and Markelova, {Maria Rivera} and J{\"o}rn Walter and Wilko Weichert and Florian Ro{\ss}ner and Natalia Kuhn and Juliane Perner and Johanna Dietz and Sylvia Ispasanie and Manfred Dietel and Reinhold Sch{\"a}fer and Volker Heinemann and Christine Sers",

note = "Publisher Copyright: {\textcopyright} 2018 UICC",

year = "2019",

month = feb,

day = "1",

doi = "10.1002/ijc.31892",

language = "English",

volume = "144",

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Bormann, F, Stinzing, S, Tierling, S, Morkel, M, Markelova, MR, Walter, J, Weichert, W, Roßner, F, Kuhn, N, Perner, J, Dietz, J, Ispasanie, S, Dietel, M, Schäfer, R, Heinemann, V & Sers, C 2019, 'Epigenetic regulation of Amphiregulin and Epiregulin in colorectal cancer', International Journal of Cancer, vol. 144, no. 3, pp. 569-581. https://doi.org/10.1002/ijc.31892

TY - JOUR

T1 - Epigenetic regulation of Amphiregulin and Epiregulin in colorectal cancer

AU - Bormann, Felix

AU - Stinzing, Sebastian

AU - Tierling, Sascha

AU - Morkel, Markus

AU - Markelova, Maria Rivera

AU - Walter, Jörn

AU - Weichert, Wilko

AU - Roßner, Florian

AU - Kuhn, Natalia

AU - Perner, Juliane

AU - Dietz, Johanna

AU - Ispasanie, Sylvia

AU - Dietel, Manfred

AU - Schäfer, Reinhold

AU - Heinemann, Volker

AU - Sers, Christine

PY - 2019/2/1

Y1 - 2019/2/1

N2 - Expression of the epidermal growth factor ligands amphiregulin (AREG) and epiregulin (EREG) is positively correlated with a response to EGFR-targeted therapies in colorectal cancer. Gene-body methylation sites, which show a strong inverse correlation with AREG and EREG gene expression, were identified in cell lines using targeted 454 FLX-bisulfite sequencing and SIRPH analyses for AREG/EREG promoters and intragenic CpGs. Upon treatment of colorectal cancer cells with 5-aza-2′-desoxycytidine, methylation decreases at specific intragenic CpGs accompanied by upregulation of AREG and EREG gene expression. The same AREG gene-body methylation was also found in human colorectal cancer samples and is independent of KRAS and NRAS mutations. Methylation is specifically decreased in the tumor epithelial compartment as compared to stromal tissue and normal epithelium. Investigation of a promoter/enhancer function of the AREG exon 2 region revealed a potential promoter function in reverse orientation. Retrospective comparison of the predictive power of AREG gene-body methylation versus AREG gene expression using samples from colorectal cancer patients treated with anti-EGFR inhibitors with complete clinical follow-up revealed that AREG expression is superior to AREG gene methylation. AREG and EREG genes undergo a complex regulation involving both intragenic methylation and promoter-dependent control.

AB - Expression of the epidermal growth factor ligands amphiregulin (AREG) and epiregulin (EREG) is positively correlated with a response to EGFR-targeted therapies in colorectal cancer. Gene-body methylation sites, which show a strong inverse correlation with AREG and EREG gene expression, were identified in cell lines using targeted 454 FLX-bisulfite sequencing and SIRPH analyses for AREG/EREG promoters and intragenic CpGs. Upon treatment of colorectal cancer cells with 5-aza-2′-desoxycytidine, methylation decreases at specific intragenic CpGs accompanied by upregulation of AREG and EREG gene expression. The same AREG gene-body methylation was also found in human colorectal cancer samples and is independent of KRAS and NRAS mutations. Methylation is specifically decreased in the tumor epithelial compartment as compared to stromal tissue and normal epithelium. Investigation of a promoter/enhancer function of the AREG exon 2 region revealed a potential promoter function in reverse orientation. Retrospective comparison of the predictive power of AREG gene-body methylation versus AREG gene expression using samples from colorectal cancer patients treated with anti-EGFR inhibitors with complete clinical follow-up revealed that AREG expression is superior to AREG gene methylation. AREG and EREG genes undergo a complex regulation involving both intragenic methylation and promoter-dependent control.

KW - DNA methylation

KW - amphiregulin

KW - expression

KW - prediction

UR - http://www.scopus.com/inward/record.url?scp=85056165771&partnerID=8YFLogxK

U2 - 10.1002/ijc.31892

DO - 10.1002/ijc.31892

M3 - Article

C2 - 30252132

AN - SCOPUS:85056165771

SN - 0020-7136

VL - 144

SP - 569

EP - 581

JO - International Journal of Cancer

JF - International Journal of Cancer

IS - 3

ER -

Epigenetic regulation of Amphiregulin and Epiregulin in colorectal cancer

Abstract

Keywords

UN SDGs

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