PMID- 30252132
OWN - NLM
STAT- MEDLINE
DCOM- 20190422
LR  - 20190422
IS  - 1097-0215 (Electronic)
IS  - 0020-7136 (Linking)
VI  - 144
IP  - 3
DP  - 2019 Feb 1
TI  - Epigenetic regulation of Amphiregulin and Epiregulin in colorectal cancer.
PG  - 569-581
LID - 10.1002/ijc.31892 [doi]
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.
CI  - (c) 2018 UICC.
FAU - Bormann, Felix
AU  - Bormann F
AD  - Charite Universitatsmedizin Berlin, Institute of Pathology, Laboratory of 
      Molecular Tumor Pathology and Systems Biology, Berlin, Germany.
FAU - Stinzing, Sebastian
AU  - Stinzing S
AUID- ORCID: 0000-0002-3297-5801
AD  - Department of Hematology and Medical Oncology, Klinikum der Universitat Munchen 
      (LMU); German Cancer Consortium site Munich (DKTK); German Cancer Research Centre 
      (DKFZ), Heidelberg, Germany.
FAU - Tierling, Sascha
AU  - Tierling S
AD  - Department of Genetics/Epigenetics, FR8.3 Life Sciences, Saarland University, 
      Saarbrucken.
FAU - Morkel, Markus
AU  - Morkel M
AD  - Charite Universitatsmedizin Berlin, Institute of Pathology, Laboratory of 
      Molecular Tumor Pathology and Systems Biology, Berlin, Germany.
AD  - DKTK, German Consortium for Translational Cancer Research, Partner Site Berlin 
      and DKFZ, German Cancer Research Center, Heidelberg, Germany.
FAU - Markelova, Maria Rivera
AU  - Markelova MR
AD  - EPO Experimental Pharmacology and Oncology, Berlin, Germany.
FAU - Walter, Jorn
AU  - Walter J
AD  - Department of Genetics/Epigenetics, FR8.3 Life Sciences, Saarland University, 
      Saarbrucken.
FAU - Weichert, Wilko
AU  - Weichert W
AD  - DKTK, German Consortium for Translational Cancer Research, Partner Site Berlin 
      and DKFZ, German Cancer Research Center, Heidelberg, Germany.
AD  - Institute of Pathology, Technical University Munich, Germany and Munich German 
      Cancer Consortium (DKTK), German Cancer Research Centre (DKFZ), Heidelberg, 
      Germany.
FAU - Rossner, Florian
AU  - Rossner F
AD  - Charite Universitatsmedizin Berlin, Institute of Pathology, Laboratory of 
      Molecular Tumor Pathology and Systems Biology, Berlin, Germany.
FAU - Kuhn, Natalia
AU  - Kuhn N
AD  - Charite Universitatsmedizin Berlin, Institute of Pathology, Laboratory of 
      Molecular Tumor Pathology and Systems Biology, Berlin, Germany.
FAU - Perner, Juliane
AU  - Perner J
AD  - Max Planck Institute for Molecular Genetics, Berlin, Germany.
FAU - Dietz, Johanna
AU  - Dietz J
AD  - Charite Universitatsmedizin Berlin, Institute of Pathology, Laboratory of 
      Molecular Tumor Pathology and Systems Biology, Berlin, Germany.
FAU - Ispasanie, Sylvia
AU  - Ispasanie S
AD  - Charite Universitatsmedizin Berlin, Institute of Pathology, Laboratory of 
      Molecular Tumor Pathology and Systems Biology, Berlin, Germany.
AD  - BSIO Berlin School of Integrative Oncology, University Medicine Charite, Berlin, 
      Germany.
FAU - Dietel, Manfred
AU  - Dietel M
AD  - Charite Universitatsmedizin Berlin, Institute of Pathology, Laboratory of 
      Molecular Tumor Pathology and Systems Biology, Berlin, Germany.
AD  - DKTK, German Consortium for Translational Cancer Research, Partner Site Berlin 
      and DKFZ, German Cancer Research Center, Heidelberg, Germany.
FAU - Schafer, Reinhold
AU  - Schafer R
AD  - Charite Universitatsmedizin Berlin, Institute of Pathology, Laboratory of 
      Molecular Tumor Pathology and Systems Biology, Berlin, Germany.
AD  - DKTK, German Consortium for Translational Cancer Research, Partner Site Berlin 
      and DKFZ, German Cancer Research Center, Heidelberg, Germany.
FAU - Heinemann, Volker
AU  - Heinemann V
AD  - Department of Hematology and Medical Oncology, Klinikum der Universitat Munchen 
      (LMU); German Cancer Consortium site Munich (DKTK); German Cancer Research Centre 
      (DKFZ), Heidelberg, Germany.
FAU - Sers, Christine
AU  - Sers C
AUID- ORCID: 0000-0002-6219-1514
AD  - Charite Universitatsmedizin Berlin, Institute of Pathology, Laboratory of 
      Molecular Tumor Pathology and Systems Biology, Berlin, Germany.
AD  - DKTK, German Consortium for Translational Cancer Research, Partner Site Berlin 
      and DKFZ, German Cancer Research Center, Heidelberg, Germany.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20181107
PL  - United States
TA  - Int J Cancer
JT  - International journal of cancer
JID - 0042124
RN  - 0 (AREG protein, human)
RN  - 0 (Amphiregulin)
RN  - 0 (EREG protein, human)
RN  - 0 (Epiregulin)
RN  - 0 (KRAS protein, human)
RN  - 0 (RNA, Messenger)
RN  - EC 2.7.10.1 (EGFR protein, human)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
SB  - IM
MH  - Amphiregulin/biosynthesis/*genetics
MH  - Caco-2 Cells
MH  - Cell Line, Tumor
MH  - Colorectal Neoplasms/*genetics/metabolism/pathology
MH  - DNA Methylation
MH  - Epigenesis, Genetic
MH  - Epiregulin/*genetics
MH  - Epithelial Cells/metabolism/pathology
MH  - ErbB Receptors/genetics/metabolism
MH  - Gene Expression
MH  - HCT116 Cells
MH  - Humans
MH  - Promoter Regions, Genetic
MH  - Proto-Oncogene Proteins p21(ras)/genetics/metabolism
MH  - RNA, Messenger/biosynthesis/genetics
MH  - Retrospective Studies
MH  - Stromal Cells/metabolism/pathology
OTO - NOTNLM
OT  - DNA methylation
OT  - amphiregulin
OT  - expression
OT  - prediction
EDAT- 2018/09/27 06:00
MHDA- 2019/04/23 06:00
CRDT- 2018/09/26 06:00
PHST- 2018/05/15 00:00 [received]
PHST- 2018/08/05 00:00 [revised]
PHST- 2018/08/20 00:00 [accepted]
PHST- 2018/09/27 06:00 [pubmed]
PHST- 2019/04/23 06:00 [medline]
PHST- 2018/09/26 06:00 [entrez]
AID - 10.1002/ijc.31892 [doi]
PST - ppublish
SO  - Int J Cancer. 2019 Feb 1;144(3):569-581. doi: 10.1002/ijc.31892. Epub 2018 Nov 7.