title: Aberrant TET1 Methylation Closely Associated with CpG Island Methylator Phenotype in Colorectal Cancer.
abstract: Inactivation of methylcytosine dioxygenase, ten-eleven translocation (TET) is known to be associated with aberrant DNA methylation in cancers. Tumors with a CpG island methylator phenotype (CIMP), a distinct subgroup with extensive DNA methylation, show characteristic features in the case of colorectal cancer. The relationship between TET inactivation and CIMP in colorectal cancers is not well understood. The expression level of TET family genes was compared between CIMP-positive (CIMP-P) and CIMP-negative (CIMP-N) colorectal cancers. Furthermore, DNA methylation profiling, including assessment of the TET1 gene, was assessed in colorectal cancers, as well as colon polyps. The TET1 was silenced by DNA methylation in a subset of colorectal cancers as well as cell lines, expression of which was reactivated by demethylating agent. TET1 methylation was more frequent in CIMP-P (23/55, 42%) than CIMP-N (2/113, 2%, P < 0.0001) colorectal cancers. This trend was also observed in colon polyps (CIMP-P, 16/40, 40%; CIMP-N, 2/24, 8%; P = 0.002), suggesting that TET1 methylation is an early event in CIMP tumorigenesis. TET1 methylation was significantly associated with BRAF mutation but not with hMLH1 methylation in the CIMP-P colorectal cancers. Colorectal cancers with TET1 methylation have a significantly greater number of DNA methylated genes and less pathological metastasis compared to those without TET1 methylation (P = 0.007 and 0.045, respectively). Our data suggest that TET1 methylation may contribute to the establishment of a unique pathway in respect to CIMP-mediated tumorigenesis, which may be incidental to hMLH1 methylation. In addition, our findings provide evidence that TET1 methylation may be a good biomarker for the prediction of metastasis in colorectal cancer.
authors.affiliation: Department of Epigenomics, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. Department of Oral and Maxillofacial Surgery, Nagoya University School of Medicine, Nagoya, Japan.
authors.forename: Norihisa
authors.initials: N
authors.lastname: Ichimura
authors.affiliation: Department of Epigenomics, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Shinjo
authors.affiliation: Department of Surgery, Ako City Hospital, Ako, Japan.
authors.forename: Byonggu
authors.initials: B
authors.lastname: An
authors.affiliation: Department of Gastrointestinal Surgery, Aichi Cancer Center, Nagoya, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Shimizu
authors.affiliation: Department of Gastroenterology, Aichi Cancer Center, Nagoya, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Yamao
authors.affiliation: Department of Epigenomics, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Fumiharu
authors.initials: F
authors.lastname: Ohka
authors.affiliation: Department of Epigenomics, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Katsushima
authors.affiliation: Department of Epigenomics, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Hatanaka
authors.affiliation: Department of Epigenomics, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Tojo
authors.affiliation: Department of Molecular Biology, Sapporo Medical University, Sapporo, Japan.
authors.forename: Eiichiro
authors.initials: E
authors.lastname: Yamamoto
authors.affiliation: Department of Molecular Biology, Sapporo Medical University, Sapporo, Japan.
authors.forename: Hiromu
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Department of Oral and Maxillofacial Surgery, Nagoya University School of Medicine, Nagoya, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Ueda
authors.affiliation: Department of Epigenomics, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. ykondo@med.nagoya-cu.ac.jp.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kondo
mesh_terms: D002288:Adenocarcinoma, Mucinous / Q000235:genetics* / Q000473:pathology; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D015153:Blotting, Western; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D006899:Mixed Function Oxygenases; D009154:Mutation; D009367:Neoplasm Staging; D010641:Phenotype; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D006899:Mixed Function Oxygenases; C462539:TET1 protein, human