title: Genes involved in development and differentiation are commonly methylated in cancers derived from multiple organs: a single-institutional methylome analysis using 1007 tissue specimens.
abstract: The aim of this study was to clarify the significance of DNA methylation alterations shared by cancers derived from multiple organs. We analyzed single-institutional methylome data by single-CpG-resolution Infinium assay for 1007 samples of non-cancerous tissue (N) and corresponding cancerous tissue (T) obtained from lung, stomach, kidney, breast and liver. Principal component analysis revealed that N samples of each organ showed distinct DNA methylation profiles, DNA methylation profiles of N samples of each organ being inherited by the corresponding T samples and DNA methylation profiles of T samples being more similar to those of N samples in the same organ than those of T samples in other organs. In contrast to such organ and/or carcinogenetic factor-specificity of DNA methylation profiles, when compared with the corresponding N samples, 231 genes commonly showed DNA hypermethylation in T samples in four or more organs. Gene ontology enrichment analysis showed that such commonly methylated genes were enriched among "transcriptional factors" participating in development and/or differentiation, which reportedly show bivalent histone modification in embryonic stem cells. Pyrosequencing and quantitative reverse transcription-PCR revealed an inverse correlation between DNA methylation levels and mRNA expression levels of representative commonly methylated genes, such as ALX1, ATP8A2, CR1 and EFCAB1, in tissue samples. These data suggest that disruption of the differentiated state of precancerous cells via alterations of expression, independent of differences in organs and/or carcinogenetic factors, may be a common feature of DNA methylation alterations during carcinogenesis in multiple organs.
authors.affiliation: Department of Pathology, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Ohara
authors.affiliation: Department of Pathology, Keio University School of Medicine, Tokyo 160-8582, Japan.|Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Arai
authors.affiliation: Biomedical Department, Solution Center, Mitsui Knowledge Industry Co., Ltd., Tokyo 105-6215, Japan.
authors.forename: Yoriko
authors.initials: Y
authors.lastname: Takahashi
authors.affiliation: Department of Pathology, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Nanako
authors.initials: N
authors.lastname: Ito
authors.affiliation: Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Shibuya
authors.affiliation: Department of Pathology and Clinical Laboratories, Pathology Division, National Cancer Center Hospital, Tokyo 104-0045, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Tsuta
authors.affiliation: Department of Pathology and Clinical Laboratories, Pathology Division, National Cancer Center Hospital, Tokyo 104-0045, Japan.
authors.forename: Ryoji
authors.initials: R
authors.lastname: Kushima
authors.affiliation: Department of Pathology and Clinical Laboratories, Pathology Division, National Cancer Center Hospital, Tokyo 104-0045, Japan.|Department of Basic Pathology, National Defense Medical College, Saitama 359-0042, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Tsuda
authors.affiliation: Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ojima
authors.affiliation: Department of Urology.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Fujimoto
authors.affiliation: Department of Thoracic Surgery.
authors.forename: Shun-Ichi
authors.initials: SI
authors.lastname: Watanabe
authors.affiliation: Department of Gastric Surgery and.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Katai
authors.affiliation: Department of Breast Surgery, National Cancer Center Hospital, Tokyo 104-0045, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Kinoshita
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo 104-0045, Japan.|Laboratory of Molecular Medicine, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-0071, Japan and.
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Shibata
authors.affiliation: Division of Genome Biology, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kohno
authors.affiliation: Department of Pathology, Keio University School of Medicine, Tokyo 160-8582, Japan.|Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
authors.forename: Yae
authors.initials: Y
authors.lastname: Kanai
mesh_terms: D000328:Adult; D000368:Aged; D001940:Breast / Q000378:metabolism / Q000473:pathology; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011230:Precancerous Conditions / Q000235:genetics* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D013270:Stomach / Q000473:pathology
chemical_list: C489985:ALX1 protein, human; D018398:Homeodomain Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger