title: Frequent involvement of chromatin remodeler alterations in gastric field cancerization.
abstract: A field for cancerization, or a field defect, is formed by the accumulation of genetic and epigenetic alterations in normal-appearing tissues, and is involved in various cancers, especially multiple cancers. Epigenetic alterations are frequently present in chronic inflammation-exposed tissues, but information on individual genes involved in the formation of a field defect is still fragmental. Here, using non-cancerous gastric tissues of cancer patients, we isolated 16 aberrantly methylated genes, and identified chromatin remodelers ACTL6B and SMARCA1 as novel genes frequently methylated in non-cancerous tissues. SMARCA1 was expressed at high levels in normal gastric tissues, but was frequently silenced by aberrant methylation in gastric cancer cells. Moreover, somatic mutations of additional chromatin remodelers, such as ARID1A, SMARCA2, and SMARCA4, were found in 30% of gastric cancers. Mutant allele frequency suggested that the majority of cancer cells harbored a mutation when present. Depletion of a chromatin remodeler, SMARCA1 or SMARCA2, in cancer cell lines promoted their growth. These results showed that epigenetic and genetic alterations of chromatin remodelers are induced at an early stage of carcinogenesis and are frequently involved in the formation of a field defect.
authors.affiliation: Division of Epigenomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Takeshima
authors.affiliation: Division of Epigenomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Niwa
authors.affiliation: Division of Epigenomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Takamasa
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Division of Epigenomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Mika
authors.initials: M
authors.lastname: Wakabayashi
authors.affiliation: Division of Epigenomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamashita
authors.affiliation: Third Department of Internal Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ando
authors.affiliation: Division of Carcinogenesis and Cancer Prevention, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Inagawa
authors.affiliation: Pathology Division and Clinical Laboratory, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Taniguchi
authors.affiliation: Gastric Surgery Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Katai
authors.affiliation: Third Department of Internal Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Sugiyama
authors.affiliation: Division of Carcinogenesis and Cancer Prevention, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Kiyono
authors.affiliation: Division of Epigenomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. Electronic address: tushijim@ncc.go.jp.
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Ushijima
mesh_terms: D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D044127:Epigenesis, Genetic; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D012307:Risk Factors; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; C499336:SMARCA1 protein, human; D014157:Transcription Factors
keywords: Chromatin remodeling; DNA methylation; Epigenetics; Field defect