title: Identification of long-range epigenetic silencing on chromosome 15q25 and its clinical implication in gastric cancer.
abstract: Recent genome-wide epigenomic and transcription profiling studies have demonstrated that epigenetic silencing can encompass multiple neighboring genes, termed as long-range epigenetic silencing (LRES). Herein, we identified a novel LRES region by comparing gene expression of human colon cancer HCT116 cells with their DNA methyltransferase 1 and DNA methyltransferase 3B double-knockout derivative double-knockout cells. Ten consecutive genes spanning 3 Mb of chromosome 15q25 were coordinately silenced, with eight genes showing promoter CpG island hypermethylation and enrichment of repressive histone marks, which were evaluated by bisulfite sequencing analysis and chromatin immunoprecipitation assay. Comparison of primary gastric tumor specimens with normal tissue confirmed that the long-range silencing of this region was tumor specific. Methylation of genes within the LRES region was evaluated in 190 gastric tumor tissues using the MethyLight assay, and their association with clinicopathological features, such as older age, high-grade differentiation, and diffuse or mixed-type histology, was determined. LRES-positive gastric cancer patients (six or more methylated genes) showed lower recurrence and better survival. Our findings emphasize the differential dynamics of DNA methylation and histone modification, indicating the importance of studying the relationship of each epigenetic modification in the context of chromatin domains. Patients with LRES showed lower recurrence and better prognosis, indicating that stratifying patients according to underlying molecular features, such as LRES regions, may better predict recurrence and survival.
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea.
authors.forename: Jee-Youn
authors.initials: JY
authors.lastname: Kang
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Sang-Hyun
authors.initials: SH
authors.lastname: Song
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea.
authors.forename: Jiyeon
authors.initials: J
authors.lastname: Yun
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea.
authors.forename: Mi-Seong
authors.initials: MS
authors.lastname: Jeon
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Cha
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea.
authors.forename: Si-Hyun
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Hwang-Phill
authors.initials: HP
authors.lastname: Kim
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Eun-Goo
authors.initials: EG
authors.lastname: Jeong
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
authors.forename: Sae-Won
authors.initials: SW
authors.lastname: Han
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Nam-Yun
authors.initials: NY
authors.lastname: Cho
authors.affiliation: Department of Pathology, National Cancer Center, Goyang, Republic of Korea.
authors.forename: Myeong Cherl
authors.initials: MC
authors.lastname: Kook
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea. Electronic address: ghkang@snu.ac.kr.
authors.forename: Gyeong Hoon
authors.initials: GH
authors.lastname: Kang
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea; Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea. Electronic address: kimty@snu.ac.kr.
authors.forename: Tae-You
authors.initials: TY
authors.lastname: Kim
mesh_terms: D000328:Adult; D000368:Aged; D002884:Chromosomes, Human, Pair 15; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D020868:Gene Silencing; D006657:Histones; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D011401:Promoter Regions, Genetic; D013274:Stomach Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D015996:Survival Rate; D055815:Young Adult
chemical_list: D006657:Histones