title: Integrated analysis of DNA methylation and mutations in esophageal squamous cell carcinoma.
abstract: The recent development of next-generation sequencing technology for extensive mutation analysis, and beadarray technology for genome-wide DNA methylation analysis has made it possible to obtain integrated pictures of genetic and epigenetic alterations, using the same cancer samples. In this study, we aimed to characterize such a picture in esophageal squamous cell carcinomas (ESCCs). Base substitutions of 55 cancer-related genes and copy number alterations (CNAs) of 28 cancer-related genes were analyzed by targeted sequencing. Forty-four of 57 ESCCs (77%) had 64 non-synonymous somatic mutations, and 24 ESCCs (42%) had 35 CNAs. A genome-wide DNA methylation analysis using an Infinium HumanMethylation450 BeadChip array showed that the CpG island methylator phenotype was unlikely to be present in ESCCs, a different situation from gastric and colon cancers. Regarding individual pathways affected in ESCCs, the WNT pathway was activated potentially by aberrant methylation of its negative regulators, such as SFRP1, SFRP2, SFRP4, SFRP5, SOX17, and WIF1 (33%). The p53 pathway was inactivated by TP53 mutations (70%), and potentially by aberrant methylation of its downstream genes. The cell cycle was deregulated by mutations of CDKN2A (9%), deletions of CDKN2A and RB1 (32%), and by aberrant methylation of CDKN2A and CHFR (9%). In conclusion, ESCCs had unique methylation profiles different from gastric and colon cancers. The genes involved in the WNT pathway were affected mainly by epigenetic alterations, and those involved in the p53 pathway and cell cycle regulation were affected mainly by genetic alterations. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan.|Division of Esophageal Surgery, National Cancer Center Hospital, Tokyo, Japan.|Department of Gastroenterological Surgery, Kagawa University, Kagawa, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Kishino
authors.affiliation: Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Niwa
authors.affiliation: Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamashita
authors.affiliation: Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan.|Division of Esophageal Surgery, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Takamasa
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan.|Division of Esophageal Surgery, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Hidetsugu
authors.initials: H
authors.lastname: Nakazato
authors.affiliation: Division of Endoscopy, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nakajima
authors.affiliation: Division of Esophageal Surgery, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Igaki
authors.affiliation: Division of Esophageal Surgery, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Tachimori
authors.affiliation: Department of Gastroenterological Surgery, Kagawa University, Kagawa, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Ushijima
mesh_terms: D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology*; D000077277:Esophageal Squamous Cell Carcinoma; D004947:Esophagus / Q000378:metabolism / Q000473:pathology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D060449:Wnt Signaling Pathway
keywords: DNA methylation; cancer-related pathway; epigenetics; esophageal squamous cell carcinoma (ESCC); genetic alterations