title: Early-Stage Induction of SWI/SNF Mutations during Esophageal Squamous Cell Carcinogenesis.
abstract: The SWI/SNF chromatin remodeling complex is frequently inactivated by somatic mutations of its various components in various types of cancers, and also by aberrant DNA methylation. However, its somatic mutations and aberrant methylation in esophageal squamous cell carcinomas (ESCCs) have not been fully analyzed. In this study, we aimed to clarify in ESCC, what components of the SWI/SNF complex have somatic mutations and aberrant methylation, and when somatic mutations of the SWI/SNF complex occur. Deep sequencing of components of the SWI/SNF complex using a bench-top next generation sequencer revealed that eight of 92 ESCCs (8.7%) had 11 somatic mutations of 7 genes, ARID1A, ARID2, ATRX, PBRM1, SMARCA4, SMARCAL1, and SMARCC1. The SMARCA4 mutations were located in the Forkhead (85Ser>Leu) and SNF2 family N-terminal (882Glu>Lys) domains. The PBRM1 mutations were located in a bromodomain (80Asn>Ser) and an HMG-box domain (1,377Glu>Lys). For most mutations, their mutant allele frequency was 31-77% (mean 61%) of the fraction of cancer cells in the same samples, indicating that most of the cancer cells in individual ESCC samples had the SWI/SNF mutations on one allele, when present. In addition, a BeadChip array analysis revealed that a component of the SWI/SNF complex, ACTL6B, had aberrant methylation at its promoter CpG island in 18 of 52 ESCCs (34.6%). These results showed that genetic and epigenetic alterations of the SWI/SNF complex are present in ESCCs, and suggested that genetic alterations are induced at an early stage of esophageal squamous cell carcinogenesis.
authors.affiliation: Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan.|Esophageal Surgery Division, National Cancer Center Hospital, Tokyo, Japan.|Department of Thoracic and Cardiovascular Surgery, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
authors.forename: Hidetsugu
authors.initials: H
authors.lastname: Nakazato
authors.affiliation: Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Takeshima
authors.affiliation: Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Kishino
authors.affiliation: Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Emi
authors.initials: E
authors.lastname: Kubo
authors.affiliation: Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Hattori
authors.affiliation: Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nakajima
authors.affiliation: Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamashita
authors.affiliation: Esophageal Surgery Division, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Igaki
authors.affiliation: Esophageal Surgery Division, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Tachimori
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Kuniyoshi
authors.affiliation: Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Ushijima
mesh_terms: D000199:Actins / Q000235:genetics; D000328:Adult; D000368:Aged; D000483:Alleles; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics*; D018899:CpG Islands; D004273:DNA, Neoplasm / Q000737:chemistry / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D005787:Gene Frequency; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011401:Promoter Regions, Genetic; D017422:Sequence Analysis, DNA; D015265:Site-Specific DNA-Methyltransferase (Adenine-Specific)
chemical_list: C467332:ACTL6B protein, human; D000199:Actins; D002868:Chromosomal Proteins, Non-Histone; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; C098075:DNA modification methylase CcrM; D015265:Site-Specific DNA-Methyltransferase (Adenine-Specific)
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