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Title :Early-Stage Induction of SWI/SNF Mutations during Esophageal Squamous Cell Carcinogenesis
Title alternative :SIW/SNF遺伝子異常の食道扁平上皮がん発がんの早期における誘発
Authors :仲里, 秀次
Authors alternative :Nakazato, Hidetsugu
Issue Date :26-Jan-2017
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.
Type Local :学位論文
Publisher :University of the Ryukyus
URI :http://hdl.handle.net/20.500.12000/36588
Grant id :18001医研第458号
Date of granted :2017-03-24
Degree name :博士(医学)
Grantor :琉球大学
Appears in Collections:Doctoral Dissertation (Graduate School of Medicine)

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