変異した染色体トポロジーは,SDH欠乏性GISTにおける腫瘍性プログラムを駆動する
William A Flavahan1,2, Yotam Drier3,4,5, Sarah E Johnstone1,2
1Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Nature
|November 1, 2019
まとめ
変異を欠く胃腸筋腫瘍 (GIST) の表遺伝的変化は,ゲノム構造を変化させることで腫瘍遺伝子を活性化します. この研究は,これらのがんに対する新しい治療標的,特にFGF受容体阻害剤を特定しています.
科学分野:
- 腫瘍学
- エピジェネティクス
- ゲノミクス
背景:
- エピジェネティック異常は がんではよく見られるが,よくわかっていない.
- サクシネート脱水素酵素 (SDH) 欠乏症の胃腸筋腫瘍 (GIST) は,キナーゼ変異ではなく,全局的なDNA超メチル化を示している.
研究 の 目的:
- エピジェネティック変異がSDH欠乏性GISTで腫瘍性プログラムを活性化するメカニズムを調査する.
- 異なるGISTサブタイプにおけるDNAメチル化,CTCF分離体,増強体,染色体トポロジをマッピングする.
主な方法:
- DNAメチル化,CTCF分離体,増強体,および染色体トポロジーの体系的なマッピング.
- GISTモデルにおけるCRISPRによる遺伝子編集
- 患者に由来する異種移植 (PDX) モデルの作成と分析
主要な成果:
- SDH欠乏のGISTは,数百の絶縁体でCTCF結合を代替するDNAメチル化を示しています.
- SDH欠乏のGISTにおける特定の絶縁体の喪失は,FGF4腫瘍遺伝子を活性化し,ゲノムトポロジーを変化させます.
- 患者から得られた異種移植モデルでは,FGFRとKIT抑制に対する表遺伝的欠陥と感受性が確認されました.
結論:
- 隔離器の欠陥やゲノムトポロジーの変化を含む表遺伝的変異は, kanonical 変異が欠けている GIST の腫瘍生成を誘導する可能性があります.
- これらの発見は,特にFGFR阻害剤を使用して,GISTの異常な表遺伝子経路を標的とした新しい治療戦略を強調しています.
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