ゲノム進化と生殖細胞腫瘍における化学抵抗

Amaro Taylor-Weiner^1,2, Travis Zack^1,3, Elizabeth O'Donnell^4,5

¹Division of Medical Sciences, Harvard University, Boston, Massachusetts 02115, USA.

Nature

|December 2, 2016

まとめ

生殖細胞腫瘍 (GCTs) は,再発性染色体腕増幅および消去を含むユニークなゲノム変異を示します. これらのゲノム特性は,GCTの発達,化学療法に対する感受性,および耐性に影響します.

科学分野:

ガンゲノミクス
腫瘍発生
分子腫瘍学

背景:

生殖細胞腫瘍 (GCT) は生殖細胞から発生し,主に丸に生じる.
化学療法で治療できるが,GCTの発症,化学反応感受性,および進行の特定のゲノム要因は不明である.
普遍的な特徴には12pの増殖とアヌプロイド性がありますが,詳細な体内ゲノム特徴は不完全です.

研究の目的:

GCTの開始,化学感受性,および進行を駆動する特定の体内ゲノム特性を解明する.
前駆体から原発性および化学抵抗性転移性GCTへのゲノム変異を調査する.
ミトコンドリアのプライミングがGCTの化学反応感受性および耐性における役割を調査する.

主な方法:

前駆体,主体,化学抵抗性GCTの全エクソームとトランスクリプトームの臨床シーケンシング.
染色体腕レベルの増幅と消去の分析 (対照性喪失).
アポプトティックシグナリングの評価とGCTの進化の遺伝分析のためのBH3プロファイリング.

主要な成果:

GCTは,他の癌と比較して,著しく増幅された,再発性染色体アーム増幅および消去 (相互LOH) を示しています.
KRAS変異は,GCTの発達中に獲得され,一次性 testicular GCT (TGCT) はTP53野生型である.
主要なTGCTは高ミトコンドリアプリミングを示し,化学療法によるアポトーシスを促進する.
化学抵抗性TGCTは,プラリポテンシーマーカー (NANOG,POU5F1) の喪失に関連して,追加の相互LOHを獲得する.

結論:

GCTは,その起源,化学的感受性,および耐性に影響を与える独特のゲノム特性を有しています.
この研究は,がんゲノミクス,ミトコンドリアプリミング,GCTの進化の収束を強調しています.
発見は,他の癌のタイプに適用可能な化学反応感受性および耐性メカニズムに関する洞察を提供します.

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