慢性肝疾患における代謝遺伝子の収束体変異

Stanley W K Ng¹, Foad J Rouhani^1,2, Simon F Brunner¹

¹Cancer Genome Project, Wellcome Sanger Institute, Hinxton, UK.

Nature

|October 14, 2021

まとめ

FOXO1,CIDEB,GPAMのような重要な代謝遺伝子の体内変異は,アルコール関連および非アルコール性脂肪肝を含む慢性肝疾患で頻繁に観察されます.

科学分野:

ゲノミクス
ヘパトロジー
癌生物学

背景:

慢性肝疾患が肝細胞がんに進行すると,がん遺伝子の体内変異が起こります.
慢性肝疾患では正常な肝臓よりも体内の突然変異の負荷とクローン膨張が高く,陽性選択を容易にする.
肝疾患におけるゲノム風景の形成は,ポジティブな選択圧力によって影響を受けます.

研究の目的:

健康な対照群,アルコール関連肝疾患 (ARLD),非アルコール性脂肪肝疾患 (NAFLD) を含む34の肝臓サンプルから1,590のゲノムにおける体内変異を分析する.
FOXO1,CIDEB,GPAMなどの特定の遺伝子の役割を肝臓疾患の変異の文脈で調査する.
肝疾患の文脈における体変異の収束進化のパターンを特定する.

主な方法:

健康なARLDとNAFLDの肝臓組織で1590個のサンプルを全ゲノム配列化しました.
34個の肝臓サンプルで体内の変異を分析し,影響を受けた遺伝子と変異のホットスポットを特定する.
特定の遺伝子変異に関連したクローン進化と拡張パターンの調査.

主要な成果:

29人の肝疾患患者のうち7人は,単一のホットスポットに影響し,核輸出を阻害する重要なインスリンシグナル転写因子であるFOXO1に変異がありました.
FOXO1変異 (S22Wホットスポット) の収束進化は,患者一人当たり最大9個の独立した肝細胞クローンで観察されました.
脂質代謝に関与するCIDEBとGPAMも,頻繁に収束する進化 (それぞれ14および7クローン) を有する過剰変異を示した.
代謝遺伝子の変異は肝臓のセグメント全体に広く広がり,クローンサイズが増加し,ARLDとNAFLDの両方で発生しましたが,肝細胞癌ではまれでした.

結論:

代謝経路のマスターレギュレータは,ARLDとNAFLDのコンバージェントソマティック変異によって頻繁に標的にされます.
代謝遺伝子の変異の収束進化は,慢性肝疾患における強い選択的圧力を示唆する.
これらの発見は,慢性肝疾患の病原性における代謝失調と体内の変異の役割を強調しています.

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