健康なヒトの肝臓と肝硬変患者の体内変異とクローン動態

Simon F Brunner¹, Nicola D Roberts¹, Luke A Wylie¹

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

Nature

|October 25, 2019

まとめ

肝臓の慢性疾患は,正常な肝臓と比較して,肝細胞の変異負荷と構造変異を著しく増加させる. これらの体内変異は肝臓疾患の進行,毒性,再生を追跡し,肝臓細胞がんの発達に関する洞察を提供します.

科学分野:

ゲノミクス
ヘパトロジー
癌生物学

背景:

ウイルス性肝炎や非アルコール性脂肪肝などの慢性肝疾患は,肝硬変,肝不全,肝細胞癌 (HCC) に進行することがあります.
肝臓細胞がんのゲノムは,正常な肝臓幹細胞とは異なり,多様な変異シグネチャーを示し,疾患の進行中に複雑性が発生することを示唆しています.
慢性肝疾患のゲノム構造を理解することは HCCへの経路を解読するのに不可欠です

研究の目的:

肝硬変と正常な肝臓の変異負荷とシグネチャーを比較する
慢性肝疾患の進行における構造変異と原発変異の役割を調査する.
肝硬変における体内変異に対するクローン構造と微環境の影響の分析.

主な方法:

5つの正常な肝臓と9つの肝硬変肝臓から482個の微小切開 (それぞれ100〜500個の肝臓細胞) の全ゲノムシーケンシング.
変異負荷,構造変異 (染色トリプシスを含む) と変異シグネチャーの分析.
肝硬変組織内のクローン膨張とその空間的分布の特徴

主要な成果:

肝硬変は正常な肝臓より高い変異負荷を示します
クロモトリプシスなどの構造的変異は肝硬変では顕著ですが,正常な肝細胞では稀です.
ドライバ変異はクローンの1- 5%で特定され,クローンの拡張はしばしば繊維帯によって隔離された.
変異シグネチャーは様々で,あるものは非悪性細胞とHCCに共通し,あるものはHCCに濃縮され,外因的なシグネチャーは患者および部位特異的な変異性を示した.
同期性HCCは肝硬変の背景とシグネチャーを共有したが,より高い変異負荷を持っていた.

結論:

肝臓の体内の変異は,疾患進行中の暴露,毒性,再生,クローン動態の歴史的記録として機能する.
肝硬変で観察されたゲノム変異は,肝細胞がんの発症の基礎となる.
肝硬変における変異シグネチャの活動には,微小環境要因が大きく影響する.

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