ヒトの成体幹細胞における組織特異変異の蓄積

Francis Blokzijl^1,2, Joep de Ligt^1,2, Myrthe Jager^1,2

¹Center for Molecular Medicine, Cancer Genomics Netherlands, Department of Genetics, University Medical Center Utrecht, Heidelberglaan 100, 3584CX Utrecht, The Netherlands.

Nature

|October 5, 2016

まとめ

遺伝子の変異は時間とともに人間の成体幹細胞 (ASC) に蓄積され,がんなどの年齢関連の疾患に寄与します. ASCにおける組織特異的な変異パターンは,腫瘍の発症を誘発する可能性があります.

科学分野:

遺伝学
分子生物学
腫瘍学

背景:

成人幹細胞 (ASC) の遺伝子変異は年齢とともに蓄積され,がんを含む年齢関連の疾患と関連しています.
癌のリスクは組織によって大きく変化し,ASCの分裂数と関連する変異によって引き起こされる可能性があります.

研究の目的:

小腸,大腸,肝臓からの正常なヒトASCのゲノム全体の変異率とパターンを決定する.
ASC変異スペクトルと癌の誘発遺伝子変異の関係を調査する.

主な方法:

3歳から87歳までのヒトドナーの原発的多能性ASCから得られたクローンオーガノイド培養物の配列決定
ゲノム全体の変異パターン分析と変異シグネチャー分析

主要な成果:

変異は,評価された組織全体でASCに安定して蓄積し,年間約40の新規変異が発生します.
肝臓ASCは,異なる変異プロセスに起因する,結腸および小腸ASCと比較して異なる変異スペクトルを示します.
ASCの変異スペクトルは,がん駆動遺伝子の変異スペクトルと高い類似性を示し,固有の変異プロセスが腫瘍発生を開始することを示唆しています.

結論:

ASCの内在的な変異過程は,腫瘍形成の開始に重要な役割を果たします.
ASCにおける組織特異的な変異パターンは,早期に確立され,生涯にわたって一貫しています.
癌発生率の変動にもかかわらず,ASCは異なる組織で比較的一貫した速度で変異を蓄積します.

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