再発時に異なったクローン選択がメドゥロブラストーマを支配する
A Sorana Morrissy1,2, Livia Garzia1,2, David J H Shih1,2,3
1Developmental &Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.
Nature
|January 14, 2016
まとめ
ターゲットを絞ったがん治療は しばしば失敗します 再発する腫瘍は 遺伝的に進化するからです この研究では,マウスとヒトの両方において,支配的な再発性腫瘍クローンは診断時に存在したマイナークローンであり,治療の失敗を説明しています.
科学分野:
- 腫瘍学
- ゲノミクス
- 癌 生物学
背景:
- 標的型抗がん療法は,がんの特定の遺伝子変異を標的として,生存率を改善し,毒性を減らすことを目的としています.
- 再発性腫瘍の遺伝的状況を理解することは 効果的な治療戦略の開発に不可欠です
研究 の 目的:
- 腫瘍の再発の遺伝的根拠を調査する
- 治療に反応して,原発性腫瘍と再発性腫瘍の間に遺伝的差異が発生するかどうかを判断する.
- 再発性髄芽細胞腫のクローン起源を特定し,標的治療の失敗を説明する.
主な方法:
- トランポゾン駆動の機能性ゲノムマウスモデルを用いて,内定療法で"人間化"した.
- 33組のヒトの診断および治療後の髄芽細胞瘤の全ゲノム配列解析を行った.
- 診断と再発時のネズミとヒトの髄芽細胞腫のサンプルにおける遺伝的イベントを分析した.
主要な成果:
- 再発したネズミの髄芽細胞腫は,マッチした診断サンプルから得られた遺伝的イベントとほとんど重複しなかった (< 5%).
- ヒトの髄芽細胞腫は治療後に有意な遺伝的差異を示し,再発時に診断出来事が12%未満にとどまった.
- 2つの種で再発した支配的なクローンは,診断時に存在していた既にあるマイナークローンから発生した.
結論:
- 腫瘍の再発は,既存の小型のクローンのクローン選択によって引き起こされ,原発性腫瘍から著しい遺伝的差異が生じます.
- 再発性腫瘍クローンの治療目標の欠如は,標的治療の臨床的失敗を説明する.
- これらの発見は,以前の臨床試験における標的治療の無効性を直接的に説明するものである.
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