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繰り返し発生する非コーディングU1snRNA変異は,SHH髄芽細胞腫における暗号的スプライシングを誘発する
Hiromichi Suzuki1,2, Sachin A Kumar1,2,3, Shimin Shuai4,5
1The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
Nature
|October 31, 2019
まとめ
高度に再発するU1 spliceosomal小核RNA (snRNA) 変異がソニック・ヘッジホッグ・メドゥロブラストーマを誘発する. これらの非コーディングRNA変異は,スプライシングを妨害し,腫瘍遺伝子と腫瘍抑制剤に影響を与え,潜在的な治療標的となる.
科学分野:
- 腫瘍学
- 遺伝学
- 分子生物学
背景:
- がんにおける再発性体型変異は,小児がんでは一般的にまれであり,主にタンパク質をコードする遺伝子に影響する.
- U1 spliceosomal small nuclear RNAs (snRNAs) は,RNAのスプライシングに関与するスプライソームの重要な構成要素である.
研究 の 目的:
- 小児がんにおける非コーディング遺伝子,特にU1 snRNAの変異の役割を調査する.
- 特定の髄芽細胞瘤サブグループ内のU1snRNAの再発性変異を特定する.
主な方法:
- 完全エクソムのシーケンシングとメドロブラストマのサンプル変異分析
- スプライシングパターンを評価し,暗号的なスプライシングイベントを特定するためにRNAシーケンシング.
- 異なる癌の種類と患者の人口統計の変異頻度の分析
主要な成果:
- ソニック・ヘッジホッグ (SHH) 髄膜芽細胞腫の約50%でU1snRNAの高度に再発するホットスポット変異 (r.3A>G) の発見.
- これらのU1snRNA変異は,成人の97%と青年期のSHH髄芽細胞腫の25%で発見されたが,乳児の症例や他の癌のタイプでは稀に発見された (<0. 1%).
- U1 snRNAの変異は,RNAのスプライシングを妨害し,5'暗号スプライシングを増加させ,腫瘍抑制剤 (PTCH1) の無活性化,および腫瘍遺伝子の活性化 (GLI2,CCND2) を引き起こします.
結論:
- U1 snRNA変異は,がんにおける非コーディング遺伝子における高度に再発性のある組織特異性変異の新種である.
- これらの変異は異常なスプライシングによって遺伝子発現を大きく変化させ,SHH髄芽細胞腫の発症を促します.
- 変異したU1snRNAによって媒介される代替スプライシングをターゲットにすることは,SHH髄芽細胞腫の潜在的な治療戦略です.
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