LMO1スーパーエンハンスターポリモルフィズムによって媒介される神経芽細胞瘤への遺伝的傾向

Derek A Oldridge^1,2, Andrew C Wood³, Nina Weichert-Leahey^4,5

¹Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.

Nature

|November 13, 2015

まとめ

LMO1遺伝子の近くの一般的な遺伝子変異は,遺伝子発現を変えることで神経芽細胞腫のリスクに影響を与えます. この発見は特定のDNAの変化が幼児のがんに対する感受性に影響を及ぼすことを説明します

科学分野:

遺伝学
腫瘍学
分子生物学

背景:

神経芽細胞腫は,共感神経系から発症する一般的な小児がんです.
LMO1ロカスポリモルフィズムが以前から神経芽細胞腫の感受性に関連していることから,腫瘍発生には遺伝的要因が関係している.
標的治療には,因果変異とそのメカニズムを理解することが重要です.

研究の目的:

神経芽細胞腫の感受性を引き起こす LMO1 の特定のDNA変異を特定する.
この変種が腫瘍発生に寄与する分子メカニズムを解明する.
転写因子の結合と遺伝子発現の調節の役割を調査する.

主な方法:

LMO1ロカス全体でゲノタイプを推定する.
シングルヌクレオチドポリモルフィズム (SNP) を規制要素にマッピングする.
クロマチンのアクセシビリティ,進化的保存,および転写因子結合部位の分析.
遺伝子発現とアレルの不均衡を評価するためのRNA配列とレポーターアッセイ.

主要な成果:

SNP rs2168101 G> Tは,最も有意に関連した変種として特定されました.
このSNPは,LMO1の最初のイントロンのスーパーエンハンスター内に位置しています.
腫瘍形成に関連した祖先のGアレルはGATA転写因子を結合し,保護性Tアレルは結合を無効化し,LMO1発現を減少させます.
Gアレルに有利なアレル不均衡が腫瘍で観察された.

結論:

LMO1の超強化剤で最近進化したポリモルフィズムが神経芽細胞腫の感受性に影響する.
この効果は,GATA転写因子結合とLMO1発現のシス調節によるものです.
発見は,規制要素の遺伝的多様性によって引き起こされる腫瘍性依存のメカニズムを強調しています.

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