家族性および散発性メラノーマにおけるTERTプロモーター変異
Susanne Horn1, Adina Figl, P Sivaramakrishna Rachakonda
1Division of Molecular Genetic Epidemiology, German Cancer Research Center, Im Neuenheimer Feld 580, 69120 Heidelberg, Germany.
Science (New York, N.Y.)
|January 26, 2013
まとめ
テロメラーゼ逆転写酵素 (TERT) プロモーターの新しい突然変異が,メラノーマ発症を誘発する. このTERTプロモーター変異は,家族性および散発性メラノーマで特定され,遺伝子の転写を増加させ,転移性メラノーマの主要な原動力となる可能性があります.
科学分野:
- 遺伝学 遺伝学とは
- 腫瘍学 腫瘍学
- 分子生物学は分子生物学である.
背景:
- 皮膚性メラノーマは,家族的および散発的な形態の両方で存在します.
- メラノーマの遺伝的基盤は,特に家族的な症例では,完全に解明されていません.
- テロメラーゼ逆転写酵素 (TERT) は,細胞の老化と癌に関与する酵素であるテロメラーゼの重要な成分です.
研究 の 目的:
- メラノーマに罹患しやすい家族におけるメラノーマの感受性に関連した遺伝子変異を特定する.
- TERT遺伝子転写に対する特定された突然変異の機能的影響を調査する.
- 主要型および転移型を含む散発性メラノーマにおけるTERTプロモーター変異の頻度および重要性を決定する.
主な方法:
- 結合分析と高通量シーケンシングを使用して,メラノーマに罹患しやすい家族内の変異を特定しました.
- レポーター遺伝子アッセイは,特定された変異を持つTERTプロモーターの転写活性を評価するために使用されました.
- TERTプロモーターの変異のスクリーニングは,ヒトメラノーマの細胞系と,偶発的な症例からの腫瘍組織で行われました.
主要な成果:
- TERTプロモーターの疾患分離性生殖系変異は,メラノーマに罹患しやすい家族で特定されました.
- この変異により,Etsと三元複合因子 (TCF) の新しい結合モチーフが生まれ,TERT転写が2倍に増加しました.
- TERTプロモーターの反復的な紫外線サインの体性変異は,転移性メラノーマ細胞系 (74%) と腫瘍組織 (85%) の高い割合,および一次性メラノーマのサブセット (33%) で発見されました.
- ほとんどの体的変異は,TERTプロモーターの2つの特定の位置で発生し,また,Ets/TCF転写因子結合モチーフを生成しました.
結論:
- TERTプロモーターの生殖系変異は,個人をメラノーマに誘発する可能性があります.
- TERTプロモーターの体内変異は,散発性メラノーマ,特に転移性メラノーマでは頻繁に見られ,UVダメージと関連しています.
- 特定されたTERTプロモーター変異は,転写因子結合部位を作成することによってTERT転写を強化し,メラノーマの病原性において重要な役割を果たしていることを示唆しています.
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