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肺腺癌における新しい活性化KRAS遺伝子変異の検討

阿部 二郎 東北大学

2022.03.25

概要

肺腺癌は複数の治療薬に反応するユニークな肺癌の亜型である。KRAS (Kirsten rat sarcoma 2 viral oncogene homolog)遺伝子は日本人の肺腺癌では約 10%に変異が見られるドライバー遺伝子で、その多くは G12(コドン 12 グリシン)、G13(コドン 13 グリシン)、Q61(コドン 61 グルタミン)の活性化型変異である。本研究では肺腺癌患者においてこれらの古典的ともいえる変異とは異なる「マイナーな」KRAS 遺伝子変異が複数同定された。マイナーな KRAS 遺伝子変異を持つ患者群は古典的な KRAS 変異を持つ患者群と比較して、術後の全生存期間では差が見られないものの、無再発生存期間においては良好な予後を示す傾向にあった。それらのマイナーな KRAS 遺伝子変異をもつ症例の 4 割近くは EGFR(Epidermal growth factor receptor)遺伝子変異を併せ持ち、単独では意義不明変異、いわゆるVUS (variants of uncertain significance)が多いと考えられた。しかし EGFR 遺伝子変異または古典的 KRAS 変異を重複しないマイナーKRAS の単独変異例にも、脳転移や胸膜播種などをきたして再発した予後不良な症例が存在した。これらの新しく同定されたマイナーKRAS 変異のうち、これまで全癌腫において報告されておらず、且つ複数の症例で変異が認められた A66T(コドン 66 アラニン→トレオニン)、A66V(コドン 66 アラニン→バリン)、G75E(コドン 75 グリシン→グルタミン酸)の 3 つのコドンについて実験的に検討した。変異遺伝子を導入したマウス胚性線維芽細胞の抽出液のウエスタンブロットでは、KRAS の下流のリン酸化 ERK タンパク質は G12V(コドン 12 グリシン→バリン)変異 KRAS と野生型 KRAS の中間程度の発現を示していた。RNA シーケンスアッセイではこれら 3 つの変異 KRAS 遺伝子の発現プロファイルは、野生型 KRAS の過剰発現とは異なるものの、古典的な変異 KRAS の発現プロファイルと類似していた。変異 KRAS を導入したマウス胚性線維芽細胞のヌードマウスへの同種移植片モデルにおいては、A66T, A66V, G75E の順のスピードで腫瘍形成が見られた。これらの結果から KRAS マイナー変異のあるものは、古典的 KRAS 変異と同様に腫瘍形成の原因となり、抗腫瘍薬としての KRAS 阻害剤開発の標的になりうると考えられた。

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