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BRCAnessに基づく遺伝性乳がん原因遺伝子の病原性変異評価法の開発

吉田 玲子 東北大学

2021.03.25

概要

背景: 遺伝性乳がん卵巣がん(Hereditary breast and ovarian cacner: HBOC)症候群の多くは相同組換え(Homologous recombination: HR)経路に関わる遺伝子の生殖細胞系列の病的変異が原因であり、相同組換え修復不全(Homologous recombination deficiency: HRD)を伴う腫瘍を発生する。これらの腫瘍に見られる特徴的なゲノムの変化と臨床病理学的所見は、BRCAnessと呼ばれている。近年のゲノム解析技術の進歩により一度に多くの遺伝子の検査が可能となり、HBOC原因遺伝子の病的意義が不明な変異(Varian of uncertain significance: VUS)が多く検出され、それらをどう扱うかが大きな課題となっている。そこで本研究では、腫瘍の「表現型」であるBRCAnessに基づいてVUSの病原性を判定する手法の開発を考えた。

 方法: 自施設の新鮮凍結保存の乳がん組織と正常組織をペアに持つ175検体に対して全エクソーム解析を行い、このうち69検体のゲノム情報を用いて、BRCAnessを予測する統計モデルを機械学習法(Lasso logistic regression: ラッソロジスティック回帰)により開発した。大規模がんゲノム情報The Cancer Genome Atlas(TCGA)に公開されている乳がん組織と正常組織のペア421検体の全エクソーム解析データから113検体を用いてモデルの精度検証を行った。残りの413検体に対しBRCAness予測値と、臨床病理学的な特徴を用いてVUSの再判定を行った。

 結果: BRCA1/2両アレル機能消失腫瘍とHR関連遺伝子に異常がない腫瘍に対するBRCAness予測モデルの正答率は、95.8%であった。TCGA検体で精度検証を行った正答率は86.7%であり、十分な精度と汎用性を備えていることが検証できた。本研究の解析で検出されたHR関連遺伝子の269種類のVUSに対し、BRCAnessモデルの予測値と、臨床病理学的な特徴を利用した結果、5種類の潜在的病原性変異、35種類の潜在的良性変異を判定した。これらのうち、症例対照研究法や機能解析法の既報の解釈と照合し、最終的に1種類の病的変異疑いと、5種類の良性疑いのVUSの病原性を再判定することができた。

 結論: HR関連HBOC原因遺伝子のVUSの再評価に、BRCAnessを利用した方法は、従来の症例対照研究法や機能解析法と共に、バリアントの病原性判定に有用である。

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