JP2022511787A - 代表的なDNAシーケンシングによる個別化されたctDNA疾患のモニタリング - Google Patents
代表的なDNAシーケンシングによる個別化されたctDNA疾患のモニタリング Download PDFInfo
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Abstract
Description
臨床監査データについては、すべてのサンプルが利用可能な幅(W)および長さ(L)寸法に関するデータを有し、腫瘍容積(T_V)を以下の式を使用して推定した:
[表1]
補足表1-代表的なシーケンシング症例のリスト
[表2]
補足表2
腫瘍組織のRep-Seqまたは生検シーケンシングのいずれかに基づいて設計された最小残存疾患ctDNA追跡パネルの比較。すべてのRep-Seqおよび生検複製物からの1時点当たりに検出された突然変異の全体的な中央数が示されており、以下はすべての個々のサンプルからの完全なデータセットである。検出された突然変異数の差%を示す。MRDが見逃される時間の割合(%)も示されており(%_MRD_ミス)、これは、疾患再発を確実に確認するためにctDNAで最低3個以上の固有の腫瘍変異を検出する必要があると仮定する。
Claims (21)
- サンプル中の複数の遺伝的バリアントを特定する方法であって、
(a)1種以上の腫瘍サンプルを均質化して均質化されたサンプルを供給することと、
(b)シーケンシングのために、前記均質化されたサンプルから単離されたゲノム材料を調製することと、
(c)調製された前記ゲノム材料をシーケンシングした後に、得られたシーケンシングデータ内の前記複数の遺伝的バリアントを特定することとを含む、方法。 - 特定された前記複数の遺伝的バリアントがクローナルであるかサブクローナルであるかを判定することをさらに含む、請求項1に記載の方法。
- 1種以上のネオ抗原が、判定されたサブクローナル変異に由来する、請求項2に記載の方法。
- 特定された前記複数の遺伝的バリアントに基づいてctDNA監視パネルを生成することをさらに含む、請求項1~3のいずれか一項に記載の方法。
- 生成された前記ctDNA監視パネルが、治療に対する応答を判定するために使用される、請求項4に記載の方法。
- 生成された前記ctDNA監視パネルが、がんの進化軌跡を判定するために使用される、請求項4に記載の方法。
- 生成された前記ctDNA監視パネルが、将来の治療戦略に対する応答を予測するために使用される、請求項4に記載の方法。
- 生成された前記ctDNA監視パネルが、治療中または治療後の患者におけるがんの有無を確認するために使用される、請求項4に記載の方法。
- 生成された前記ctDNA監視パネルが、疾患寛解後、治療に対する完全奏効後、または検出不能な疾患の診断後の患者におけるがんの存在を確認するために使用される、請求項4に記載の方法。
- 生成された前記ctDNA監視パネルが、原発性腫瘍の外科的除去後の最小残存疾患を検出するために使用される、請求項4に記載の方法。
- 生成された前記ctDNA監視パネルが、転移性腫瘍の外科的除去後の最小残存疾患を検出するために使用される、請求項4に記載の方法。
- 原発性および転移性腫瘍が同じ手術中に除去され、ctDNA監視試験が、単一の患者由来の複数の腫瘍において検出されたバリアントを含む、請求項10および11のいずれか一項記載の方法。
- 特定された前記複数の遺伝的バリアントに基づいてクローナル構造をコンピュータで計算することをさらに含む、請求項1~12のいずれか一項に記載の方法。
- 前記クローナル構造を計算することが、(i)特定された前記複数の遺伝的バリアントのそれぞれについてがん細胞画分推定値を計算すること、および(ii)計算された前記がん細胞画分推定値を突然変異クラスターに分類することを含む、請求項13に記載の方法。
- 個々の特定された遺伝的バリアントの分離を評価することをさらに含む、請求項14に記載の方法。
- 前記ゲノム材料の調製の前に、前記均質化されたサンプル内の細胞粒子を選別することをさらに含む、請求項1~15のいずれか一項に記載の方法。
- 前記細胞粒子の選別がサイズに基づく、請求項16に記載の方法。
- 前記細胞粒子の選別が、1種以上のバイオマーカーの存在に基づく、請求項16に記載の方法。
- 1種以上の高リスクサブクローナルバリアントが特定された前記複数の遺伝的バリアントの中で特定された場合、ヒト対象が急速な疾患進行のリスクが高いかどうかを評価することをさらに含む、請求項2に記載の方法。
- 特定された前記複数の遺伝的バリアント内の1以上の特定のサブクローナルバリアントの特定に基づいて治療戦略を決定することをさらに含む、請求項2に記載の方法。
- 前記複数の遺伝的バリアントが、全ゲノムシーケンシング(WGS)、全エクソームシーケンシング(WES)、一塩基多型(SNP)分析、ディープシーケンシング、標的遺伝子シーケンシング、ポリメラーゼ連鎖反応(PCR)、またはそれらの任意の組み合わせを使用して特定される、請求項1~20のいずれか一項に記載の方法。
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