JP6871271B2 - Dlbclを分類するための方法および組成物 - Google Patents
Dlbclを分類するための方法および組成物 Download PDFInfo
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Description
I.序論
びらん性大細胞型B細胞リンパ腫(DLBCL)の起始細胞(COO)サブタイプを決定するための、新規多重リアルタイム定量的逆転写(qRT)-PCR分類子(classifier)が提供される。当該分類子は、qRT-PCR多重反応を利用して16の遺伝子標的(決定群15、対照群1)を定量し、DLBCLのCOOサブタイプを決定する。ある態様では、該アッセイは5チューブqRT-PCRである。DLBCLからのホルマリン固定パラフィン包埋組織(FFPET)におけるqRT-PCR分類子の実行可能性および精度が下記に示される。
用語「多重」とは、複数の(2以上の)標的が検出されるアッセイのことを指す。
用語「容器(receptacle)」、「器(vessel)」、「チューブ」、「ウェル」、「チャンバー」、「マイクロチャンバー」等は、試薬またはアッセイ液を収容できる容器のことを指す。容器がキットの形であり試薬を収容しているか、または増幅反応に使用する予定である場合、汚染や蒸発を防ぐために密閉または密封することができる。容器がアッセイに使用される場合、少なくとも該アッセイの設定の間、開放状態にまたは利用可能にすることができる。
核酸増幅のためのサンプルは、核酸を含むと思われる任意の源より取得することができる。サンプルはホルマリン固定パラフィン包埋組織(FFPET)、組織生検(バイオプシー)、気管支肺胞洗浄液または培養細胞(例えば患者から取得したものまたは対照を表すもの)から取得することができる。本開示の範囲内では、サンプルは典型的に肺組織からまたは胚細胞を含む細胞集団、例えば肺癌細胞から採取される。ある場合には、サンプルは例えば尿、皮膚、痰、唾液、血液または血液画分から、非侵略的方法で取得される。
びらん性大細胞型B細胞リンパ腫(DLBCL)は、非ホジキンリンパ腫の最も一般的なサブタイプである。患者のおよそ40%が、難治性であるか初期反応後に再発する疾病を有し、再発性DLBCLを有する患者の大部分が該疾病のために死亡する。DLBCLには2つの主要な生物学的に異なる分子サブタイプがある:胚中心B細胞(GCB)および活性化B細胞(ABC)。ABC DLBCLは、標準化学療法で処置すると実質的に悪い予後(アウトカム)に関連付けられる。
核酸サンプルは、例えば核酸増幅を使って、例えば任意のプライマー依存性方法を使って、検出および定量に用いることができる。ある態様では、予備的な逆転写工程が実施される(RT-PCRとも呼称される;リアルタイムPCRと混同してはならない)。例えば、Hierro他(2006)72:7148を参照のこと。本明細書中で用いる用語「qRT-PCR」とは、逆転写に続く定量的PCRを指す。両反応は中断なく単一のチューブの中で実施することができ、例えば試薬を添加することができる。例えば、ポリTプライマーを用いて、ポリAテールを有するサンプル中の全てのmRNAを逆転写することができ、ランダムオリゴヌクレオチドを使うことができ、あるいはcDNAに逆転写される特定の標的転写物に特異的であるプライマーを設計することができる。cDNAは定量的増幅に最初の鋳型鎖を形成することができる(リアルタイムまたは定量的PCR、すなわちRT-PCRまたはqPCR)。qPCRは、PCR工程の各サイクル中に生成する生成物の信頼できる検出と測定を可能にする。そのような技術は当業界で周知であり、キットや試薬は例えばロシュ・モレキュラーシステムズ(Roche Molecular Systems)、ライフテクノロジーズ社(Life Technologies)、バイオラッド社(Bio-Rad)等から市販されている。例えば、Pfaffl (2010) Methods: The ongoing evolution of qPCR、第50巻を参照のこと。
DLBCL患者のCOOサブタイプを分類するための多重qRT-PCRアッセイ用キットが提供される。ある態様では、該キットは、GCBおよびABCマーカー遺伝子産物(RNA)の増幅、検出および定量用のプライマーとプローブとの混合物を含む。GCBマーカーはZNF318、PDK3、HMGN1、PTK2、SSBP2、BCL6およびLRMPを含み、それらの遺伝子の転写物が非癌性患者またはABC患者からのサンプル中よりもGCB患者からのサンプル中のほうが高いレベルで存在する。ABCマーカーはARID3A、CCND2、FOXP1、KIAA0226L、JADE3、PIM2、TCF4およびFAM46Cを含み、それらの遺伝子の転写物が非癌性患者またはGCB患者からのサンプル中よりもABC患者からのサンプル中のほうが高いレベルで存在する。
COOサブタイプ決定シグネチャーの設計
分類子遺伝子(表1)を選択するのに市販のDLBCL FFPET検体のセット(トレーニングコホート1;n=32)のセットを使った。Roche社製のFFPET RNAキットを使ってサンプルを調製した。
25μL RNA+25μL反応混合物
反応混合物:5μLの酢酸マンガン+10μLのRNAマスター混合物原液+10μLのプライマー/プローブ混合物(最終濃度100〜300 nM)。
反応は4つのフィルターをセットしたcobas(登録商標)LC480中で実施し、表2に示すようにプローブを検出した。
qRT-PCR分類子を、市販のDLBCL FFPET検体(バリデーションコホート2;n=29、およびバリデーションコホート3;n=46)においてバリデートした。qRT-PCRとAffymetrixマイクロアレイベースの分類子との間の一致率は97.1%であった(表5および表6)。
6遺伝子を有するqRT-PCR分類子を、市販のDLBCL FFPET検体(バリデーションコホート;n=50)においてバリデートした。6遺伝子シグネチャーに含まれる遺伝子は、ABC遺伝子CCND2、FOXP1およびJADE3と、GCB遺伝子ZNF318、SSBP2およびPTK2を含んだ。qRT-PCRおよびAffymetrixマイクロアレイをベースにした分類子の間の一致率は95%であった(表7)。
Claims (23)
- びまん性大細胞型リンパ腫(DLBCL)を有する個体を同定する方法であって、
(a) 個体から得られたサンプルを提供し(DLBCLサンプル);
(b) DLBCLサンプル中の胚中心B細胞(GCB)マーカー ZNF318、PTK2、およびSSBP2の発現をqRT-PCRにより検出し;
(c) DLBCLサンプル中の活性化B細胞(ABC)マーカー CCND2、FOXP1、およびJADE3の発現をqRT-PCRにより検出し;そして
(d) DLBCLサンプル中の対照遺伝子の発現をqRT-PCRにより検出する
ことを含み、ここで
(i) GCBマーカー発現対ABCマーカー発現の比が前記個体のサンプル中のGCB閾値よりも高いことが、R-CHOP(リツキシマブまたはエトポシド;シクロホスファミド;ドキソルビシン;ビンクリスチン;およびプレドニソロン)の投与に対する前記個体の感受性を示し;または
(ii) ABCマーカー発現対GCBマーカー発現の比が前記個体のサンプル中のABC閾値よりも高いことが、代替投与に対する前記個体の感受性を示し、
前記代替投与がBTK阻害剤、SYK阻害剤、NFκB阻害剤または免疫活性調節剤を含むことを特徴とする方法。 - 前記(b)および/または(c)が
(b) DLBCLサンプル中の胚中心B細胞(GCB)マーカーZNF318、PDK3、HMGN1、PTK2、SSBP2、BCL6、およびLRMPの発現をqRT-PCRにより検出し;
(c) DLBCLサンプル中の活性化B細胞(ABC)マーカーARID3A、CCND2、FOXP1、KIAA0226L、JADE3、PIM2、TCF4、およびFAM46Cの発現をqRT-PCRにより検出する
ことにより実施されることを特徴とする、前記ステップ(a)〜(d)を含む請求項1記載の方法。 - 前記代替投与がR-CHOPを更に含む、請求項1または2記載の方法。
- 前記ステップ(b)および(c)において各遺伝子について検出された発現レベルを、(d)において対照遺伝子の検出された発現レベルに基づいて調整することを含む、請求項1〜3のいずれか一項記載の方法。
- びまん性大細胞型リンパ腫(DLBCL)を有する個体について起始細胞(COO)サブタイプを決定する方法であって、
(a) 個体から得られたサンプルを提供し(DLBCLサンプル);
(b) DLBCLサンプル中の胚中心B細胞(GCB)マーカー ZNF318、PTK2、およびSSBP2の発現をqRT-PCRにより検出し;
(c) DLBCLサンプル中の活性化B細胞(ABC)マーカー CCND2、FOXP1、およびJADE3の発現をqRT-PCRにより検出し;
(d) DLBCLサンプル中の対照遺伝子の発現をqRT-PCRにより検出し;そして
(e) 個体のCOOサブタイプが
(i) GCBマーカー発現対ABCマーカー発現の比がGCB閾値よりも高い場合はGCB、または
(ii) ABCマーカー発現対GCB発現の比がABC閾値よりも高い場合はABC
であることを決定する
ことを含む方法。 - 前記ステップ(b)および/または(c)が
(b) DLBCLサンプル中の胚中心B細胞(GCB)マーカーZNF318、PDK3、HMGN1、PTK2、SSBP2、BCL6、およびLRMPの発現をqRT-PCRにより検出し;
(c) DLBCLサンプル中の活性化B細胞(ABC)マーカーARID3A、CCND2、FOXP1、KIAA0226L、JADE3、PIM2、TCF4、およびFAM46Cの発現をqRT-PCRにより検出する
ことにより実施されることを特徴とする、前記ステップ(a)〜(d)を含む請求項5記載の方法。 - 前記GCB閾値が、GCB陽性対照におけるGCBマーカー発現対ABCマーカー発現の比に基づいて設定される、請求項1〜6のいずれか一項記載の方法。
- 前記ABC閾値が、ABC陽性対照におけるABCマーカー発現対GCBマーカー発現の比に基づいて設定される、請求項1〜7のいずれか一項記載の方法。
- 前記サンプルが肺生検または気管支肺胞洗浄細胞からのものである、請求項1〜8のいずれか一項記載の方法。
- 前記サンプルがホルマリン固定パラフィン包埋組織(FFPET)である、請求項1〜9いずれか一項記載の方法。
- 前記サンプルが血液、血漿または血清である、請求項1〜10いずれか一項記載の方法。
- 前記(b)および(c)の検出が多容器中で多重方式で実施される、請求項1〜11いずれか一項記載の方法。
- 各GCBマーカーおよびABCマーカーが個別に検出される、請求項1〜12いずれか一項記載の方法。
- 前記(b)の検出が各サンプルについて単一容器中で実施される、請求項1〜13いずれか一項記載の方法。
- 前記(c)の検出が各サンプルについて単一容器中で実施される、請求項1〜14いずれか一項記載の方法。
- 前記(d)の検出が(b)および(c)の検出と同一容器中で実施される、請求項1〜15いずれか一項記載の方法。
- 前記ステップ(b)および(c)において各遺伝子について検出された発現レベルを、(d)において対照遺伝子の検出された発現レベルに基づいて調整することを含む、請求項5〜16いずれか一項記載の方法。
- (a) 胚中心B細胞(GCB)マーカー ZNF318、PTK2およびSSBP2遺伝子産物の各々を特異的に増幅し検出する、プライマーセットと蛍光標識されたプローブとを含む混合物;および
(b) 活性化B細胞(ABC)マーカー CCND2、FOXP1およびJADE3遺伝子産物の各々を特異的に増幅し検出する、プライマーセットと蛍光標識されたプローブとを含む混合物
を含んでなる、びまん性大細胞型リンパ腫(DLBCL)を有する個体を同定するため、及び/又はびまん性大細胞型リンパ腫(DLBCL)を有する個体について起始細胞(COO)サブタイプを決定するためのキット。 - 前記(a)または(b)の混合物が、対照遺伝子産物を特異的に増幅し検出するプライマーセットと蛍光標識されたプローブとを更に含み、ここで前記対照遺伝子産物を特異的に検出する蛍光標識されたプローブが、混合物(a)または混合物(b)中の蛍光標識されたプローブとは異なるように標識されていることを特徴とする、請求項18記載のキット。
- 前記混合物(a)中の蛍光標識されたプローブが全て同一の蛍光標識により標識されているか、または、前記混合物(b)中の蛍光標識されたプローブが全て同一の蛍光標識により標識されている、請求項18または19記載のキット。
- 逆転写酵素および/または耐熱性DNAポリメラーゼを更に含む、請求項18〜20のいずれか一項記載のキット。
- 逆転写酵素活性とDNAポリメラーゼ活性の両方を有する酵素を更に含む、請求項18〜21のいずれか一項記載のキット。
- 少なくとも1つの対照サンプルを更に含む、請求項18〜22のいずれか一項記載のキット。
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