JP6076901B2 - 被験者の血液サンプル中の疾患マーカーの存在の分析方法 - Google Patents
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Description
本発明は、疾患検出のためのマーカー、疾患検出方法、及び疾患治療の有効性を決定するための方法に関する。
(a)無核血液細胞画分を準備するための前記血液サンプル中の、無核血液細胞、好ましくは血小板から核酸を抽出するステップ、及び
(b)疾患マーカーの存在のために前記無核血液細胞抽出核酸を分析するステップを含み、前記疾患マーカーが、前記被験者の有核細胞の遺伝子に疾患に特有の変異であるか、又は前記疾患マーカーが、前記被験者の有核細胞の遺伝子の疾患特異的発現プロフィルである。
(i)少なくとも1つの核酸変異特異的増幅プライマー又はプローブを用いる逆転写ポリメラーゼ連鎖反応による前記変異の増幅、又は
(ii)前記mRNAをコード化する染色体遺伝子の発現レベルを決定し、それにより前記遺伝子の発現プロフィルを提供し、かつ前記発現プロフィルを参照プロフィルと比較するために、逆転写ポリメラーゼ連鎖反応による複数のmRNAの増幅、である。
−最初の時点で本発明の血液サンプル分析方法を用いて疾患マーカーの存在を被験者の血液サンプルを分析し、それにより前記被験者の前記疾患マーカーのレベルの第1の値を与え;
−前記最初の時点よりも前後、好ましくは後の第2の時点で、本発明の血液サンプル分析方法を用いて疾患マーカーの存在を被験者の血液サンプルを分析し、それにより前記被験者の前記疾患マーカーのレベルの第2の値を与え、前記被験者が前記第1及び第2の時点の間に疾患治療の対象とされており、及び
−前記第1の値と第2の値を比較することで、前記被験者への前記治療の有効性を決定する、ことを含む。
疾患の段階を決定するために、本発明の方法で決定された疾患マーカー値を疾患段階と関連付けることは有用である。疾患マーカーの単一測定は、それにより1以上の参照値と比較され、疾患の段階の指標を得ることができる。
−本発明による疾患マーカーの存在を被験者の血液サンプルを分析する方法を用いて疾患マーカーの存在を被験者の血液サンプルにつき分析し、それにより前記被験者の疾患マーカーのレベルとして一つの試験値を提供し、
−疾患の特定の段階に関連付けされる前記疾患マーカーのレベルのための参照値を提供し、及び
−前記試験値及び参照値を比較して前記被験者の疾患の段階を決定する、ことを含む。
−血液サンプルから分離された無核血液細胞、好ましくは血小板を保持する容器;
−前記無核血液細胞から核酸を抽出する試薬;
−前記無核血液細胞から抽出された前記核酸から、前記疾患特異的マーカー、例えば被験者の有核細胞の遺伝子の疾患特異的変異又は前記被験者の有核細胞からの疾患特異的発現プロフィルを、例えば逆転酵素ポリメラーゼ連鎖反応増幅により、選択的に増幅するための試薬、及び
−前記記載の本発明の方法を実施するための印刷又は電子的指示書を含む包装物を含み、
前記キットがさらに:
−前記疾患の参照値を含み、前記参照値は、前記無核血液細胞抽出核酸画分内の疾患マーカーの存在の指標である。
増幅システムには、ポリメラーゼ連鎖反応(PCR)システム、リガーゼ連鎖反応(LCR)システム、核酸配列に基づく増幅(NASBA、Cangene、Mississauga、Ontario)、Qベータレプリカーゼシステム、転写に基づく増幅システム(TAS)及び鎖置換増幅システムが含まれる。例えば、「診断分子微生物 原理及び応用、 D. H. Persing et al.、Ed.、American Society for Microbiology、Washington、D.C.(1993)」を参照すること。増幅産物はアンプリコンとされる。
ポリメラーゼ連鎖反応(PCR;Mullis 1987、米国特許第4、683、195、4683202、及び800159号)又は増幅反応例えばリガーゼ連鎖反応(LCR;Barany 1991、Proc.Natl.Acad.Sci.USA88:189−193;欧州特許出願第320308号)、自己保持配列増幅(3SR;Guatelliら、1990、Proc.Natl.Acad.Sci.USA 87:1874−1878)、鎖転位増幅(SDA;米国特許第5270184及び545566号)、転写増幅システム(TAS;Kwohら、Proc.Natl.Acad.Sci.USA 86:1173−1177)、Q−ベータレプリカーゼ(Lizardiら、1988、Bio/Technology 6:1197)、回転サークル増幅(RCA;米国特許第5871921g号)、核酸配列系増幅(NASBA)、開裂断片長多形(米国特許第5719028号)、等温及びキメラプライマー開始核酸増幅(ICAN)、分岐−延長増幅方法(RAM;米国特許第5719028及び942391)又はDNA増幅のための適切な方法、が含まれる。
例えばイノシトール残基又は不明瞭な塩基などを含むプライマー配列又は前記標的配列に比較して1以上のミスマッチを含むプライマー配列の使用も可能である。一般に、少なくとも65%、より好ましくは少なくとも80%の標的DNAオリゴヌクレオチド配列との同一性を示す配列が、本発明の方法での使用に適すると考えられる。配列ミスマッチはまた、低ストリンジェントハイブリダイゼーション条件を用いる場合には重要ではない。
Tm=81.5℃+16.6(logM)+0.41(%C)−0.6(%ホルム)−500/L;
ここでMは一価のカチオンのモル濃度、%GCはDNAの中のグアノシン及びシトシンヌクレオチドのパーセント、%ホルムはハイブリダイゼーション溶液中のホルムアミドのパーセント及びLは塩数でのハイブリッドの長さを示す。Tmは約1℃低くなる毎に、それぞれ1%のミスマッチとなり;従ってハイブリダイゼーション及び/又は洗浄条件は、望ましい同一性配列にハイブリダイズさせるように調節され得る。例えば、90%超える同一性配列を探す場合には、Tmは10℃低減させることができる。一般的に、ストリンジェント条件は、所定のイオン強度及びpHで、特定の配列及びその相補鎖について、Tmよりも約5℃低く選択される。しかし、より厳しいストリンジェント条件では、ハイブリダイゼーション及び/又は洗浄をTmよりも1、2、3又は4℃低い温度で実施することができ;中程度のストリンジェント条件では、ハイブリダイゼーション及び/又は洗浄をTmよりも6、7、8、9又は10℃低い温度で実施することができ;弱いストリンジェント条件では、ハイブリダイゼーション及び/又は洗浄をTmよりも11、12、13、14、15又は20℃低い温度で実施することができる。前記式、ハイブリダイゼーション及び洗浄組成物、及び望ましいTmを用いることで、当業者は、前記ハイブリダイゼーション及び/又は洗浄の種々のストリンジェント性が説明されていることを理解するであろう。望ましい程度のミスマッチが、45℃(水溶液)又は32℃(ホルムアミド溶液)未満のTmとなる場合には、SSC濃度を上げてより高い温度が使用できるようにすることが好ましい。核酸のハイブリダイゼーションの広範なガイドは、「Tijssen、Laboratory Techniques in Biochemistry and Molecular Biology−Hybridization with Nucleic Acid Probes、Part I、Chapter2”Overview of principles of hybridization and the strategy of nucleic acid probe assays”、Elsevier.New York(1993);及びCurrent Protocols in Molecular Biology、Chapter2、Ausubel、et al.、Eds.、Greene Publishing and Wiley−Interscience、New York(1995)」である。
血小板細胞は、膠芽細胞腫患者4人、および健康なドナーから遠心分離ステップにより分離された。血小板細胞はその後Trizol RNA分離を用いてRNA抽出の対象とされた。精製血小板細胞RNA抽出サンプルはcDNAへ変換され、標準のミクロアレイ手順に従いAgilent 4x44K発現ミクロアレイにより分析した。これにより異なる血小板調製物のmRNAのプロフィルが可能となった。
1A:4人の患者のうち4人で検出され、コントロールサンプルからの血小板細胞からは検出されない血小板細胞の転写物
イントロダクション
診断、モニター及び患者の層別化のために非常に予想可能な診断用プラットフォームが、個別医療の発展にとってキーとなる装置である。この例では、腫瘍細胞がインビトロで血液血小板へ(変異)RNAを転移すること、及び膠芽細胞腫及び前立性癌患者から分離した血液血小板が、癌関連RNAバイオマーカーEGFRvIII及びPCA3及びPSAををそれぞれ含むことを示す。さらに、遺伝子発現アレイは、膠芽細胞腫患者からの血小板中のmRNAが、正常コントロール被験者と比較して区別できる特徴を明らかにした。血小板は容易に入手でき、分離できることから、これらは癌の比較診断のための有力なプラットフォームを形成し得る。
血小板分離及び組織切除
血小板は、EDTA抗凝固剤を含む紫色キャップのBDバキュテナー内に標準の遠心分離で収集し、純度と品質(活性及び凝固性)が顕微鏡で検査され、0.1%未満の赤血球又は白血球の混在が示された。次に、分離された血小板ペレットをさらに使用するために瞬間凍結させた。VU大学医学センター及びUmea大学で、文献(J.Skog et al.、Nat Cell Biol.10(12)、1470−6(2008))に記載の方法で、膠芽細胞腫と前立腺癌患者から膠芽細胞腫組織切除及び全血液を採取した。
ミクロベシクルは、U87−EGFRvIII膠芽細胞腫細胞から分離し、既に記載された方法でラベル化した(J.Skogら、Nat Cell Biol.10(12)、1470−6(2008))。U87−dEGFRミクロベシクルインキュベーションの後、血小板を洗浄し、RNアーゼ酵素で処理して、EGFRvIII RNAが前記血小板へ転移され、それによりRNアーゼ媒介分解から保護されていることを保証した。共焦点顕微鏡分析のために、血小板構造を示すために前記血小板がテキサスレッド共役ジャームアグルチニンで染色され、緑色PKH67の存在によりミクロベシクル取り込みを分析した。
RNAは、miRvana(Ambion)又はmiRNeasy(AQuiagen)を用いて製造者指示書に従って分離した。RNA濃度及び品質は、Bioanalyzer 2100により、全RNA Pico chip (Agilent)を用いて決定した。
EGFRvIII、PCA3、PSA及びGAPDHのRT−PCRは、文献(J.Skogら、Nat Cell Biol.10(12)、1470−6(2008))記載の方法で次のプライマーセットを用いて行った。
GAPDHプライマー:
前方 5´−GAAGGTGAAGGTCGGAGTC−3´
後方 5´−TCAGAAGATGGTGATGGGATTTC−3´
PSAプライマー:
前方 5’−ATGTGGGTCCCGGTTGTCTT−3’
後方 5’−TCCCACAATCCGAGACAGGA−3’
ネストPCA3プライマー:
PCR1:
前方 5’−AGTCCGCTGTGAGTCT−3’
後方 5’−CCATTTCAGCAGATGTGTGG−3’
PCR2:
前方 5’−ATCGACGGCACTTTCTGAGT−3’
後方 5’−TGTGTGGCCTCAGATGGTAA−3’
ネストEGFRvIIIプライマー:
PCR1:
前方 5’−CCAGTATTGATCGGGAGAGC−3’
後方 5’−TGTGGATCCAGAGGAGGAGT−3’
PCR2:
前方 5’−GAGCTCTTCGGGGAGCAG−3’
後方 5’−GCCCTTCGCACTTCTTACAC−3’
mRNA発現アレイは、VU大学医学センターミクロアレイコア施設で、Agilent 4x44K 遺伝子発現アレイを用いて行った。血小板RNAの完全性はAgilent 2100 Bioanalyzer (Agilent Technologies、Inc.)を用いて行った。RNAサンプルは、Agilent Low RNA Input Linear Amplification Kit Plus(5188−5340)を用いて製造者の指示書に従い行った。
遺伝子発現データのヒートマップをエクセル((Microsoft Office 2007)で、S.A.M.分析プラグインを用いて、偽発見率<0.5%で、中間値中心アレイを用いて精製した。トップ30の有意に異なる発現遺伝子は、ヒートマップビルダv1.1ソフトウェア(Kingら、「Physiol Genomics.Sep 21 2005;23(1):103−118」)を用いて図示した。
この例では、健康なコントロール被験者から分離された血小板は、ヒト脳腫瘍細胞(膠芽細胞腫)から誘導されたRNAを含有ミクロベシクルを取り込み、変異EGFRvIIIを含む腫瘍関連RNAを含むことが示された。PKH67ラベル化膠芽腫細胞誘導ミクロベシクルが、血液血小板でFACS分析及び共焦点顕微鏡で示される。加えて、健康なコントロール被験者から血小板への変異EGFRvIIIRNAの血小板へのミクロベシクル介在転移が生じることがRT−PCRにより示される。さらに、膠芽腫患者から分離された循環血小板がRNAバイオマーカーを含むことが決定された(図3B)。RT−PCRは、変異EGFRvIIImRNAが、切開された高度膠芽腫組織で見出され(n=18)るかどうかを決定するために使用され、その結果は、同じ患者からの血小板、及び健康なコントロール被験者からの血小板(N=30)と比較された。前記サンプルは、コード化され、RT−PCRはブラインド検定で実施された。18の膠芽腫サンプルのうち4(22.8%)は、以前の観察と同様にEGFRvIII転写物を含んでいた。特に、EGFRvIIIは、これらの4人のEGFRvIII陽性患者のうちの3人の血小板から増幅されたが、健康なドナーの血小板のいずれからも増幅されなかったが一方、GAPDHmRNAは全ての血小板サンプルで検出された。可能な偽陰性シグナルは一人の患者からのみ検出され、これは血液サンプルに処理が不適切であったことによる。逆に、一人のEGFRvIII陰性組織サンプルの患者は、血小板サンプルでEGFRvIII陽性であり、これは高度の膠芽腫でのEGFRvIII陽性の病巣が不均一であることによるものであろう。
Claims (10)
- 癌マーカーの存在について被験者から採取された血液サンプルを分析する方法であり、前記方法は次のステップ、
(a)無核血液細胞から核酸を抽出し、前記血液サンプル中の、無核血液細胞抽出核酸画分を提供するステップ、及び
(b)前記無核血液細胞抽出核酸画分を癌マーカーの存在について分析するステップを含み、
前記癌マーカーが、前記被験者の有核細胞の遺伝子の癌特異的変異であるか、
前記癌マーカーが、前記被験者の有核細胞の遺伝子の癌特異的発現プロフィルであり、
前記癌が、固形腫瘍癌である、方法。 - 請求項1に記載の方法であり、前記無核血液細胞が血小板又は赤血球である、方法。
- 請求項1に記載の方法であり、前記癌が、結腸、膵臓、脳、膀胱癌、乳癌、前立腺癌、肺癌、乳癌、卵巣、子宮、肝臓、腎臓、脾臓、胸腺、甲状腺、神経組織、上皮組織、リンパ節、骨、筋肉及び皮膚から選択される固形腫瘍癌である、方法。
- 請求項1乃至3のいずれか一項に記載の方法であり、前記癌特異的変異が染色体遺伝子であるか、前記癌特異的発現プロフィルが染色体遺伝子のものである、方法。
- 請求項1乃至4のいずれか一項に記載の方法であり、前記核酸が、リボ核酸(RNA)である、方法。
- 請求項1乃至5のいずれか一項に記載の方法であり、前記核酸が、mRNAである、方法。
- 請求項1乃至6のいずれか一項に記載の方法であり、前記癌マーカーの存在についての前記無核血液細胞抽出核酸画分の分析ステップ(b)は次の選択的増幅:
(i)少なくとも1つの核酸変異特異的増幅プライマー又はプローブを用いる逆転写ポリメラーゼ連鎖反応による前記変異の増幅、又は
(ii)前記mRNAをコード化する染色体遺伝子の発現レベルを決定し、それにより前記遺伝子の発現プロフィルを提供し、かつ前記発現プロフィルを参照プロフィルと比較するために、逆転写ポリメラーゼ連鎖反応による複数のmRNAの増幅、を含む、
方法。 - 請求項1乃至7のいずれか一項に記載の方法を実施するために適合される部品のキットであり、前記キットは、
−蛍光マーカーラベル化抗無核血液細胞抗体;
−血液サンプルから分離された無核血液細胞を保持する容器;
−前記無核血液細胞から核酸を抽出するカオトロピック試薬;
−前記無核血液細胞から抽出された前記核酸から、被験者の有核細胞の遺伝子の癌特異的変異を、逆転酵素ポリメラーゼ連鎖反応増幅により、選択的に増幅するための増幅プライマー、及び
−請求項1乃至7のいずれか一項に記載の方法を実施するための印刷又は電子的指示書を含む包装物を含み、
前記キットがさらに:
−前記癌の参照値を含み、前記参照値は、前記無核血液細胞抽出核酸画分内の癌マーカーの存在の指標であり、
前記指示書が、ビーズ系無核血液細胞分離の指示書、無核血液細胞のFACS選別の指示書、遠心分離による又は非無核血液細胞成分の負選別による無核血液細胞回収のための指示書から選択される、キット。 - 請求項8に記載のキットであり、前記参照値は、健康なコントロール被験者、又は癌を患うコントロール被験者の血小板中の前記癌特異的変異を含む核酸のレベルについての参照値であり、又は前記参照値は、健康なコントロール被験者の又は癌を患うコントロール被験者からの無核血液細胞中の複数のmRNAの参照発現プロフィルである、キット。
- 癌診断のための装置であり、前記装置は、
支持体及び前記被験者の無核血液細胞サンプル内の少なくとも1つの核酸変異のレベル及び/又は活性を特異的に決定するための少なくとも1つの試薬を含み、前記試薬は前記支持体に結合され、及び請求項1乃至7のいずれか一項に記載の方法を実施するためのコンピュータ実行可能命令を持つコンピュータ読取可能な媒体を含み、
少なくとも1つの試薬が、オリゴヌクレオチドプローブ又は配列分析プライマーであり、
前記装置は、次の核酸ハイブリダイゼーション反応を実施するための、側方流動装置、ディップスティック又はカートリッジを含み:
−無核血液細胞抽出核酸と少なくとも1つの核酸変異特異的増幅プライマー又はオリゴヌクレオチドプローブとの間のハイブリダイゼーションである、ここで前記核酸変異特異的増幅プライマー又はオリゴヌクレオチドプローブが癌特異的変異に特異的であり、又は
−無核血液細胞抽出核酸と、癌特異的遺伝子発現プロフィルを与えるための複数の遺伝子特異的増幅プライマー又はオリゴヌクレオチドプローブとのハイブリダイゼーションである、装置。
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EP2593787A2 (en) | 2013-05-22 |
WO2012008839A2 (en) | 2012-01-19 |
JP2017018099A (ja) | 2017-01-26 |
WO2012008839A9 (en) | 2012-05-03 |
MX351242B (es) | 2017-10-05 |
CN103168235A (zh) | 2013-06-19 |
WO2012008839A3 (en) | 2012-03-01 |
BR112013001136B1 (pt) | 2020-12-15 |
BR112013001136A2 (pt) | 2016-07-05 |
EP2593787B1 (en) | 2018-07-04 |
SG187101A1 (en) | 2013-02-28 |
MX2013000606A (es) | 2013-06-28 |
AU2011277178B2 (en) | 2016-10-20 |
US20130196873A1 (en) | 2013-08-01 |
AU2011277178A1 (en) | 2013-01-31 |
CN103168235B (zh) | 2016-01-13 |
AU2011277178A2 (en) | 2013-02-07 |
CA2805586A1 (en) | 2012-01-19 |
JP2013534429A (ja) | 2013-09-05 |
US10174364B2 (en) | 2019-01-08 |
CA2805586C (en) | 2020-09-01 |
JP6171057B2 (ja) | 2017-07-26 |
HK1186767A1 (zh) | 2014-03-21 |
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