JP2012531612A - ヒストンマクロh2aアイソフォームに基づいて癌再発のリスクを予測する診断方法 - Google Patents
ヒストンマクロh2aアイソフォームに基づいて癌再発のリスクを予測する診断方法 Download PDFInfo
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Classifications
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57407—Specifically defined cancers
- G01N33/57415—Specifically defined cancers of breast
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57407—Specifically defined cancers
- G01N33/57423—Specifically defined cancers of lung
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- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
- Investigating Or Analysing Biological Materials (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Peptides Or Proteins (AREA)
Abstract
Description
macro マクロ
in percent パーセント
Sample, Patient 試料、患者
protein expression level タンパク質発現レベル
図2
macro マクロ
in percent パーセント
Sample, Patient 試料、患者
Provability 確率
protein expression level タンパク質発現レベル
Disease-free survival time (in months) 無病生存期間(月)
図3
macro マクロ
Antibody 抗体
Overlay オーバーレイ
anti 抗
図4
Empty vector 空ベクター
Anti-macro 抗マクロ
図5
Histone ヒストン
Sample, Patient 試料、患者
図6
macro マクロ
Sample, Patient 試料、患者
in percent パーセント
Provability 確率
protein expression level タンパク質発現レベル
Disease-free survival time (in months) 無病生存期間(月)
図7
macro マクロ
Sample, Patient 試料、患者
ヒストン及びmRNA抽出、ウエスタンブロッティング並びにリアルタイムPCR
スイッチ可能なMEK1−ER融合タンパク質を発現するITM細胞の生成について上述した。40HTあり又はなしでのインキュベーションの後、細胞を採取し分注した。1つの細胞アリコットを、0.4M HCl内に再懸濁させ、4時間インキュベートしてヒストンタンパク質を抽出し、遠心分離して、水に透析した。RNeasy Mini Prepキット(Qiagen)を用いてRNAを抽出した。RNAeasyスピンカラムのフロースルーから、アセトンによりタンパク質を沈殿させた。タンパク質抽出物を、投入前にブラッドフォード(Bradford)アッセイにより正規化した。アイソフォーム特異的なマクロH2A抗体とともに、H2Aに対する市販の抗体(Abcam、ab15653、1:3000)及びH3に対する市販の抗体(Abcam、ab1791、1:30000)を用いて、ウエスタンブロットを行った。Superscript II逆転写酵素(Invitrogen)を用いて、第一鎖cDNA合成を行った。cDNAを、以下のオリゴを用いてリアルタイムPCR(Applied Biosystems)によって連続的に解析した。
mH2A1.1 AAGTTGTACAGGCTGACATTGC(配列番号1);
GTTCTTTTTCCGGAGTTCCA(配列番号2)、
mH2A1.2 CTTTGAGGTGGAGGCCATAA(配列番号3);
CACAAACTCCTTGCCACCTT(配列番号4)、
mH2A2 GGACGTCCAAAAAGTCCAAA(配列番号5);
GCTTCTGTCCCAGAACAAGG(配列番号6)、
and GAPDH TGGGTGTGAACCATGAGAAGTA(配列番号7);
CCTTCCACGATACCAAAGTTGT(配列番号8)。
試料を、本発明者らが試験実行におけるこれらの実験に対して信頼性の高い対照として事前に同定したGAPDHに正規化した。
マクロH2A1.1(アミノ酸198〜226)及びマクロH2A1.2(アミノ酸198〜228)を発現させ、GST融合タンパク質として精製した。マクロH2A2(アミノ酸162〜372)のマクロドメインを、(His)6−タグ融合タンパク質として精製した。抗原をウサギ(Eurogentec)に注入した。製造業者の指示に従って、HiTrap Protein−G HPカラム(GE Healthcare Life Sciences)を用いてウサギ血清から抗体を回収した。3つのマクロH2Aアイソフォームの組換え(His)6−タグ付きマクロドメインを、HiTrap NHS活性化HP(GE Healthcare)に結合した。これらのカラムを、後に、アイソフォームに特異的な抗体のアフィニティ精製に用いた。
National Center of TumorDiseases(NCT)、Heidelberg、Germanyによって、乳癌TMAが提供された。それらは、異なるブロックに分散された、各スライドに患者当り2つの試料で、260人の患者のホルマリン固定されかつパラフィン包理された試料を含んでいた。すべての乳癌患者は女性、中央年齢は58歳(範囲、30歳〜88歳)であった。これらの患者に関する臨床データは、さらなる解析には不十分であった。
Thoraxklinik Heidelberg、Germany及びNCTによって肺癌TMAが提供された。スライドは、切除可能であることが分かり、かつ2004年3月から12月の間に手術を受けた、NSCLCの41人の患者の試料を含んでいた(23人が腺腫、18人が扁平上皮癌)。
特徴 中央(範囲)/度数
性別(男/女) 31/8
診断時の年齢(歳) 64(43-80)
全身状態(0/1/2) 28/11/0
腫瘍細胞タイプ(AC/SCC) 22/17
手術のタイプ(LO-BI-PN) 26/2/11
切除状態(R0/R1/R2) 32/5/2
疾患の病期(手術後)(Ia/Ib/IIa/IIb/IIIa/IIIb/IV)
1/11/0/4/13/6/4
1年以内の腫瘍再発(y/n) 18/21
(AC:腺癌、SCC:扁平上皮癌、BI:二葉切除、LO:肺葉切除、PN:肺全摘出)
R2切除患者のうち、1人が再発(遠隔転移)、1人が再発なく生存、R1切除患者のうち、3人が再発(2人は局所転移、1人は遠隔転移)、2人は再発なく生存、R0切除患者のうち、15人が再発、17人が再発なく生存。
連続TMAスライドを用いて、マクロH2A1.1、マクロH2A1.2、マクロH2A2、Ki−67(Dako Cytomation、モノクローナルマウス抗ヒトKi−67、クローンMIB−1、1:100)及びヒストンH3(Abcam;ab1791;1:1000希釈液)に対する免疫組織化学染色を行った。Aperio Scanscope System及びImageScopeソフトウェアを用いてDepartment of Pathology(HeidelbergUniversity)でスライドをスキャンした。
Ki−67とマクロH2A1.1との関係を、アレイによって層別化された条件付き線形関連検定(conditional linear association test)を用いて評価した(Hothorn他、2006)。無病生存期間の依存度を、同様にアレイで層別化された条件付きログ−ランク検定(long-rank test)によって確立した(Hothorn他、2006)。
Chen Z, Trotman LC, Shaffer D, Lin HK, Dotan ZA,Niki M et al. (2005). Crucial role of p53-dependent cellular senescence insuppression of Pten-deficient tumorigenesis. Nature 436: 725-730.
Collado M, Gil J, Efeyan A;Guerra C, Schuhmacher AJ, Barradas M et al. (2005). Tumour biology: senescencein premalignant tumours. Nature 436: 642.
Collado M, Serrano M. (2006). The power and thepromise of oncogene-induced senescence markers. Nat Rev Cancer 6: 472-476.
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Claims (24)
- 哺乳類患者における癌再発のリスクを判定するための測定方法であって、前記患者から取得される生体試料においてマクロH2A1.1及び/又はマクロH2A2の発現を検出することを含み、前記マクロH2A1.1及び/又はマクロH2A2の発現の低下又は減弱は、前記患者における癌再発のリスクの増大を示す、方法。
- 前記発現が、前記試料及び/又は対照試料におけるマクロH2A1.2の発現に正規化される、請求項1に記載の方法。
- マクロH2A1.1又はマクロH2A2の発現と無病生存期間との相関が、P<0.05、又はP<0.01、又はP<0.006である、請求項1又は2に記載の方法。
- 前記癌が、固形癌、肺癌、乳癌、腎臓癌、肝臓癌、頭頸部癌、前立腺癌、膵臓癌、胃癌、結腸癌、甲状腺癌、食道癌及び脳癌の群から選択される、請求項1〜3のいずれか一項に記載の方法。
- 前記生体試料が、肺腫瘍、乳腺腫瘍、腎臓腫瘍、肝臓腫瘍、頭頸部腫瘍、前立腺腫瘍、膵臓腫瘍、胃腫瘍、結腸腫瘍、甲状腺腫瘍、食道腫瘍及び脳腫瘍、全血、血清、血漿、尿、リンパ液、胸膜液並びに脳液からの細胞の群から選択される、請求項1〜4のいずれか一項に記載の方法。
- さらなる癌マーカーであるKi−67の発現を検出することを更に含む、請求項1〜5のいずれか一項に記載の方法。
- 前記試料における前記マクロH2A1.1及び/又はマクロH2A2の前記発現が、Ki−67の発現に逆相関する、請求項6に記載の方法。
- マクロH2A1.1の発現に基づく、該腫瘍における老化細胞、又は癌細胞の測定を更に含む、請求項1〜7のいずれか一項に記載の方法。
- 前記測定に基づく前記癌再発の予測を更に含む、請求項1〜5のいずれか一項に記載の方法。
- 前記試料が、手術中の患者から採取される、請求項1〜9のいずれか一項に記載の方法。
- 発現を検出することが、PCR若しくはrtPCR、マクロH2A1.1に特異的な若しくはマクロH2A2に特異的な抗体を用いる免疫組織化学染色、及び/又はmRNA解析を含む、請求項1〜10のいずれか一項に記載の方法。
- マクロH2A1.1又はマクロH2A2に特異的な薬剤に対するスクリーニング方法であって、マクロH2A1.1又はマクロH2A2に潜在的に特異的な薬剤とマクロH2A1.1又はマクロH2Aを接触させること、及び前記薬剤が特にマクロH2A1.1又はマクロH2Aと結合するか否かを測定することを含む、方法。
- マクロH2A1.1又はマクロH2A2に潜在的に特異的な前記薬剤が、化合物ライブラリ、ファージディスプレイライブラリ、sc−Fvファージディスプレイライブラリ、又は抗体のライブラリに存在する、請求項12に記載のスクリーニング方法。
- マクロH2A1.1又はマクロH2A2に潜在的に特異的な前記薬剤が、診断薬及び/又は治療薬である、請求項12又は13に記載のスクリーニング方法。
- 請求項12〜14のいずれか一項に記載の方法に従ってスクリーニングされた診断薬及び/又は治療薬。
- マクロH2A1.1若しくはマクロH2A2に特異的な抗体、又はそのマクロH2A1.1若しくはマクロH2A2に特異的な断片を製造する方法であって、
a)クロマトグラフィカラムに結合されたマクロH2A1.1ドメイン若しくはマクロH2A2ドメインを用いる、抗体を含む血清若しくは細胞培養上清をアフィニティ精製する工程、又は
b)マクロH2A1.1ドメイン若しくはマクロH2A2ドメインを用いてsc−Fvファージディスプレイライブラリをスクリーニングする工程、
を含む、方法。 - 請求項16に記載の方法によって製造された、マクロH2A1.1若しくはマクロH2A2に特異的な抗体、又はそのマクロH2A1.1若しくはマクロH2A2に特異的な断片。
- 任意にラベルを有する、モノクローナル抗体、ポリクローナル抗体、ヒト抗体、ヒト化抗体及び/又は組換え抗体から選択される、請求項17に記載のマクロH2A1.1又はマクロH2A2に特異的な抗体。
- 請求項15に記載の診断薬、及び/又は、請求項17又は18に記載の、マクロH2A1.1若しくはマクロH2A2に特異的な抗体、又はそのマクロH2A1.1若しくはマクロH2A2に特異的な断片を、任意選択的に請求項1〜11のいずれか一項に記載の方法を行うための追加の補助剤とともに具備する診断キット。
- 哺乳類患者の癌を治療する方法であって、請求項1〜11のいずれか一項に記載の方法、並びに患者における癌再発のリスクが増大していると特定された前記患者の前記癌の再発を治療及び/又は予防することを含む、方法。
- 前記治療が、該治療を必要とする前記患者に対する、請求項10〜12のいずれか一項に記載の方法に従ってスクリーニングされた薬剤の投与を含む、請求項20に記載の哺乳類患者の癌を治療する方法。
- マクロH2A1.1の発現に基づいて、前記治療に応じて該腫瘍における老化細胞又は癌細胞の量及び/又は比をモニタリングすることを更に含む、請求項20又は21に記載の哺乳類患者の癌を治療する方法。
- 請求項12〜14のいずれか一項に記載の方法によってスクリーニングされる薬剤、並びに/又は、請求項16又は17に記載のマクロH2A1.1若しくはマクロH2A2に特異的な抗体、又はそのマクロH2A1.1若しくはマクロH2A2に特異的な断片、又は癌の予防、治療及び/若しくは診断、又は癌再発の予防、治療及び/若しくは診断のための請求項19に記載のキットの使用。
- 前記癌が、固形癌、肺癌、乳癌、腎臓癌、肝臓癌、頭頸部癌、前立腺癌、膵臓癌、胃癌、結腸癌、甲状腺癌、食道癌及び脳癌の群から選択される、請求項23に記載の使用。
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