JP4649331B2 - 乳房細胞増殖障害の改良治療方法および核酸 - Google Patents
乳房細胞増殖障害の改良治療方法および核酸 Download PDFInfo
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Description
5−メチルシトシンを検出する別な公知方法に関する概要は、次の総説文献:レイン(Rein)T、デパムフィリス(DePamphilis)M.L, ゾルバス(Zorbas)H, Nucleic Acids Res. 1998, 26, 2255から集めてもよい。
オリゴマーアレー製造における先行技術の概要は、1999年1月に発行されたNature Geneticsの特別版(Nature Genetics Supplement, Volume21, January 1999)およびそこに引用された文献から集めることができる。
ゲノムDNAは標準方法によって細胞、組織または他の試験試料DNAから得られる。この標準的方法論は、フリッシュ(Fritsch)およびマニアティス(Maniatis)編、Molecular Cloning:「研究室マニュアル」、1989などの参考文献に見られる。
-STMN1, PITX2, PSA および CGA
-STMN1, SFN, S100A2, TGFBR2, SYK, GRIN2D, PSA, COX7A2L, VTN およびPRKCD
-ONECUT2, WBP11, CYP2D6, DAG1, ERBB2, S100A2, TFF1, TP53, TMEFF2, ESR1, SYK, RASSF1, PITX2, PSAT1, CGA および PCAF
TP53, PTGS2, CYP2D6 および MSMB、ここで、この遺伝子の配列は配列番号: 68, 50, 92 および 99を含むことがさらに好ましく、
PITX2、ここで、この遺伝子の配列は配列番号: 83を含むことがさらに好ましく、
WBP11, TMEFF2, ERBB2, ESR1, PITX2 および PCAF、ここで、この遺伝子の配列は配列番号: 137, 132, 133, 134, 135 および 136を含むことがさらに好ましい。
FGFR1, PSA および CGA、ここで、これらの遺伝子の配列は配列番号: 74, 90 および 91を含むことがさらに好ましく、
STMN1, PSA および CGA、ここで、これらの遺伝子の配列は配列番号: 27, 90 および 91を含むことがさらに好ましく、
STMN1, SFN, S100A2, TGFBR2, SYK, GRIN2D, PSA, COX7A2L, VTN および PRKCD、ここで、これらの配列は配列番号: 27, 40, 41, 43, 78, 86, 90, 105, 115, 121を含むことがさらに好ましく、
ONECUT2, CYP2D6, DAG1, S100A2, TFF1, TP53, SYK, RASSF1, PSAT1 および CGA、ここで、これらの遺伝子の配列は配列番号: 126, 129, 125, 122, 123, 131, 127, 130, 124 および 128を含むことが好ましい。
本方法の第一工程では、ゲノムDNA試料はDNA、DNA源、例えば、セルライン、組織学的スライド、生検、パラフィン中に包埋された組織、乳房組織、血液、血漿、リンパ液、リンパ組織、管細胞、管洗浄液、乳頭吸引液、骨髄およびこれらの組合せを含む細胞または細胞成分などの起源から単離されなければならない。抽出は当業者にとって標準的である手段によって行う。これらは洗浄剤溶解物、超音波およびガラスビースによるボルテキシングの使用を含む。核酸は一度抽出されると、ゲノム二本鎖DNAが分析に使用される。
DNA試料はウィザードキット(Promega)を使用して抽出し、200名の患者から得た試料を分析し、候補マーカーを選択して4つのデータ分析を実施した。
全ての試料の全ゲノムDNAを重亜硫酸塩で処理して非メチル化シトシンをウラシルへ変換した。残存するメチル化シトシンはそのままであった。重亜硫酸塩処理はオレク(Olek)ら、(1996)が記載するプロトコールをわずかに変更して実施した。重亜硫酸塩化した後、各DNA試料10ngを6〜8プライマー対を含む次のmPCR反応に使用した。
400μM dNTP
2pmol 各プライマー
1 U HotStarTaq (Qiagen)
10ng DNA (重亜硫酸塩処理)
95℃で15分間の変性、続いて55℃で45分間のアニーリング、65℃で2分間のプライマー伸長を40回、繰り返した。65℃で最終伸長を10分間、実施した。
次いで、個々の試料のそれぞれから得た全PCR産物は、分析下の各CpG位置における固定化された1対のオリゴヌクレオチドを有するガラススライドとハイブリダイズさせた。これらの検出オリゴヌクレオチドは、それぞれ、本来、非メチル化(TG)またはメチル化(CG)された1つのCpG部位のまわりの重亜硫酸塩変換配列にハイブリダイズするように設計されていた。使用したハイブリダイゼーションオリゴヌクレオチドのさらに詳細なことは、表2を参照のこと。ハイブリダイゼーション条件はTGおよびCG変異体間の1つのヌクレオチドの相違を検出できるように選択した。
チップデータの分析:生ハイブリダイゼーション強度からメチル化割合へ;各CpG位置のログメチル化割合(log(CG/TG))は下記工程を含む標準化された前処理情報ラインに従って測定した。各スポットでは、中央背景画素強度が中央前景画素強度から差し引かれる(これはハイブリダイゼーション強度を訂正した背景の良い推定値となる)。各CpG位置のCGおよびTG検出オリゴヌクレオチドでは、4つの余分なスポット強度の背景補正中央値が採用される。各チップおよび各CpG位置では、log(CG/TG)割合が計算される。各試料では、余分なチップ反復以上のlog(CG/TG)強度が採用される。この割合はハイブリダイゼーションノイズが可能性あるメチル化割合の完全な範囲を越えるおよそ一定の変動を有するとの性質を有する(フーバー(Huber)ら、2002)。
主成分分析(PCA)は新規な座標系上に測定ベクター(例えば、チップデータ、いくつかのCpGなどの上のメチル化プロフィールなど)を描出する。新規な座標軸は主成分として参照される。第1主成分はデータの最も大きな変動の方向をスパンする。次の成分は減少する変動により順序付けられ、互いに直交する。異なったCpG位置は、異なったウェイトでもって異なった成分に従うデータクラウドの伸長に寄与する。PCAは未管理技術、すなわちデータポイントの標識を考慮にいれない技術である(さらに詳細は、例えばリップレイ(Ripley)(1996)参照)。
主たる仕事は、2つのクラス間のメチル化の平均的程度における有意な相違を示すマーカーを同定することである。有意な相違は、2つのクラスの平均的メチル化が同じであるとの帰無仮説がp<0.05でもって拒絶され得るときに検出される。我々はこの検定を潜在的マーカーの全体的セットに応用するから、我々は多重検定におけるp−値を補正しなければならない。これはフォールス・ディスカバリー・レート (FDR) 法 (デュドワ(Dudoit)ら、2002)を応用して実施された。
選択カーカーのCpG全体が相違した組織クラス間をいかに十分に差別化することができるかについての信頼性ある評価を与えるために、我々は分類によってその予測の正確性を決定することができる。この目的のために、我々はそれらのクラス標識によってあるセットの組織試料を使用して、メチル化プロフィールに基づく予測機能を計算する。この段階はトレーニングと呼ばれ、それはデータ標識によって示される先の知識を活用する。次いで、この機能の予測正確性は交差確証により、または1設置の独立した試料で検定される。選択方法としては、我々はサポート・ベクター・マシン(SVM)アルゴリズム(デューダ(Duda) (2001), クリスチアンニニ(Christiannini) (2000))を使用して、予測機能を学習する。もしも他に言及されていないなら、この報告では、偽陽性または偽陰性分類を伴うリスクがそれぞれのクラスの大きさに等しく関連しているとされる。これは学習アルゴリズムが目的とともにクラス予測機能を得て、独立した試料セットの正確性を至適化することを伴う。したがって、得られた分類物の感度と特異性はおよそ等しいと期待され得る。
データセット1および2(図5〜13)
次いでデータはアルゴリズムを使用して2つのクラスの組織間のCpGメチル化相違に従ってランク付けされたマトリックスス中に分類する。図5、7、9および11〜13は灰色段階で示され、ここで、最も有意なCpG位置は上部に向かって減少する有意差をもつマトリックスの底部に存在する。黒色は所与のCpG位置の全メチル化を示し、白色は特定の位置の非メチル化を示し、メチル化程度は明るい灰色(メチル化の低割合)から暗い灰色(メチル化の高割合)で示される。各列は1つの遺伝子内の1つの特定CpG位置を示し、各欄は1つの試料における異なったCpGのメチル化プロフィールを示す。CpGおよび遺伝子同定物が示される左側には、これは問題の遺伝子および使用された検出オリゴマーを確証するために添付する表(表5)に相互参照されている。p−値は観察された分布がデータセットで偶然に生じた可能性である。図6、8、10および12は先の図(すなわち、それぞれ図5、7、9および11)の元の赤−緑バージョンである。暗い灰色は所与のCpG位置の全メチル化を示し、明るい灰色は特定位置の非メチル化を示す。
外科手術後、直ちに補助治療としてタモキシフェンで治療した患者試料のメチル化パターン分析(図1)は、図5〜8のマトリックス中に示される。この分析では、PTGS2、MSMB、TP53およびCYP2D6遺伝子は2つのクラスの組織(治療に対する反応者と治療に対する非反応者)間で有意に相違してメチル化されていた。
転移活動環境においてタモキシフェンで治療した患者試料のメチル化パターンの分析(図2参照)は図9〜12のマトリックス中に示される。この分類で分析された被検者は最初の治療に続いて再発し、続いての転移はタモキシフェンで治療した。
図12は非反応者と対比する薬剤の反応者の全試料セットの分析を示す。ここで、薬剤に対する反応者が非反応者と対比され、2つのクラスの組織間にメチル化におい有意な相違がSTMN1 およびPSA遺伝子において観察された。
各CpGは、公知予測マーカーN−段階と腫瘍サイズとともにコックス 比例ハザードモデル中に入れた。最もよいマーカーはPITX2遺伝子であった。
タモキシフェン治療の成功または失敗を予測する各遺伝子プロモーターの能力を決定するために、測定された個々のCpGをホテリング(Hotelling)のT2統計量を使用して遺伝子毎に組み合わせた。いくつかの遺伝子は多重比較において適度保存フォールス・ディスカバリー・レート25%補正後、タモキシフェンに対する反応に有意に関連していた(図3参照)。この遺伝子はONECUT2、WBP11、CYP2D6、DAG1、ERBB2、S100A2、TFF1、TP53、TMEFF2、ESR1、SYK、RASSF1、PITX2、PSAT1、CGAおよびPCAFであった。
各増幅産物において、その増幅産物のための全オリゴ対における平均メチル化が計算され、その集団はその平均メチル化値によって等しい大きさの群に分けられた。その結果はカプラン−マイヤー(Kaplan-Meier)法で推定された無疾患生存曲線として、図17〜21に示される。p−値は、次の通りであった。
PCAF:p = 0.0105
PITX2:p = 3e-04
TMEFF2:p = 0.0106
WBP11:p = 0.0366
ERBB2:p= 0.018
タモキシフェン治療の成功または失敗を予測する各遺伝子プロモーターの能力を決定するために、測定された個々のCPGをホテリング(Hotelling)のT2統計量を使用して遺伝子毎に組み合わせた。潜在的マーカーを同定するには、本発明者らは客観的反応(CR+PR、45名の患者)または治療開始からまさしく進行性疾患(PD、78名)のいずれか極度の反応タイプを示した123名の患者について最初の分析を実施した。いくつかの遺伝子は多重比較において適度保存フォールス・ディスカバリー検定25%補正後、タモキシフェンに対する反応に有意に関連していた(図3参照)。この遺伝子はSTMN1、SFN、S100A2、TGFBR2、SYK、GRIN2D、PSA、COX7A2L、VTNおよびPRKCDであった。
以下の実施例では、PSAT1遺伝子のタモキシフェン反応関連メチル化状態がブロッカーオリゴヌクレオチドおよびLightcyclerプローブを含むリアルタイム分析を使用して、24名の患者試料の分析によって証明した。
プライマー: AAAACTCACATCCCCATTAA (配列番号:2144)
プローブ: TTTTTTGTATTGATTAAAAATGGGGGTTGAAATAGTA (配列番号:2145)
メチル化特異的プローブ: CGCGAGGAGGAGTAATTGTTTC (配列番号:2146)
メチル化特異的プローブ: TGTGAGGAGGAGTAATTGtTTTGATTT (配列番号:2147)
反応溶液:
Qiagen HotStarTaq 5U
10×PCR緩衝液 1x
MgCl2 3mM
プライマー 各300nM
プローブ 各250nM
dNTPs 各200nM
BSA 0.25mg/ml
鋳型DNA 10ng
サイクリングプロフィール:
15分間、95℃ 変性
55回:95℃で10 秒、55℃で20 秒、57℃で3秒、72℃で20秒、結果は表4に示される。
Claims (19)
- 少なくとも1つの抗エストロゲン薬剤を含む治療に対する乳房組織の細胞増殖障害を有する被検者の反応性を予測する方法であって、ハイブリダイゼーション特性において、その5'−位置で非メチル化されるシトシン塩基をシトシンと異なって検出され得る塩基に変換する少なくとも1つの薬剤に、治療前あるいは治療中に被検者から得た生体試料中の標的核酸の少なくとも1つを接触させることによって、PITX2遺伝子および/またはそれらの制御領域を含む少なくとも1つの標的核酸のメチル化パターンを分析することを含む方法。
- 請求項1に記載のPITX2遺伝子の分析において、
−STMN1, PSAおよびCGAからなる群から選択される、または
−ONECUT2, WBP11,CYP2D6, DAG1, ERBB2, S100A2, TFF1, TP53, TMEFF2, ESR1, SYK, RASSF1, PSAT1, CGA および PCAFからなる群から選択される、
遺伝子がさらに分析される方法。 - 請求項1に記載のPITX2遺伝子の分析において、TP53, PTGS2, CYP2D6, MSMB,WBP11, TMEFF2, ESR1, ERBB2およびPCAFからなる遺伝子群から選択される遺伝子がさらに分析される方法。
- 前記遺伝子群は、WBP11,TMEFF2, ESR1, ERBB2およびPCAFからなる群である、請求項3に記載の方法。
- 前記標的核酸は、配列番号: 27, 83,90および91、ならびにこれらに相補的な配列からなる群から得られる1つまたはそれ以上の配列を含む、請求項2に記載の方法。
- 前記標的核酸は、配列番号: 126, 137,129, 125, 132, 122, 123, 131, 133, 134, 127, 130, 135, 124, 128および136、およびこれらに相補的な配列からなる群から得られる1つまたはそれ以上の配列を含む、請求項2に記載の方法。
- 乳房組織の前記細胞増殖障害は、インサイチュ管癌腫、小葉癌腫、膠質癌腫、尿細管癌腫、髄様癌、異形成癌腫、インサイチュ管内癌腫、インサイチュ小葉癌腫およびインサイチュ乳頭癌腫からなる群から選択される、請求項1〜6に記載の方法。
- 前記被検者は、エストロゲンおよび/またはプロゲステロン受容体陽性である、請求項1〜7に記載の方法。
- 前記治療は、乳房組織の再発性または転移性細胞増殖障害の処置のための治療である、請求項1〜3に記載の方法。
- 前記治療は補助的治療である、請求項1〜6に記載の方法。
- 前記被検者は化学治療を受けなかった、請求項10に記載の方法。
- 配列番号: 411, 412, 515,516, 685, 686, 789および790、ならびにこれらに相補的な配列からなる群から選択される配列のうちの1つによる長さが少なくとも18塩基の配列の核酸分子からなるタモキシフェン治療における乳房組織の細胞増殖障害を有する被検者の反応性を予測するための診断剤。
- オリゴヌクレオチドまたはペプチド核酸(PNA)−オリゴマーであって、配列番号:411, 412, 515, 516, 685, 686, 789および790に記載の核酸配列のうちの1つにハイブリダイズするかあるいは同一である、長さ少なくとも18ヌクレオチドを有する少なくとも1つの塩基配列のオリゴマーからなるタモキシフェン治療における乳房組織の細胞増殖障害を有する被検者の反応性を予測するための診断剤。
- 塩基配列は少なくとも1つのCpGジヌクレオチドを含む、請求項13に記載されるオリゴマーからなるタモキシフェン治療における乳房組織の細胞増殖障害を有する被検者の反応性を予測するための診断剤。
- 請求項13または14のいずれかに記載される少なくとも2つのオリゴマーを含むオリゴマーのセットからなるタモキシフェン治療における乳房組織の細胞増殖障害を有する被検者の反応性を予測するための診断剤。
- 少なくとも1つのオリゴヌクレオチドが固相体に結合していることを特徴とする請求項13〜15に記載されるオリゴヌクレオチドのセットからなるタモキシフェン治療における乳房組織の細胞増殖障害を有する被検者の反応性を予測するための診断剤。
- 配列番号: 411, 412, 515, 516, 685, 686, 789および790、ならびにこれらに相補的な配列のうちの1つを含む核酸配列の増幅のためのプライマーオリゴヌクレオチドとして使用される、請求項13〜15のうちの1つに記載される少なくとも2つのオリゴヌクレオチドのセットからなるタモキシフェン治療における乳房組織の細胞増殖障害を有する被検者の反応性を予測するための診断剤。
- 重亜硫酸塩試薬ならびに請求項13〜17の1つに記載されるオリゴヌクレオチドおよび/またはPNA−オリゴマーを含むキットからなるタモキシフェン治療における乳房組織の細胞増殖障害を有する被検者の反応性を予測するための診断剤。
- さらに、MS−SNuPE、MSP、Methyl light、Heavy Methyl、核酸配列決定およびこれらの組合せからなる群から得られるメチル化分析を実施するための標準的試薬を含む、請求項18に記載のキットからなるタモキシフェン治療における乳房組織の細胞増殖障害を有する被検者の反応性を予測するための診断剤。
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