JP2004290200A - メチル化特異的検出 - Google Patents
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Abstract
【解決手段】
被験者におけるTIMP−2核酸中のCpG島のメチル化と関連した細胞増殖性疾患を検出する方法であって、
被験者由来の組織または生物学的液体である検体中の標的核酸を、該標的核酸であるTIMP−2のメチル化を検出する試薬と接触させ、そして
TIMP−2標的核酸を検出すること
を含んでなり、
その際、標的核酸である標的TIMP−2の高メチル化が、TIMP−2と関連した細胞増殖性疾患を示す、上記方法。
【選択図】なし
Description
本発明は、概して遺伝子発現の調節に関するものであり、さらに詳細には所与の遺伝子座中のCpG部位のDNAメチル化状態を測定するための方法に関する。
高等真核生物において、DNAは、CpGジヌクレオチド中のグアノシンの5’側に位置するシトシンでのみメチル化される。この修飾は、遺伝子発現において、特に含まれているCpGに富む領域(CpG島として知られている)が多くの遺伝子のプロモーター領域に存在する場合に重要な制御効果を有する。常染色体では殆ど全ての遺伝子関連の島がメチル化から保護されているが、CpG島の広範にわたるメチル化は、所与の刷込み遺伝子の転写の不活性化および雌の不活性X染色体上の遺伝子の転写の不活性化と関連している。通常はメチル化されていないCpG島の異常なメチル化は、不死化細胞または形質転換細胞では頻繁に見られる事象であることが記載されており、ヒト癌における特定の癌抑制遺伝子の転写の不活性化と関連している。
最近、CpGに富む領域(すなわち「CpG島」)が17p13.3において同定され、この領域は、ヒト癌の多くの共通タイプにおいて異常に高メチル化(hypermethylated)されている(Makos,M.ら,Proc.Natl.Acad.Sci.USA,89:1929,1992;Makos,M.ら,cancerRes.,53:2715,1993;Makos,M.ら,Cancer Res.53:2719,1993)。この高メチル化は、脳の癌、結腸癌および腎臓癌における17p喪失およびp53変異のタイミングや頻度と符号している。通常はメチル化されていないプロモーター領域CpG島の高メチル化に関わるサイレント遺伝子転写は、癌抑制遺伝子を不活性化するためのコード領域の突然変異のもう1つの機構と見なされている(Baylin,S.B.ら,Cancer Cells,3:383,1991;Jones,PA.およびBuckley,J.D.,Adv.Cancer Res.,54:1-23,1990)。現在、この変化は、3pに存在する腎臓癌の癌抑制遺伝子であるVHL(J.G.Hermanら,Proc.Natl.Acad.Sci.USA,91:9700-9704)、6q上に存在するエストロゲン受容体遺伝子(Ottaviano,YL.ら,Cancer Res.,54:2552,1994)および11p上に存在するH19遺伝子(Steenman,M.J.C.ら,Nature Genetics,7:433,1994)の発現の喪失と関連づけられている。
CpG島におけるDNAメチル化パターンの正確なマッピングは、X染色体不活性化、ヒト癌で沈黙している癌抑制遺伝子、刷込み遺伝子の調節といった様々な生物学的プロセスを理解するために必要不可欠になってきている。本発明は、メチル化感受性制限酵素の使用に依存しない、CpG島内の任意のCpG部位群のメチル化状態の迅速な評価方法を提供する。PCRの使用と重亜硫酸修飾の使用に関する当業者の知識にもかかわらず、本発明以前には、独立して、PCR反応そのものを用いて化学的に修飾されたメチル化DNAと非メチル化DNAとを区別するような、重亜硫酸反応に特異的なプライマーをだれひとりとして作製したものはいなかった。
本発明は、DNAメチル化パターンを同定するためのメチル化特異的PCR(MSP)を提供する。MSPはPCR反応そのものを利用して修飾されたメチル化DNAと非メチル化DNAとを識別するものであるが、これによりメチル化検出感度が改良される。
*このほかに、上記の配列の修飾体が含まれる:例えば、5'末端に配列TCACを有する配列番号107;5'末端に付加された配列CCを有する配列番号107;配列5-TTATTAGAGGGTGGGGCGGATCGC-3'を有する配列番号108;配列5-GACCCCGAACCGCGACCGTAA-3'を有する配列番号109;5'末端に付加された配列TGGを有する配列番号110;5'末端に付加された配列TACCを有する配列番号111。これらの修飾プライマーはすべて、65℃でアニールする。
DNAおよび細胞系 ゲノムDNAは、文献(Merloら,Nature Medicine,1:686,199;Hermanら,Cancer Research,56:722,1996;Graffら,Cancer Research,55:5195,1995)の記載に従って、細胞系、原発癌および正常な組織から取得した。腎癌細胞系は、メリーランド州ベセスダ(Bet sda,MD)の国立がん研究所(National Cancer Institute)のMichael Lehrman博士の厚意により入手した。
初期の研究は、CpG島のメチル化状態を評価するというMSPの戦略の正当性を立証するために必要であった。5'CpG島の高メチル化を有することが報告されているp16癌抑制遺伝子(Merloら、上記;Hermanら,Cancer Research,55:4525,1995;Gonzalez-Zuluetaら,Cancer Res.55:4531,1995,27)は、多くの癌のタイプにおける遺伝子発現の完全な消失と関連しており、試験される重要な領域におけるメチル化の密度が、本明細書において開示されるプライマーのデザインを容易にするのに十分な程度に大きいか否かを決定するための代表的な遺伝子として用いた。メチル化感受性酵素に対する認識配列に位置するCpG部位以外については、メチル化の密度およびその転写のサイレンシング(silencing)との相互関係はまだ確立されていなかった。そこで、この関係性を探るためにゲノム配列決定技術を用いた。
上記のp16を用いた実験を、ヒトの癌において5'CpG島の異常な高メチル化によって転写をサイレントにされた他の三つの遺伝子を含むように拡張した。
p16の間接的in situメチル化。間接的in situ PCR(間接的IS-PCR)は、標識取り込みのない熱サイクルによりアンプリコンが生成される技術である。サイクル反応の終了後に、増幅産物を、標識プローブを使用する標準的なin situハイブリダイゼーションにより検出する。
痰サンプルにおけるメチル化の変化についてMSPの使用を試験する。痰サンプル由来のDNAにメチル化の変化があるかを検出するためにMSPを使用した。調べたサンプルの中には、p16に対するプライマー(表1;配列番号105〜110)、および肺癌を患っていることが分かっている2人の患者の痰サンプルから抽出したDNAが含まれていた。p16については、非メチル化対立遺伝子は検出されたがメチル化対立遺伝子は検出されなかった。MSPはメチル化されていない対立遺伝子と作用したことから、患者の痰はメチル化p16を持っていなかったと考えられる。この仮説を調べるため、1つの痰サンプルに、高メチル化p16遺伝子を有する確立した肺癌細胞系Calu3由来の細胞でスパイクした(spiked with)。これらのp16メチル化対立遺伝子は、この混合DNAにおいて容易に検出された。
hMLH1およびhMSH2高メチル化を検出するためのMSP。hMLH1遺伝子およびhMSH2遺伝子はミスマッチ修復タンパク質をコードし、hMLH1遺伝子およびhMSH2遺伝子のそれぞれにおける突然変異はマイクロサテライト不安定性の特徴を有する遺伝性形態の結腸癌を生じる場合がある。非遺伝性の結腸癌を患う患者の約20%も、マイクロサテライト不安定性の表現型の腫瘍を有する。この後者の腫瘍を生じる正確なメカニズムについては明確でない。Kaneら(Cancer Research,57:808,1997)は、マイクロサテライト不安定性の散発性結腸癌を患う患者由来の一連の小さい腫瘍において、hMLH1遺伝子のプロモーターが高メチル化されていることを報告している。この所見について、一連のより大きい腫瘍においてさらに調査するために、hMSH2およびhMLH1の条件およびプライマーセット(表2;配列番号161-172)を用いたMSPを使用した。このような腫瘍を持つ約14人の患者の内、85%がhMLH1の高メチル化を生じており、マイクロサテライト不安定性のない21個の結腸癌では5%のみがこの変化を示した。hMSH2の高メチル化は、どちらのグループにおいても認められなかつた。このデータから、マイクロサテライト不安定性の腫瘍を持っていることが分かっている結腸癌を患う全患者のおよそ15%が腫瘍DNAにおいてhMLH1遺伝子の高メチル化を生じ、この変化と関連した転写サイレンシング(transcriptional silencing)がこの場合における遺伝子不安定性の原因であることが示される。
メタロプロテイナーゼII(TIMP2)遺伝子の組織阻害剤のMSP研究。TIMP2は、多様な細胞型の侵食能を制限するのに必要なメタロプロテイナーゼ阻害剤のフアミリーのメンバーである。この遺伝子のための条件およびMSPプライマー(表2;配列番号157〜160)を用いたところ、原発性結腸癌の約50%においてTIMP2プロモーターの高メチル化が認められた。この変化、およびこれに伴うこの遺伝子の発現の低下は、これに関わる結腸癌の侵食能を増す要因である可能性がある。
TGF-β受容体IおよびII遺伝子のMSP研究。上記したMSPプライマーおよび条件(表2;配列番号177〜184)をTGF-β受容体IおよびII遺伝子のためにうまく用いた。腫瘍におけるプロモーターの高メチル化の形跡は今までのところ認められていない。
Claims (6)
- 被験者におけるTIMP−2核酸中のCpG島のメチル化と関連した細胞増殖性疾患を検出する方法であって、
被験者由来の組織または生物学的液体である検体中の標的核酸を、該標的核酸であるTIMP−2のメチル化を検出する試薬と接触させ、そして
TIMP−2標的核酸を検出すること
を含んでなり、
その際、標的核酸である標的TIMP−2の高メチル化が、TIMP−2と関連した細胞増殖性疾患を示す、上記方法。 - メチル化を検出する前記試薬が制限エンドヌクレアーゼである、請求項1に記載の方法。
- 前記制限エンドヌクレアーゼがメチル化感受性である、請求項2に記載の方法。
- 前記制限エンドヌクレアーゼがMspI、HpaIIおよびBssHIIよりなる群から選択される、請求項3に記載の方法。
- 前記検体が血清、尿、唾液、脳脊髄膜、痰、射出精液、血液および糞便よりなる群から選択される、請求項1に記載の方法。
- 前記検体が脳、結腸、尿生殖器、肺、腎臓、造血組織、乳房、胸腺、精巣、卵巣および子宮よりなる群から選択される組織に由来する、請求項1に記載の方法。
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US08/656,716 US5786146A (en) | 1996-06-03 | 1996-06-03 | Method of detection of methylated nucleic acid using agents which modify unmethylated cytosine and distinguishing modified methylated and non-methylated nucleic acids |
US08/835,728 US6017704A (en) | 1996-06-03 | 1997-04-11 | Method of detection of methylated nucleic acid using agents which modify unmethylated cytosine and distinguishing modified methylated and non-methylated nucleic acids |
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AU7829398A (en) * | 1997-06-09 | 1998-12-30 | University Of Southern California | A cancer diagnostic method based upon dna methylation differences |
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CA2257104A1 (en) | 1997-12-11 |
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EP1690948A3 (en) | 2006-11-22 |
CA2257104C (en) | 2008-01-29 |
JP3612080B2 (ja) | 2005-01-19 |
PT954608E (pt) | 2006-08-31 |
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