JP5213202B2 - 細胞アレイならびに遺伝障害マーカーの検出および使用方法 - Google Patents
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Description
本出願は、いずれも全体が参照として本明細書に組み入れられる1998年10月28日出願の米国仮特許出願第60/106,038号、および1999年8月24日出願の米国仮特許出願第60/150,493号から優先権を主張する。
本発明は、癌のような遺伝障害のマーカーを発見するための、組織試料およびゲノム領域のスクリーニングに関する。
組織検体の顕微鏡検査によって、多くの疾患の生物学的機構が明らかになってきた。さらに組織病理学的検査によって、様々な疾病に有効な医学的治療の開発が可能になった。標準的な解剖病理では、細胞の形態および染色特性に基づいて、診断が行われる。例えば、腫瘍検体を調べて、腫瘍の種類および腫瘍の攻撃性を予測することができる。この腫瘍の顕微鏡検査および分類によって医学的治療は改善したものの、標準的な方法(例えば、ヘマトキシリンおよびエオシン)で染色された検体の観察で得られる診断および分子情報は、限定されたものにすぎないことが多い。
本発明は、新しい方法で、2つの非常に異なるタイプのアレイを組み合せて、癌およびトリソミーのようなさまざまな遺伝障害のマーカーとなり得る遺伝子の増幅または欠失のような、ゲノムコピー数の変化を、高い解像度で迅速かつ正確に検出することができるという発見に基づいている。
である。遺伝子増幅の例には、オンコジーンのコピー数の増加がある。「遺伝子欠失」とは、遺伝子配列に通常存在する1つまたは複数の核酸の欠失であり、極端な例には、遺伝子全体または染色体の一部の欠失が含まれ得る。
組織アレイを他のアレイ技術と組み合わせて使用すると、様々な種類の組織(異なる種類の腫瘍など)、および特定の組織学的タイプの組織(乳房の分泌管内癌のような特定の種類の腫瘍など)における多くの遺伝的変化の頻度または遺伝子発現パターン、ならびに試験される分子マーカーの組織分布に関する情報が得られる。
本発明のマイクロアレイを作製する装置の第1の態様は、図1および2に示されており、プラットフォーム32上であらかじめ定められた方向でドナー容器31を保持する、L型エッジガイド34付き静止プラットフォーム32上に取り付けられた長方形容器31中に、(組織の)ドナーブロック30が示されている。パンチ装置38は、上述のプラットフォーム32に取り付けられており、垂直ガイドプレート40および水平位置決定プレート42を含む。位置決定プレート42は、一対のデジタルマイクロメーターによって正確に位置決定できるx-yステージ(図には示さず)上に取り付けられている。
自動化腫瘍アレイ技術によって、同一の腫瘍セットから、数十または数百のマーカーの検査を簡単に行うことができる。これらの検査は、重複する腫瘍アレイブロックまたは切片を他の検査室に送ることにより、多施設の環境でも実施できる。同じ手法は、新しく発見された分子マーカーの診断、予後、または治療への有用性を調べるために、特に有用だろう。組織アレイ技術は、DNA、RNA、および蛋白質レベルで何百または何千もの腫瘍の迅速なプロファイリングのためのプラットフォームを提供し、多数の腫瘍のコレクションから相関するバイオマーカーのデータベースを作製することによって、癌の基礎研究も促進する。たとえば、増幅標的遺伝子の探索には、同一の細胞群における何十もの候補遺伝子および遺伝子座の増幅と発現の相関した分析が必要である。規定される多数の腫瘍のそのような広範囲な分子分析は、通常の技術では実施が難しいだろう。
本発明は以下の実施例でさらに説明されるが、これらは請求の範囲に記載される本発明の範囲を制限するものではない。
合計645の乳癌検体を用いて、乳癌腫瘍組織マイクロアレイが作製された。試料には、372の新しく凍結されエタノール固定された腫瘍、ならびに273のホルマリン固定された乳癌、正常組織、および固定対照が含まれていた。1986〜1997年に外科的に切除された1500以上の凍結乳癌を含む、バーゼル大学病理学研究所の腫瘍銀行から、凍結乳癌試料のサブセットが無作為に選択された。この腫瘍銀行の腫瘍のみが、分子分析に使用された。このサブセットは病理学者が観察し、腺管癌259、小葉癌52、髄様癌9、粘液癌6、篩状癌3、管状癌3、乳頭癌2、組織球性癌1、明細胞癌1、および脂質に富む癌1が含まれると決定した。さらに、インサイチューの腺管癌が15、癌肉腫が2、手術前に化学療法を受けた原発癌が4、再発腫瘍が8、および転移が6あった。
組織アレイの作製とドナーブロックの切り出しを行った後、免疫組織化学用に標準的な免疫ペルオキシダーゼ手順が使用された(ABC-Elite, Vector laboratories)。DAKO(Glostrup、デンマーク)のモノクローナル抗体を用いて、p53 (DO-7、マウス、1:200)、erbB-2(c-erbB-2、ウサギ、1:4000)、およびエストロゲン受容体(ER ID5、マウス、1:400)が検出された。p53(90℃で30分)およびerbB-2抗原(90℃で60分)の回復には、マイクロ波による前処理が施された。色原体としてジアミノベンジジンが使用された。陽性対照には、陽性が既知の腫瘍が用いられた。陰性対照には、一次抗体は割愛された。腫瘍細胞の少なくとも10%において核に明確な陽性が見られれば、ERまたはp53陽性と判断された。erbB-2染色は、主観的に3つのグループに分けられた:陰性(染色なし)、弱い陽性(膜に弱い陽性)、強い陽性(膜に強い陽性)。
2色のFISHハイブリダイゼーションでは、スペクトラムオレンジ標識のサイタリンD1、myc、またはerbB2プローブと、対応するFITC標識セントロメア参照プローブ(Vysis)とが合わせて使用された。1色のFISHハイブリダイゼーションでは、スペクトラムオレンジ標識の20q13最小共通領域(Vysis、およびTannerら、Cancer Res.54:4257-4260 (1994)参照)、mybL2および17q23プローブ(Barlundら、Genes Chrom.Cancer 20:372-376 (1997))が用いられた。ハイブリダイゼーション前に、腫瘍アレイ切片を脱パラフィン化して、空気乾燥し、70、85、および100%エタノールで脱水後、70%ホルムアミド-2 x SSC溶液中で74℃で5分間、変性させた。ハイブリダイゼーション反応液には、各プローブ30 ngと、ヒトCot1-DNAが15μg含まれていた。加湿チャンバー中で37℃で一晩ハイブリダイゼーションを行った後、スライドを洗浄し、抗退色溶液中で0.2μM DAPIで対比染色した。FISHシグナルは、FITCおよびスペクトラムオレンジシグナルを同時に可視化するための二重帯域フィルターを装備したツァイス(Zeiss)蛍光顕微鏡を用いて測定した。1細胞あたり10のFISHシグナル、またはシグナルの密なクラスターがあれば、遺伝子増幅を示すと判断された。
mRNAインサイチューハイブリダイゼーションには、ハイブリダイゼーション前に、腫瘍アレイ切片を脱パラフィン化し、風乾を行った。erbB2 mRNAに対する合成オリゴヌクレオチドプローブ(Genbank寄託番号X03363、ヌクレオチド350〜396)の3´末端を、末端デオキシヌクレオチド転移酵素を用いて33P-dATPで標識した。切片は、ハイブリダイゼーション反応液(50%ホルムアミド、10%硫酸デキストラン、1%サルコシル、0.02 Mリン酸ナトリウム、PH 7.0、4 x SSC、1 x Denhardt’s溶液、および10 mg/ml ssDNA)100μL中、1 x 107 CPM/mlのプローブと、加湿チャンバー中で42℃で18時間ハイブリダイズを行った。ERBB2 mRNA発現を可視化するために、切片はホスホリメージャー(phosphorimager)スクリーンに3日間露出した。陰性対照切片は、ハイブリダイゼーション前にRNase処理したが、これによりハイブリダイゼーションシグナルがすべて破壊された。
悪性腫瘍の多様性に相関した分子的変化の迅速スクリーニングを達成するために、17の異なる腫瘍試料(総数397の腫瘍)からなる組織マイクロアレイを、単一のパラフィンブロックにアレイした。組織マイクロアレイから切り出した連続切片を用い、3種類の蛍光色素を利用したインサイチューハイブリダイゼーション(FISH)法による実験で、3種類のオンコジーン(CCND1、MYC、ERBB2)の増幅を分析した。乳癌、肺癌、頭部および頸部癌、さらに膀胱癌およびメラノーマにCCND1の増幅が見いだされた。膀胱癌、乳癌、大腸癌、胃癌、精巣癌、および肺癌にERBB2の増幅が検出された。また、MYCの増幅が、乳癌、大腸癌、腎臓癌、肺癌、卵巣癌、膀胱癌、頭部および頸部癌、および子宮内膜癌に認められた。
本実験では、実施例5のマルチ腫瘍組織アレイを用いた。Vysis Inc.(Downers Grove、IL)製の血小板由来増殖因子β(PDGFB)のプローブを用いて本実験を行った。大きなサイズのゲノムDNAをインサートとして含むライブラリーをPCRでスクリーニングし、このプローブを得た。このライブラリーは、PCRによるライブラリースクリーニングに使用したPCRプライマーの標的となる2つのタグ配列部位(STS)を遺伝子配列中に含む。ゲノムライブラリーのスクリーニングで得られた陽性クローンをさらにSTSが含まれるか否か、また中期の染色体に対するプローブを用いたFISH法でハイブリダイゼーションを実施し確認した。この実験では、PDGFBに関して該当する染色体の位置にシグナルが得られた。
本研究では、異なる300以上の前立腺腫瘍の試料を含むホルマリン固定組織のマイクロアレイの連続切片を、FISH法を用いて、5つの異なる遺伝子増幅(AR、CMYC、ERBB2、サイタリンD1、およびNMYC)について調べた。ここでは、前立腺癌の悪化の各段階での遺伝子増幅に関する包括的検索を行うことを課題としている。これは遠位の転移巣に由来する試料を含むものである。該組織マイクロアレイには、371の試料に由来する少量試料を使用した。
本実施例では、まずcDNAアレイ用いて腎細胞癌(RCC)において何らかの役割を演じている遺伝子を同定し、次に得られた候補遺伝子について腫瘍アレイ上で分析し、それらに関して内在する臨床意義を調べる。核酸のアレイと腫瘍アレイを組み合わせた方法が、RCCにおいて生物学的役割を演じる遺伝子を迅速に同定し、さらにそれらを評価するために有用性の高い方法であることを示す。
本実施例では、比較ゲノムハイブリダイゼーション(CGH)で検出した染色体上での増幅に関する標的遺伝子の迅速同定法を示し、またこれらの遺伝子が如何なる臨床意義を有するかを調べる方法を示す。ここで利用されるのは、新規のハイスループットなマイクロアレイ法の組み合わせである。中期染色体に対するCGH(図14、染色体のCGH)によって、乳癌の細胞株であるSum-52細胞の染色体7q31、8p11-p12および10q25の領域に高いレベルのDNA増幅があることが判明した。Sum-52 細胞株のゲノムDNAを新規のCGHマイクロアレイ(図14、ゲノセンサーCGH、Vysis、Downers Grove、IL)に対してハイブリダイゼーションさせた。このマイクロアレイは、遺伝子のコピー数に関して、既知のオンコジーンもしくはオンコジーンと予想される遺伝子を含む31遺伝子座(図13示した遺伝子座)を同時にスクリーニングできる。このgCGH分析から、MET遺伝子(染色体7q31)およびFGFR2遺伝子(染色体10q25)が特異的かつ高度に増幅していることが判明した。また、およびFGFR1遺伝子(染色体8p11-P12)低レベルの増幅を起こしていることも分かった。このことは、通常のCGH分析で観察された増幅領域がこれら3種類の遺伝子を含むものであることを示唆している。
組織アレイを用い、例えば、DNA配列決定、DNAマイクロアレイもしくはSAGE(遺伝子発現の連続解析)(Velculescu 等の Science、270:484−487、1995)等のハイスループットなゲノム学によって発見された遺伝子および標的を追跡することができる。cDNAアレイ技術(Schena1995および1996)による遺伝子発現パターンの比較分析は、腫瘍の進行に関する分子機構を解明し、新規の予後マーカーおよび治療上の潜在的な標的を発見する目的において、発現変化のスクリーニングのハイスループットなツールを提供する。組織アレイは、病理学的および正常の生理学的条件下におけるこのような遺伝子の正確な頻度および分布情報を与える。
AmpliOncTMDNAアレイを用いて乳癌の細胞株SKBR3をスクリーニングしたところ、血小板由来増殖因子B(PDGFB)が増幅していることが分かった。この情報を基に、AmpliOncTMアレイで用いたPDGFBローンと同一のクローン用いてPDGFBプローブを作製した。このプローブを用い乳癌の腫瘍アレイをスクリーニングした。スクリーニングした全乳癌のうちわずか2%にのみPDGFBの増幅が観察された。次に、このプローブを用いマルチ腫瘍アレイ(実施例6に記載した)を調べた。その結果、期せずして、肺癌および膀胱癌でかなり高い割合でPDGFB遺伝子が増幅していることが分かった。このように、本発明を利用して、診断上重要な新規のマーカーを別のタイプの腫瘍に関しても同定できたのである。
組織アレイを用いて、非常に多くの腫瘍組織の試料をスクリーニングし、特定の治療法に感受性を有する腫瘍を調べることができる。実施例1の説明にあるように、例えば、HER-2遺伝子(実施例1においてはERBB2とも別称される)の発現を、乳癌アレイをスクリーニングして調べることもできる。HER-2遺伝子を過剰に発現および/もしくは増幅している腫瘍は、HER-2の発現を抑制する抗体であるHerceptinを用いた治療の候補として有望である。HER-2抗体もしくはDNAプローブでマルチ腫瘍組織アレイをスクリーニングし、その治療法が効果的である乳癌以外の癌に関する情報を得ることもできる。
病歴と転帰が既知である患者の腫瘍から構築した腫瘍組織アレイ用い、予後に関するマーカーの評価を行うことができる。本実施例では、腫瘍内に不均一性があっても膀胱癌の予後マーカーを腫瘍組織アレイで評価できることが示されている。
組織アレイを用い、癌およびその他の療法の新規標的を見つけだすことができる。数百の異なる遺伝子が与えられた癌において差分的に制御されている(例えば、マイクロアレイ、ハイブリダイゼーション、もしくは配列決定またはSAGE等のその他のハイスループット発現スクリーニング法等でcDNAを基に考察する)。それぞれの遺伝子候補の大規模組織アレイによる解析によって、いずれが新規の薬剤、阻害剤等の開発に関する最も確実な標的であるかを調べることができる。例えば、数千の多様な腫瘍試料を含む腫瘍アレイを、オンコジーンもしくは新規のシグナル伝達分子をコードする遺伝子のプローブを用いてスクリーニングしてもよい。このようなプロ一ブは、単一もしくは複数の異なる種類の腫瘍に結合することができる。このプローブによって、多くの腫瘍で特定の遺伝子が過剰発現しているおよび/もしくは増幅していることが明らかになれば、その遺伝子は組織学的に単一種類の数多くの腫瘍もしくは異なる種類の腫瘍において機能している重要な標的であると考えられる。このような遺伝子の発現を抑制する治療法、もしくはその遺伝子由来の遺伝子産物の機能を抑制する治療法は、新規の抗癌剤として有望である。特に、組織アレイは薬剤開発における標的の選択に用いる最も有用な方法であるといえる。
多くの前例で主張されていることは、組織アレイを行う前に予めDNAアレイを利用するというものであるが、本発明の方法では、これらのアレイをいずれかの順番で用いるか、もしくは他の分析技術と組み合わせて実施するものである。従って、組織アレイ分析において複数の腫瘍試料を単一のプローブで見いだした目的遺伝子を、次の段階でにDNAアレイに用いることもできる。すなわち、該目的遺伝子に由来するユニークな配列を、アレイの基質に結合させるプローブの一つとして用いるものである。例えば、マイクロアレイ実験で得られた情報を基に診断、予後、もしくは治療に最も適切であると考えられるDNAチップを作製することができる。
培養細胞もしくは非固形組織もしくは非固形腫瘍(血液試料、骨髄生検試料、もしくは針穿刺吸引生検で得られた細胞学的試料等)から単離した細胞を、組織アレイ技術を用いて解析することもできる。これは、ヒトもしくは動物から直接得た、または細胞培養の実験(医薬品のスクリーニングに用いるマイクロタイター容器の形態で行った特異的なホルモン試験もしくは化学療法試験等)後にインビトロで得た個々の細胞、もしくは細胞集団の分析に対する組織アレイ技術の重要な応用例である。悪性腫瘍の分析に関してはこれを用いることにより、上記の固形腫瘍に対して用いた方法と同一の方法に従って、白血病とリンパ腫の組織もしくはその他の液性腫瘍の分析を実施することが可能となる。
本発明の原理は様々な実施態様に応用可能であり、ここに例示した態様は本発明の例に過ぎないと理解されるべきものである。また、本発明の範囲を限定するものでもない。むしろ、以下に示す請求項によって本発明の範囲が定められるものである。それ故、以下の請求項に示す請求の範囲と趣旨に沿って、ここに本発明の請求を行うものである。
Claims (2)
- 組織検体中で血小板由来成長因子β(PDGFB)遺伝子コピー数が組織中においてインビボで正常組織中の該遺伝子コピー数に比べて増加しているかどうかを決定する段階を含み、遺伝子コピー数の増加が組織検体中に癌性細胞の存在を示し、組織検体が肺組織、膀胱組織、および子宮内膜組織からなる群より選択される、組織検体中に癌性細胞の存在を検出する方法。
- PDGFB遺伝子コピー数が検体中においてインビボで増加しているかどうかの決定を行うために、蛍光インサイチュー・ハイブリダイゼーション(FISH)を実施する請求項1記載の方法。
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Also Published As
Publication number | Publication date |
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US9260758B2 (en) | 2016-02-16 |
JP2018064554A (ja) | 2018-04-26 |
US20020132246A1 (en) | 2002-09-19 |
JP2010162029A (ja) | 2010-07-29 |
JP2002528097A (ja) | 2002-09-03 |
US20130143770A1 (en) | 2013-06-06 |
WO2000024940A1 (en) | 2000-05-04 |
US20090092993A1 (en) | 2009-04-09 |
US9284610B2 (en) | 2016-03-15 |
US20050244880A1 (en) | 2005-11-03 |
EP1131470A1 (en) | 2001-09-12 |
US6905823B2 (en) | 2005-06-14 |
EP1131470A4 (en) | 2004-11-10 |
JP2016189780A (ja) | 2016-11-10 |
US20160168650A1 (en) | 2016-06-16 |
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