JP6966508B2 - 尿バイオマーカーコホート、遺伝子発現特性、およびその使用の方法 - Google Patents
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Description
本出願は、2013年8月6日に出願された米国特許仮出願番号第61/862,630号の利益を主張するものであり、その内容の全体を参照により本明細書中に援用する。
本発明は、概してバイオマーカー分析の分野、特に尿サンプルから遺伝子発現特性を決定することに関する。
癌関連バイオマーカーとしては、例えば、遺伝子配列における特異的突然変異(Cortez and Calin, 2009; Diehl et al., 2008; Network, 2008; Parsons et al., 2008)、mRNAおよびmiRNA発現の上方および下方調節(Cortez and Calin, 2009; Itadani et al., 2008; Novakova et al., 2009)、mRNAスプライシングのバリエーション、DNAメチル化パターンの変化(Cadieux et al., 2006; Kristensen and Hansen, 2009)、ゲノム領域の増幅および欠失(Cowell and Lo, 2009)、および反復DNA配列の異常発現(Ting et al., 2011)が挙げられる。変異解析や、ゲノムDNAのメチル化状態や、遺伝子発現分析などの様々な分子診断アッセイは、これらのバイオマーカーを検出し、そして、患者、医師、臨床医、および研究者にとって貴重な情報を生じることもある。今までのところ、これらのアッセイは主に、外科的に取り出された腫瘍組織または生検検体によって得られた組織から得られた癌細胞に対しておこなわれてきた。例えば、PCA3、TMPRSS2:ERG、およびERGは、正常前立腺組織と比較して、前立腺癌において示差的に発現されることが、生検検体分析によってこれまでに示されてきた(Bussemakers et al., 1999; Petrovics et al., 2005; Tomlins et al., 2005)。
このコピー数計算は、各マーカー遺伝子(例えば、PCA3および/またはERG)ならびに基準遺伝子(例えば、KLK3またはSPDEF)に関して独立におこなわれる。そして、マーカー遺伝子(例えば、PCA3および/またはERG)からの得られたシグナルの「正規化」は、基準遺伝子コピー数によって遺伝子マーカーコピー数を除算することによって達成される(例えば、ERG/SPDEF、ERG/KLK3、PCA3/SPDEF、およびERG/SPDEF)。
尿サンプルからの微小胞画分の調達
核酸抽出のための方法は一般に、当該技術分野でよく知られる手順に基づいている。当業者は、特定の生物学的サンプルに好適な抽出手法を選択する。抽出手法の例は、特許公開広報WO2009/100029、US201/00196426、US2011/0003704、US2011/0053157、WO2011/009104、およびWO2011/031892に提供されている。これらの刊行物は、微小胞核酸抽出方法および技術に関係するそれらの開示についての参照により本明細書中に援用される。
バイオマーカー検出は、多くの異なった方法で抽出された核酸においておこなわれ、多くの態様を構成する。いくつかの実施形態において、1もしくは複数の尿サンプルからの核酸バイオマーカーの検出は、抽出された核酸のすべてまたは一部のプロファイルを得ることである。
多くのバイオマーカーは、対象の疾患または他の医学的状態の存在または不存在に関連する可能性がある。そのため、本明細書中に開示された方法に従った、単離された微小胞からの核酸抽出物中の斯かるバイオマーカーの存在または不存在の検出は、対象における疾患または他の医学的状態の診断、予後診断、あるいは経過または再発の観察を助ける可能性がある。
本発明は、例えば、癌、特に侵襲性の強い癌などの疾患に関して診断、予後診断、モニタリング、または治療法選択に役立つように対象からの尿サンプル中の1もしくは複数のバイオマーカーを検出する方法を提供する。
・パターン1−癌性前立腺は正常前立腺組織に非常に類似している。腺は、小さく、よく整っており、密に詰まっている。
・パターン2−組織にはよく整った腺がまだあるが、それらは、大きく、それらの間にはより多くの組織がある。
・パターン3−組織には認識可能な腺がまだあるが、細胞はより暗い。高倍率では、これらの細胞の一部が、腺を残して、周辺組織に浸潤し始めている。
・パターン4−組織には認識可能な腺がわずかしかない。多くの細胞が周辺組織に浸潤している。
・パターン5−組織には認識可能な腺がない。周辺組織中にまさしく細胞シートが存在することが多い。
プライマー/プローブ配列:尿バイオマーカーコホートを検出するためのキットおよび方法は、以下のプライマー/プローブ配列を使用する。以下の略語は、以下の表1で使用される:Integrated DNA Technologies製のプローブは「IDT」と示され、5’−FAMは5’レポーター色素を指し、「3IABkFQ」は3’−IowaBlackクエンチャーを指し、および「ZEN」はIDT製の配列内ZEN(商標)クエンチャーを指す。
患者集団サンプルを、尿由来微小胞から抽出した核酸からの前立腺癌の検出に有用なバイオマーカーを同定するのに使用した。この実施例で「コホート7」と呼ばれる、258人の対象から成る患者コホートを、この分析に組み入れた。258人の対象のうち、196人は彼らの初めての生検を受け、そして、59人は再度の生検を受けた。最初の生検の患者のうち、87人は陽性の生検結果を有し、そして、109人は陰性の生検結果を有した。再生検患者のうち、15人は陽性の生検結果を有し、そして、44人は陰性の生検結果を有した。
多変量解析を、PCA3を含めた遺伝子セットを使用しておこなった。図15に示したように、PCA3含有モデル(すなわち、AMACR、BIRC5、HOXC6及びSPARCL1などの追加遺伝子をともなったPCA3およびERG)は、PCA3を含まないFTO三遺伝子モデルより一貫して優れていた。図15における正規化のためのいずれかの遺伝子を使用した一貫したAUC値によって示されるように、使用した基準遺伝子はKLK3またはSPDEFであり得る。
患者コホート7からの尿サンプルは20〜100mLの範囲に及んだ。コホート7の中の20mL以下、40mL以下だが20mL超、および40mL超の体積を有するサンプルの分布を図1に示した。
実施例6.患者サンプルのスコア化とその統計的な較正
Claims (9)
- 対象において高グリーソンスコア前立腺癌のリスクを決定するために尿サンプルを分析する方法であって、ここで前記高グリーソンスコア前立腺癌が、6よりも高いグリーソンスコアを有し、以下のステップ:
a.対象から得た尿サンプルから1又は複数のmRNAを抽出し;
b.PCA3、ERGおよびSPDEFのmRNA発現レベルを検出し;
c.PCA3およびERGのmRNA発現レベルをSPDEFに対して正規化し;
d.PCA3およびERGの正規化したmRNA発現レベルに関して式:
e.EXO106スコアを、所定のカットオフ値と比較して、高グリーソンスコア前立腺癌のリスクが高い対象と、高グリーソンスコア前立腺癌のリスクが低い対象とを識別すること、
を含む、前記方法。 - 前記尿サンプルが、膀胱から排尿された最初の40mLである、請求項1に記載の方法。
- 前記尿サンプルが、膀胱から排尿された最初の20mLである、請求項1に記載の方法。
- 前記所定のカットオフ値が10である、請求項1〜3のいずれか一項に記載の方法。
- ステップ(a)が、前記尿サンプルから微小胞画分を単離し、そして、該微小胞画分から前記1又は複数のmRNAを抽出することを含む、請求項1〜4のいずれか1項に記載の方法。
- 前記微小胞画分を単離するステップが、サンプルを処理して細胞および細胞破片を取り除き、そして、前記微小胞画分を限外濾過または濾過濃縮器にかけることによって微小胞画分を濃縮し、そして、該微小胞画分から前記1もしくは複数のmRNAを抽出する前に微小胞画分を洗浄することを含む、請求項5に記載の方法。
- 前記方法が、前記微小胞画分から前記1もしくは複数のmRNAを抽出する前に、前記微小胞画分にRNアーゼ阻害剤を加えることをさらに含む、請求項6に記載の方法。
- ステップ(a)の前に、前記尿サンプルに既知量の対照粒子を添加し、ここで前記対照粒子が、少なくとも1の標的遺伝子を含む対照核酸を含む、請求項1〜7のいずれか一項に記載の方法。
- 前記少なくとも1の標的遺伝子の発現レベルがステップ(b)で検出され、そして前記少なくとも1の標的遺伝子の検出された発現レベルが、対照粒子の前記既知量と比較される、請求項8に記載の方法。
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EP3030675B1 (en) | 2018-10-03 |
JP7358434B2 (ja) | 2023-10-10 |
US10301681B2 (en) | 2019-05-28 |
RU2668164C2 (ru) | 2018-09-26 |
BR112016002716B1 (pt) | 2023-02-28 |
JP2019141094A (ja) | 2019-08-29 |
EP3495509A1 (en) | 2019-06-12 |
WO2015021158A1 (en) | 2015-02-12 |
JP2016526922A (ja) | 2016-09-08 |
CA2920429C (en) | 2021-11-16 |
EP3030675A1 (en) | 2016-06-15 |
US20200056244A1 (en) | 2020-02-20 |
AU2014305994B2 (en) | 2019-02-21 |
BR112016002716A2 (pt) | 2020-02-11 |
RU2016107882A (ru) | 2017-09-14 |
EP3495509B1 (en) | 2021-12-15 |
CN106029900A (zh) | 2016-10-12 |
US20160177401A1 (en) | 2016-06-23 |
JP2022023159A (ja) | 2022-02-07 |
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