JP2018534595A - 疾患の不均一性を特徴づけるための転移性疾患における、循環腫瘍細胞(ctc)の単一細胞ゲノムプロファイリング - Google Patents
疾患の不均一性を特徴づけるための転移性疾患における、循環腫瘍細胞(ctc)の単一細胞ゲノムプロファイリング Download PDFInfo
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Abstract
【選択図】図1
Description
連続的な癌治療の後、癌細胞の複数の亜集団が生じ、これらはそれぞれ薬物への抵抗性又は感受性を付与し得る異なる遺伝的異常を備える。組織生検ではこれらの亜集団を検出することができないが、血液の液体生検は、これらの重要な腫瘍細胞を同定し、患者の腫瘍がどのように経時的に発展してきたかを特徴づける一助とすることができる。単一細胞ゲノムプロファイリングは、癌の発展及び多様性を研究し、並びに腫瘍の発達における希少細胞の役割を理解するための、強力な新たなツールである。クローンの多様性は、浸潤、転移、及び治療への抵抗性の発展において重要な役割を果たすように運命づけられる。
本発明は、癌患者において疾患の不均一性を検出する方法であって、(a) 該患者から取得した血液試料中の有核細胞の、免疫蛍光染色及び形態的特性評価を含む直接的分析を実施して、循環腫瘍細胞(CTC)を同定し、かつ計数すること;(b) 該試料から該CTCを単離すること;(c) ゲノムパラメータを個別に特徴づけて、該CTCの各々に対するゲノムプロファイルを作成すること;及び(c) 該プロファイルに基づいて該癌患者における疾患の不均一性を決定すること、を含む、前記方法を提供する。いくつかの実施態様において、該癌は、前立腺癌である。いくつかの実施態様において、該前立腺癌は、ホルモン不応性である。
本件開示は、統合一細胞全ゲノムCNV分析が、複数のレプリケート間で再現的なコピー数プロファイルを提供し、ARの増幅及びPTENの喪失を含む既知の局所CNV事象の存在を確認するという発見に部分的に基づいている。本件開示はさらに、全ゲノムコピー数分析を使用して、LST及びPGAを測定することによりゲノム不安定性を再現的に特徴づけることができるという発見に部分的に基づいている。本明細書に開示されるような、野生型(LNCaP)と比較してp53変異体細胞株(PC3及びVCaP)において検出されるのは最も高いゲノム不安定性である。サブクローン性CNV駆動因子の変化の頻度及び個別のCTCにおけるゲノム不安定性を細胞表現形と組合わせて理解することにより、不均一な疾患のより正確な観察、潜在的な治療反応が可能となり、かつ新規抵抗性の機構を特定することができる。
CTCの試料の評価を、Epic Sciencesプラットフォームを使用して過去に報告した通りに実施した。Marrinucciらの文献、Phys Biol 9:016003, 2012。Epic CTC収集及び検出プロセスは、以下の流れである:(1) 血液を溶解させ、血液試料由来の有核細胞をスライド上に載せる;(2) スライドを-80℃の生物貯蔵容器中で保存する;(3) スライドをCK、CD45、DAPI、及びARで染色する;(4) スライドをスキャンする;(5) マルチパラメータデジタル病理アルゴリズムを実行する、及び(6) ソフトウェア及びヒト解読者によるCTCの確認並びにバイオマーカーの発現の定量化である。続くCTCの回収及びゲノムプロファイリングワークフローの間、個別の細胞を単離し、全ゲノム増幅、及びNGSライブラリ調製に付した。配列決定をIllumina NextSeq 500により実施した。
Claims (12)
- 癌患者における疾患の不均一性を検出する方法であって、
(a) 該患者から取得した血液試料中の有核細胞の、免疫蛍光染色及び形態的特性評価を含む直接的分析を実施して、循環腫瘍細胞(CTC)を同定し、かつ計数すること;
(b) 該試料から該CTCを単離すること;
(c) ゲノムパラメータを個別に特徴づけて、該CTCの各々に対するゲノムプロファイルを作成すること;及び
(c) 該プロファイルに基づいて該癌患者における疾患の不均一性を決定すること、を含む、前記方法。 - 前記癌が、前立腺癌である、請求項1記載の方法。
- 前記前立腺癌が、ホルモン不応性である、請求項2記載の方法。
- 前記有核細胞の免疫蛍光染色が、汎サイトケラチン、表面抗原分類(CD)45、及びジアミジノ-2-フェニルインドール(DAPI)を含む、請求項1〜3のいずれか1項記載の方法。
- 前記ゲノムパラメータが、コピー数多型(CNV)特徴を含む、請求項1〜4のいずれか1項記載の方法。
- 前記コピー数多型(CNV)特徴が、遺伝子の増幅又は欠失を含む、請求項5記載の方法。
- 前記CNV特徴が、アンドロゲン非依存的細胞成長と関連する遺伝子を含む、請求項6記載の方法。
- 前記欠失が、ホスファターゼ・テンシン・ホモログ遺伝子(PTEN)の喪失を含む、請求項6記載の方法。
- 前記遺伝子の増幅が、AR遺伝子の増幅を含む、請求項6記載の方法。
- 前記ゲノムパラメータが、ゲノム不安定性を含む、請求項1〜4のいずれか1項記載の方法。
- 前記ゲノム不安定性が、大規模トランジション(LST)を測定することによって特徴づけられる、請求項10記載の方法。
- 前記ゲノム不安定性がゲノム変化率(PGA)を測定することによって特徴づけられる、請求項10記載の方法。
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PCT/US2016/059877 WO2017079139A1 (en) | 2015-11-03 | 2016-11-01 | Single cell genomic profiling of circulating tumor cells (ctcs) in metastatic disease to characterize disease heterogeneity |
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JP2022526227A (ja) * | 2019-03-28 | 2022-05-24 | ランドチ ダイアグノスティクス アーベー | 2型糖尿病リスク予測におけるフォリスタチンの使用 |
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JP6352588B2 (ja) | 2009-10-21 | 2018-07-04 | ザ スクリプス リサーチ インスティテュート | 希少ではない細胞を用いて希少細胞を検出する方法 |
EP3100047B1 (en) | 2014-01-27 | 2021-08-11 | Epic Sciences, Inc. | Circulating tumor cell diagnostics for prostate cancer biomarkers |
EP3108246B1 (en) | 2014-02-21 | 2019-10-09 | Epic Sciences, Inc. | Methods for analyzing rare circulating cells |
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US9671405B2 (en) * | 2012-09-19 | 2017-06-06 | Cornell University | Identifying taxane sensitivity in prostate cancer patients |
US20150147339A1 (en) * | 2013-11-15 | 2015-05-28 | Psma Development Company, Llc | Biomarkers for psma targeted therapy for prostate cancer |
EP3100047B1 (en) * | 2014-01-27 | 2021-08-11 | Epic Sciences, Inc. | Circulating tumor cell diagnostics for prostate cancer biomarkers |
ES2868077T3 (es) * | 2014-01-30 | 2021-10-21 | Epic Sciences Inc | Diagnóstico mediante células tumorales circulantes para biomarcadores predictivos de la resistencia a las terapias selectivas del receptor de andrógenos (RA) |
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WO2014165785A2 (en) * | 2013-04-05 | 2014-10-09 | Myriad Genetics, Inc. | Methods and materials for assessing homologous recombination deficiency |
WO2015048740A1 (en) * | 2013-09-30 | 2015-04-02 | The Scripps Research Institute | Genotypic and phenotypic analysis of circulating tumor cells to monitor tumor evolution in prostate cancer patients |
WO2015106341A1 (en) * | 2014-01-17 | 2015-07-23 | Ontario Institute For Cancer Research (Oicr) | Biopsy-driven genomic signature for prostate cancer prognosis |
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