JP7215675B2 - 腫瘍状態の評価方法 - Google Patents
腫瘍状態の評価方法 Download PDFInfo
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- JP7215675B2 JP7215675B2 JP2018561442A JP2018561442A JP7215675B2 JP 7215675 B2 JP7215675 B2 JP 7215675B2 JP 2018561442 A JP2018561442 A JP 2018561442A JP 2018561442 A JP2018561442 A JP 2018561442A JP 7215675 B2 JP7215675 B2 JP 7215675B2
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Description
本願は、2017年1月16日に、日本に出願された特願2017-005102号に基づき優先権を主張し、その内容をここに援用する。
上記第一態様において、前記被験者が、前記血液試料の採取時点において腫瘍部分の外科的切除処置又は抗腫瘍療法を受けているか、又は前記血液試料の採取時以前に腫瘍部分の外科的切除処置又は抗腫瘍療法を受けたことがあってもよい。
上記第一態様において、前記回収工程において、前記血液試料からの末梢血単核細胞層の回収を、Ficoll密度勾配遠心法により行ってもよい。
上記第一態様において、前記体細胞変異を有する腫瘍マーカー遺伝子由来核酸の検出を、リアルタイムPCR法、デジタルPCR法、次世代シーケンサー法、又は電気化学的検出方法により行ってもよい。
上記第一態様において、前記腫瘍が、転移性髄芽腫、消化管間質腫瘍、隆起性皮膚線維肉腫、結腸直腸癌、大腸癌、肺癌、非小細胞肺癌、小細胞肺癌、慢性骨髄増殖性疾患、急性骨髄性白血病、甲状腺癌、すい臓癌、膀胱癌、腎臓癌、黒色腫、乳癌、前立腺癌、卵巣癌、子宮頸癌、頭頚部癌、脳腫瘍、肝細胞癌、血液悪性腫瘍、又はこれらの癌を引き起こす前癌であってもよい。
本発明の一実施形態に係る腫瘍マーカー遺伝子の体細胞変異の検出方法(以下、「本発明に係る検出方法」ということがある。)は、腫瘍マーカー遺伝子の体細胞変異を検出するための供試試料として、PBMC層のDNAを用いることを特徴とする。PBMC層のDNAを用いることによって、血清や血漿に含まれるDNAを用いる場合よりも、cfDNA中の腫瘍マーカー遺伝子の体細胞変異をより高感度に検出することができる。本実施形態に係る検出方法は、具体的には、被験者から採取された血液試料からPBMC層を回収する回収工程と、回収されたPBMC層に含まれるDNAから、体細胞変異を有する腫瘍マーカー遺伝子由来核酸が検出されるか否かを調べる変異検出工程と、を有する。
本実施形態に係る検出方法においては、特にKRAS遺伝子の体細胞変異の検出をすることが好ましい。
本発明の一実施形態に係る腫瘍状態の評価方法(以下、「本発明に係る評価方法」ということがある。)は、本発明の上記実施形態に係る検出方法により、被験者のPBMC層に含まれるDNAから、体細胞変異を有する腫瘍マーカー遺伝子由来核酸が検出されるか否かを調べ(検査工程)、その検出結果に基づいて、前記被験者について、腫瘍の発症若しくは再燃の有無、又は分子標的薬に対する感受性を評価する(評価工程)。
本実施形態に係る腫瘍状態の評価方法では、さらに、検査工程の前又は後に、血液試料から回収された血漿又は血清に含まれるDNAから前記体細胞変異を有する腫瘍マーカー遺伝子由来核酸が検出されるか否かを調べてもよい(血漿血清検出工程)。この場合、前記血液試料から回収された血漿又は血清に含まれるDNAからは、前記体細胞変異を有する腫瘍マーカー遺伝子由来核酸が検出されなくてもよい。
本実施形態に係る腫瘍状態の評価方法では、さらに、検査工程の前又は後に、前記血液試料から末梢血循環がん細胞が検出されるか否かを調べてもよい(末梢血循環がん細胞検出工程)。この場合、前記血液試料から末梢血循環がん細胞が検出されなくてもよい。また、これらの工程は、検査工程と並行して行ってもよい。
3名の再発性大腸癌患者(患者A~C)のPBMC層の核酸から、体細胞変異型のKRAS遺伝子由来核酸が検出されるか否かを調べた。
既に原発巣は切除されており、かつ新たに転移巣(肝臓)がある再発性大腸癌患者3名(患者A~C)の末梢血6~9mLを、転移巣の外科的切除手術の術前又は術後に採血した。患者Aの採血日は2015年7月29日、患者B、Cの採血日は2015年7月22日で、PBMC分離以降の遺伝子変異検出まで同日に行った。
再発性大腸癌患者(患者A~C)について、末梢血の一部からFicoll密度勾配遠心法によりPBMC層の分離を、以下の手順にて行った。全血試料をFicoll密度勾配遠心にかける方法は、単球細胞の分離に最もよく使用される方法である。
得られた調製PBMCsからDNAを抽出・精製した。DNAの抽出・精製は、QIAamp(登録商標) DNA Mini(キアゲン社製)キットを用い、当該キットに付属のインストラクションに従って行った。
大腸癌患者3名(A~C)から採取した末梢血の一部を遠心分離処理(1,500rpm、10分間)した。得られた粗血漿成分をさらに遠心分離処理(1,500rpm、10分間)した後、細胞断片を除去した上清部を回収し、これを血漿試料とした。
血漿からのcfDNAの単離精製は、QIAamp Circulating Nucleic Acid Kit(キアゲン社製)を用いて、当該キットに付属されているインストラクションに従って行った。当該キットに供した調製血漿の量は1mLとし、スピンカラムからの最終溶出は、TE緩衝液50μLを用いて行った。
cfDNAの定量は、Qubit(登録商標) Fluorometer(Life Technologies社製)を用いて行った。測定するサンプルは全て、単離したDNAを所定の反応液で200倍に希釈して用いた。
QUANTSTUDIO(登録商標) 3DデジタルPCRシステムにより、各患者の調製PBMCs及び血漿試料から抽出精製したDNA中のKRAS遺伝子の体細胞変異を検出した。検出には、FAM(登録商標)で標識したプローブをKRAS変異型(G12V)のアリルに特異的にハイブリダイズ可能なプローブとして用い、VIC(登録商標)で標識したプローブをKRAS野生型のアリルに特異的にハイブリダイズ可能なプローブとして用いた。また、図示はしないが、KRAS変異型(G12D)の検出も同様に行った。
図中、丸で囲われた領域のドットが、KRAS遺伝子の体細胞変異の検出を示すドットである。
血漿中のCA19-9、CEAを、CLEIA法(化学発光酵素免疫測定法)により測定した。CA19-9の基準値は、37U/mL以下、CEAの基準値は5.0ng/mL以下とした。
CTC濃縮回収装置(製品名:「ClearCell FX システム」、ClearBridge社製)を用い、患者A~Cの末梢血7.5mLを供し、CTCの個数を計測した。
患者A~Cの転移巣及び原発巣から採取した組織標本として、これらのホルマリン固定パラフィン包埋切片(FFPE切片)からもDNA単離を行った。FFPE切片からのDNA単離精製は、QIAamp DNA FFPE Tissue Kit(キアゲン社)を用いて、当該キットに付属されているインストラクションに従って行った。1サンプルにつき、10μmにスライスされたFFPE切片を3枚用い、これから抽出したDNAをTE緩衝液100μLに溶出した。
原発巣や転移巣の手術標本として上記FFPE切片から抽出したDNAに含まれるKRAS遺伝子由来核酸、並びに原発巣の外科的切除手術の術前又は術後に採取された血漿中のKRAS遺伝子由来核酸の塩基配列解析は、ダイレクトシークエンシングにて行った。より詳細には、KRAS遺伝子の塩基配列に特異的なプライマーを用い、ビッグダイターミネーター法によるサイクルシークエンシングを常法により行った。
Claims (4)
- 被験者について、腫瘍の発症若しくは再燃の有無を評価する腫瘍状態の評価方法であって、
前記被験者から採取された血液試料から回収された血漿又は血清中のcfDNAから、体細胞変異を有する腫瘍マーカー遺伝子由来核酸が検出されるか否かを調べ、前記体細胞変異を有する腫瘍マーカー遺伝子由来核酸が検出されていない場合に、
当該被験者から採取された血液試料から回収された末梢血単核細胞層に含まれるDNAから、前記体細胞変異を有する腫瘍マーカー遺伝子由来核酸が検出されるか否かを調べ、
前記被験者が、過去に、腫瘍マーカー遺伝子が体細胞変異を有する原発巣に対して、腫瘍部分の外科的切除処置又は抗腫瘍療法を受けたことがあり、
前記被験者の前記末梢血単核細胞層に含まれるDNAから前記体細胞変異を有する腫瘍マーカー遺伝子由来核酸が検出された場合に、
前記被験者の腫瘍が再発又は新たな転移が生じている可能性が高いと評価し、
前記末梢血単核細胞層に含まれるDNAからの前記体細胞変異を有する腫瘍マーカー遺伝子由来核酸の検出を、
前記被験者から採取された血液試料から末梢血単核細胞層を回収する回収工程と、
前記末梢血単核細胞層に含まれるDNAから、前記体細胞変異を有する腫瘍マーカー遺伝子由来核酸が検出されるか否かを調べる変異検出工程と、
により行い、
前記体細胞変異を有する腫瘍マーカー遺伝子由来核酸の検出を、デジタルPCR法により行い、
前記腫瘍マーカー遺伝子がKRAS遺伝子である、腫瘍状態の評価方法。 - 前記被験者が、前記血液試料の採取時点において腫瘍部分の外科的切除処置又は抗腫瘍療法を受けているか、又は前記血液試料の採取時以前に腫瘍部分の外科的切除処置又は抗腫瘍療法を受けたことがある、請求項1に記載の腫瘍状態の評価方法。
- 前記回収工程において、前記血液試料からの末梢血単核細胞層の回収を、Ficoll密度勾配遠心法により行う、請求項1又は2に記載の腫瘍状態の評価方法。
- 前記腫瘍が、転移性髄芽腫、消化管間質腫瘍、隆起性皮膚線維肉腫、結腸直腸癌、大腸癌、肺癌、非小細胞肺癌、小細胞肺癌、慢性骨髄増殖性疾患、急性骨髄性白血病、甲状腺癌、すい臓癌、膀胱癌、腎臓癌、黒色腫、乳癌、前立腺癌、卵巣癌、子宮頸癌、頭頚部癌、脳腫瘍、肝細胞癌、血液悪性腫瘍、又はこれらの癌を引き起こす前癌である、請求項1~3のいずれか一項に記載の腫瘍状態の評価方法。
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