JP6856544B2 - 遺伝子融合体を検出するための多重pcr - Google Patents
遺伝子融合体を検出するための多重pcr Download PDFInfo
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- JP6856544B2 JP6856544B2 JP2017554014A JP2017554014A JP6856544B2 JP 6856544 B2 JP6856544 B2 JP 6856544B2 JP 2017554014 A JP2017554014 A JP 2017554014A JP 2017554014 A JP2017554014 A JP 2017554014A JP 6856544 B2 JP6856544 B2 JP 6856544B2
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Description
多くの癌は遺伝子融合体と関連している。おそらく最も初期に報告された例は、60年代のBML−ABLと慢性骨髄性白血病(CML)との関連である(Nowell and Hungerford (1960), J. Natl. Cancer Inst. 25:85)。それ以来、多くの異なる組織の癌について数百の遺伝子融合体が報告されている(Presner and Chinnaiyan (2009), Curr. Opin Genet. Dev. 19:82)。
(2)前記融合部位の5’である前記第1遺伝子領域の一部に特異的な第2プライマー対と、
(3)前記融合部位の3’である前記第1遺伝子領域の一部に特異的な第3プライマー対と
を含む、組成物が提供される。あるいは、前記第2及び第3プライマー対は、第2遺伝子領域に特異的であり得る。
(1)本明細書中及び上に記載された生物学的試料及び組成物を用いて、増幅反応を実施する工程と、
(2)少なくとも1つの第1プライマー対からの増幅産物の量を測定する工程(例えば、少なくとも1つの第1プライマー対に関連する標識物からのシグナルを検出することにより)と、
(3)第2プライマー対からの増幅産物量と第3プライマー対からの増幅産物の量の差の有無を検出する工程(例えば、第2及び第3プライマー対に関連する標識物のシグナルを検出及び比較することにより)と、
(4)
(i)工程(2)で測定された少なくとも1つの第1プライマー対からの増幅産物の量が、少なくとも1つの第1プライマー対からの増幅産物と対照融合遺伝子を保有しないポリヌクレオチドとの量よりも多い場合、又は
(ii)工程(3)において差異の存在が検出される場合、遺伝子融合を検出する工程と
を含む。
本発明者らは、遺伝子領域間の融合体を検出する新規な定量的及びt多重(multiplex)方法を発見した。本開示の方法は、非侵襲的に集めることができる患者試料、例えば血漿由来の循環する遊離RNA(cfRNA)の、少量を必要とするのみである。
「遺伝子融合体 (genetic fusion)」は、以前は分離されていた2つの染色***置の結合により形成される混成染色体配列である。融合は、同じ染色体上の遺伝子(例えば、間質欠失又は染色体反転)又は異なる染色体(例えば、転座)上で起こり得る。
多くの癌関連融合遺伝子が知られており、すべての様式の癌に現れる。これらは、融合体の1つのメンバーが成長促進シグナル伝達経路に関与するキナーゼであり、他のメンバーが、上昇した又は構成的な発現又はシグナル伝達に寄与する場合に、一般的に生じる。融合部位を増幅し検出するように、及び融合部位の上流及び下流の領域を増幅及び検出するように、プライマーを設計することができるため、現在記載されている組成物及び方法は、任意の遺伝子融合を検出するために使用することができる。さらに、開示された方法は、限定された量のcfRNAを用いて実施することができるため、腫瘍の局在化及び生検が必要とされない。
遺伝子融合体について試験するための試料は任意の供給源から得ることができるが、非侵襲的に得られるもの、例えば血液又は血液画分が有利である。本方法のための試料は、気管支肺胞洗浄液又は生検組織から採取することもできる。生物学的試料から核酸を単離する方法は、例えば Sambrook に記載されているように公知であり、いくつかのキットが市販されている(例えば、RocheからのHigh Pure RNA Isolation Kit, High Pure Viral Nucleic Acid Kit, 及び MagNA Pure LC Total Nucleic Acid Isolation Kit)。
核酸増幅は、任意のプライマー依存性方法を用いて行うことができる。いくつかの実施態様において、増幅は定量的であり、その結果、所定の増幅標的の相対量又は実際の量を、増幅産物の量により決定することができる。
いくつかの実施態様において、本開示の方法を実施するための試薬及び材料がキットに含まれる。いくつかの実施態様において、キットは、試料を入手し、保存し、及び/又は調製するための成分を含む。そのような成分には、例えば無菌針及びシリンジ、EDTAで内側が被覆されたチューブ、緩衝液(例えば、核酸をマトリックスに結合させ、そしてマトリックスから溶出するため)、RNase阻害剤、及び/又はDNaseなどが含まれる。
(i)遺伝子融合体中の融合部位に特異的な少なくとも1つの第1プライマー対と、
(ii)融合部位の上流(5’)の配列の一部に特異的な第2プライマー対と、
(iii)融合部位の下流(3’)の配列の一部に特異的な第3プライマー対と、
を含む。いくつかの実施態様において、キットはさらに、陽性対照プライマー対(例えば、ハウスキーピング遺伝子由来の配列、又は試料中に存在すると予想される別の配列)、及び/又は陰性対照プライマーセット(例えば、異なる生物由来の配列のような、試験されることが期待されない試料中の配列を増幅するように設計された)を含む。少なくとも1つの第1プライマー対(i)は、遺伝子融合体の変異体を検出することができる2つ以上のプライマー対を含むことができる。いくつかの実施態様において、複数のプライマー対は、同じリバースプライマーを利用する複数のフォワードプライマー、又は同じフォワードプライマーを利用する複数のリバースプライマーを含む。
A.実施例1:血漿中のEML4−ALK融合体、及び力価測定された細胞性RNAの検出
この例では、EML4−ALK融合体を検出するための多重定量的RT−PCR法を試験した。測定可能で信頼できる結果を得るために必要な試料の量を減らすために、4つの異なるプライマーセットがシングルチューブアッセイで使用される。
この例では、細胞系及び血漿由来のRNAにおけるCCDC6−RET融合体を検出する能力について多重qRT−PCRを試験した。
Claims (19)
- 以下を含む組成物:
− 遺伝子1と遺伝子2との間の融合部位に特異的な少なくとも1つの第1プライマー対であって、前記融合部位の5’側から開始する少なくとも1つのフォワードプライマーと、前記融合部位の3’側から開始する少なくとも1つのリバースプライマーとを含む、第1プライマー対、
− 前記融合部位の5’である遺伝子1の一部に特異的な第2プライマー対、
− 前記融合部位の3’である遺伝子1の一部に特異的な第3プライマー対、及び
− 前記プライマー対の各々から生じる増幅産物の各々に特異的な標識プローブ。 - 対照配列に特異的な第4のプライマーセットをさらに含む、請求項1に記載の組成物。
- 前記少なくとも1つの第1プライマー対が、少なくとも3つのプライマー対を含む、請求項1又は2に記載の組成物。
- 熱安定性DNAポリメラーゼをさらに含む、請求項1〜3のいずれか1項に記載の組成物。
- 逆転写酵素をさらに含む、請求項1〜4のいずれか1項に記載の組成物。
- 個体由来の生物学的試料をさらに含む、請求項1〜5のいずれか1項に記載の組成物。
- 前記生物学的試料が血漿由来のRNAである、請求項6に記載の組成物。
- 遺伝子1が、ALK、RET、ROS、NTRK、BRAF、ABL、及びFGFRから選択される、請求項1〜7のいずれか1項に記載の組成物。
- 遺伝子1がALKであり、遺伝子2が、EML4、KIF5B、HIP1、KLC1、及びTFGからなる群より選択される、請求項8に記載の組成物。
- 遺伝子1がRETであり、遺伝子2が、KIF5B、CCDC6、NCOA4、及びTRIM33からなる群より選択される、請求項8に記載の組成物。
- 個体由来の生物学的試料が融合遺伝子を保有するかどうかを検出するための方法であって、
a) 個体由来の生物学的試料と請求項1〜5のいずれか1項に記載の組成物とを用いて増幅反応を実施する工程と、
b) 前記少なくとも1つの第1プライマー対からの増幅産物の量を測定する工程と;
c) 前記第2プライマー対からの増幅産物の量と前記第3プライマー対からの増幅産物の量との差の有無を検出する工程と、
d) (i)工程b)で測定された前記少なくとも1つの第1プライマー対からの増幅産物の量が、融合遺伝子を保有しない対照ポリヌクレオチドと前記少なくとも1つの第1プライマー対からの増幅産物の所定量よりも多い場合、又は
(ii)差の存在が工程c)において検出される場合、
融合遺伝子を検出する工程と、
を含み、
ここで、前記増幅反応が、定量的逆転写ポリメラーゼ連鎖反応(qRT−PCR)と熱安定性DNAポリメラーゼを使用して実施され、前記生物学的試料が個体の血漿由来のRNAである、方法。 - 遺伝子1がALK、RET、ROS、NTRK、BRAF、ABL、及びFGFRから選択される、請求項11に記載の方法。
- 遺伝子1がALKであり、遺伝子2がEML4、KIF5B、HIP1、KLC1、及びTFGからなる群より選択される、請求項11又は12に記載の方法。
- 遺伝子1がRETであり、遺伝子2がKIF5B、CCDC6、NCOA4、及びTRIM33からなる群より選択される、請求項11又は12に記載の方法。
- 個体由来の生物学的試料中の融合遺伝子を検出するためのキットであって、
− 遺伝子1と遺伝子2との間の融合部位に特異的な少なくとも1つの第1プライマー対であって、融合部位の5’側から開始する少なくとも1つのフォワードプライマーと、融合部位の3’側から開始する少なくとも1つのリバースプライマーとを含む、第1プライマー対と、
− 前記融合部位の5’である遺伝子1の一部に特異的な第2プライマー対、
− 前記融合部位の3’である遺伝子1の一部に特異的な第3プライマー対、及び
− 前記プライマー対の各々から生じる増幅産物の各々に特異的な標識プローブを含み、
前記第1、第2、第3プライマー対が、それぞれ別の容器中にあるか、又は2つ以上が単一の容器中に貯蔵される、
キット。 - 対照配列に特異的な第4のプライマーセットをさらに含み、ここで、前記第4プライマーセットは、前記第1、第2、第3プライマー対とは別の容器中にあるか、又は同じ容器に貯蔵される、請求項15に記載のキット。
- 熱安定性DNAポリメラーゼをさらに含む、請求項15又は16に記載のキット。
- 逆転写酵素をさらに含む、請求項15〜17のいずれか1項に記載のキット。
- 少なくとも1つの対照試料をさらに含む、請求項15〜18のいずれか1項に記載のキット。
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