JP2020521440A - Alk、ret、およびros融合の多重pcr検出 - Google Patents
Alk、ret、およびros融合の多重pcr検出 Download PDFInfo
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Abstract
Description
本発明者らは、遺伝子領域間の融合を検出する、新規で定量的かつ多重的な方法を発見した。現在開示されている方法は、非侵襲的に収集することができる少量の患者試料、例えば血漿に由来する循環遊離RNA(cfRNA)のみを必要とする。
「遺伝子融合」とは、以前は別々であった2つの染色体位置が連結して形成されたハイブリッド染色体配列である。融合は、同じ染色体上の遺伝子間(例えば、間質性欠失もしくは染色体逆位)でも、または異なる染色体上の遺伝子間(例えば、転座)でも起こりうる。
数々のがん関連融合遺伝子が知られており、あらゆる種類のがんに発生する。例としては、肺がん(例として、非小細胞肺がん(NSCLC)、肺扁平上皮がん、肺腺がん)、膀胱がん、神経膠芽腫、頭頸部がん、神経膠腫、甲状腺がん、卵巣がん、白血病、リンパ腫、前立腺がん、膵臓がん、腎がん、および乳がんが含まれる。がん関連融合遺伝子は一般に、融合の1つのメンバーが増殖促進シグナル伝達経路に関与するキナーゼであり、もう一方のメンバーが発現またはシグナル伝達の上昇または構成に寄与する場合に生じる。これが、ALK、RET、およびROS1の融合の場合である。ALKの一般的な融合パートナーは、EML4およびKIF5Bである。RETの一般的な融合パートナーは、KIF5B、CCDC6、およびNCOA4である。いくつかの遺伝子は、ROS1と融合することが知られており、これには、CD74、EZR、TPM3、SDC4、SLC34A2、およびLRIG3が含まれる(例えば、Yoshihara et al.(2015)Oncogene 34:4845を参照)。
遺伝的融合を検査するための試料は、あらゆる供給源から得ることができるが、有利には、非侵襲的様式、例えば、血液または血液画分(例として、血漿、血清、血小板など)から得る。本発明の方法のための試料はまた、尿、気管支肺胞洗浄、または組織生検から採取することもできる。生体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(例として、ロシュ社のHigh Pure RNA Isolation Kit、High Pure Viral Nucleic Acid Kit、およびMagNA Pure LC Total Nucleic Acid Isolation Kit)。
核酸増幅は、あらゆるプライマー依存的方法を用いて行うことができる。いくつかの実施形態では、増幅は定量的であるため、所与の増幅標的の相対的または実際の存在量は、増幅産物の量によって決定することができる。
いくつかの実施形態では、現在開示されている方法を実施するための試薬および材料は、キットに含まれる。いくつかの実施形態では、キットは、試料を入手し、保存し、および/または調製するための構成要素を含む。そのような構成要素としては、例えば、滅菌針およびシリンジ、EDTAラインチューブ、緩衝液(例として、核酸のマトリックスへの結合、およびマトリックスからの溶出)、リボヌクレアーゼ阻害剤、ならびに/またはデオキシリボヌクレアーゼなどが含まれる。
A.実施例1:ALK、RET、およびROS1融合パネルの検出用マルチプレックスアッセイ
この例では、ALK、RET、およびROS1融合(ALK/RET/ROS1パネル)を検出するために、多重定量RT−PCR法を試験した。測定可能で信頼できる結果を達成するのに必要な試料の量を減らすために、4つの異なるセットのプライマーおよびプローブを単一チューブ(または、容器、ウェル、チャンバー、コンパートメント)アッセイにおいて使用する。これら4つのセットは、(i)ALK(第1の標識で標識された1つ以上のプローブで検出)、(ii)RET(第2の標識で標識された1つ以上のプローブで検出)、(iii)ROS1(第3の標識で標識された1つ以上のプローブで検出)、および(iv)内部標準(第4の標識で標識されたプローブで検出)と対応する。標識は、本明細書に開示されたものから選択することができ、いくつかの実施形態では、互いに識別可能である。本実施例では、ALK融合はFAM標識プローブで検出され、RET融合はHEX標識プローブで検出され、ROS1融合はJA270標識プローブで検出され、内部標準はCy5.5標識プローブで検出される。
実施例1、表1に示されるALKおよびRET融合変異体の検出限界について、多重qRT−PCRを試験した。ALKまたはRET融合陽性転写物を、250、100、50、または25コピーで0.1ngのユニバーサルヒトRNA(UHR)に力価測定することによって、マルチプレックスアッセイを試験した。増幅および検出反応を3回繰り返した。
ALK、RET、およびROS1融合について検出の直線性を判定するため、図3〜5に示した上で解説するように、さらなる研究を実施した。
Claims (31)
- マルチプレックスアッセイ組成物であって、
A.少なくとも1つのALK融合遺伝子を特異的に増幅および検出する少なくとも1つのプライマーセットおよびプローブと、
B.少なくとも1つのRET融合遺伝子を特異的に増幅および検出する少なくとも1つのプライマーセットおよびプローブと、
C.少なくとも1つのROS1融合遺伝子を特異的に増幅および検出する少なくとも1つのプライマーセットおよびプローブ、および
D.内部標準を特異的に増幅および検出するプライマーセットおよびプローブと、
を含むマルチプレックスアッセイ組成物。 - 前記少なくとも1つのALK融合遺伝子が、EML4エクソン13−ALKエクソン20、EML4エクソン20−ALKエクソン20、EML4エクソン6a/b−ALKエクソン20、EML4エクソン2−ALKエクソン20、EML4エクソン18−ALKエクソン20、KIF5Bエクソン17−ALKエクソン20、およびKIF5Bエクソン24−ALKエクソン20からなる群から選択される、請求項1に記載の組成物。
- Aが、2つ以上のALK融合遺伝子を増幅および検出する少なくとも1つのプライマーセットおよびプローブを含む、請求項1または2に記載の組成物。
- Aが、EML4エクソン13−ALKエクソン20、EML4エクソン20−ALKエクソン20、EML4エクソン6a/b−ALKエクソン20、EML4エクソン2−ALKエクソン20、EML4エクソン18−ALKエクソン20、KIF5Bエクソン17−ALKエクソン20、およびKIF5Bエクソン24−ALKエクソン20を増幅および検出する少なくとも1つのプライマーセットおよびプローブを含む、請求項1〜3のいずれか一項に記載の組成物。
- 前記少なくとも1つのRET融合遺伝子が、KIF5Bエクソン15−RETエクソン12、KIF5Bエクソン16−RETエクソン12、KIF5Bエクソン22−RETエクソン12、KIF5Bエクソン23−RETエクソン12、CCDC6エクソン1−RETエクソン12、およびNCOA4エクソン6−RETエクソン12からなる群から選択される、請求項1〜4のいずれか一項に記載の組成物。
- Bが、2つ以上のRET融合遺伝子を増幅および検出する少なくとも1つのプライマーセットおよびプローブを含む、請求項1〜5のいずれか一項に記載の組成物。
- Bが、KIF5Bエクソン15−RETエクソン12、KIF5Bエクソン16−RETエクソン12、KIF5Bエクソン22−RETエクソン12、KIF5Bエクソン23−RETエクソン12、CCDC6エクソン1−RETエクソン12、およびNCOA4エクソン6−RETエクソン12を増幅および検出する少なくとも1つのプライマーセットおよびプローブを含む、請求項1〜6のいずれか一項に記載の組成物。
- 前記少なくとも1つのROS1融合遺伝子が、CD74エクソン6−ROS1エクソン34、CD74エクソン6−ROS1エクソン32、EZRエクソン10−ROS1エクソン34、TPM3エクソン8−ROS1エクソン35、SDC4エクソン4−ROS1エクソン34、SDC4エクソン2−ROS1エクソン34、SDC4エクソン2−ROS1エクソン32、SDC4エクソン4−ROS1エクソン32、SLC34A2エクソン13−ROS1エクソン34、SLC34A2エクソン13−ROS1エクソン32v2、SLC34A2エクソン4−ROS1エクソン32、SLC34A2エクソン4−ROS1エクソン35、およびLRIG3エクソン16−ROS1エクソン35からなる群から選択される、請求項1〜7のいずれか一項に記載の組成物。
- Cが、2つ以上のROS1融合遺伝子を増幅および検出する少なくとも1つのプライマーセットおよびプローブを含む、請求項1〜8のいずれか一項に記載の組成物。
- Cが、CD74エクソン6−ROS1エクソン34、CD74エクソン6−ROS1エクソン32、EZRエクソン10−ROS1エクソン34、TPM3エクソン8−ROS1エクソン35、SDC4エクソン4−ROS1エクソン34、SDC4エクソン2−ROS1エクソン32v2、SDC4エクソン2−ROS1エクソン32、SLC34A2エクソン13−ROS1エクソン34、SLC34A2エクソン13−ROS1エクソン32v2、SLC34A2エクソン4−ROS1エクソン32、SLC34A2エクソン4−ROS1エクソン35、およびLRIG3エクソン16−ROS1エクソン35を増幅および検出する少なくとも1つのプライマーセットおよびプローブを含む、請求項1〜9のいずれか一項に記載の組成物。
- 熱安定性DNAポリメラーゼをさらに含む、請求項1〜10のいずれか一項に記載の組成物。
- 逆転写酵素をさらに含む、請求項1〜11のいずれか一項に記載の組成物。
- 個体に由来する生体試料をさらに含む、請求項1〜12のいずれか一項に記載の組成物。
- 前記生体試料が、血漿に由来するRNAを含む、請求項13に記載の組成物。
- マルチプレックスアッセイ組成物であって、
A.少なくとも1つのALK融合遺伝子を特異的に増幅および検出する少なくとも1つのプライマーセットおよびプローブと、
B.少なくとも1つのRET融合遺伝子を特異的に増幅および検出する少なくとも1つのプライマーセットおよびプローブ、および
C.内部標準を特異的に増幅および検出するプライマーセットおよびプローブと、
を含むマルチプレックスアッセイ組成物。 - 前記少なくとも1つのALK融合遺伝子が、EML4エクソン13−ALKエクソン20、EML4エクソン20−ALKエクソン20、EML4エクソン6a/b−ALKエクソン20、EML4エクソン2−ALKエクソン20、EML4エクソン18−ALKエクソン20、KIF5Bエクソン17−ALKエクソン20、およびKIF5Bエクソン24−ALKエクソン20からなる群から選択される、請求項15に記載の組成物。
- 前記少なくとも1つのRET融合遺伝子が、KIF5Bエクソン15−RETエクソン12、KIF5Bエクソン16−RETエクソン12、KIF5Bエクソン22−RETエクソン12、KIF5Bエクソン23−RETエクソン12、CCDC6エクソン1−RETエクソン12、およびNCOA4エクソン6−RETエクソン12からなる群から選択される、請求項15または16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15〜17のいずれか一項に記載の組成物。
- 逆転写酵素をさらに含む、請求項15〜18のいずれか一項に記載の組成物。
- 個体に由来する生体試料をさらに含む、請求項15〜19のいずれか一項に記載の組成物。
- 前記生体試料が、血漿に由来するRNAを含む、請求項20に記載の組成物。
- がんを有する個体を同定する方法であって、
A.前記個体に由来する生体試料を、請求項1〜12および15〜19のいずれか一項に記載の組成物と接触させるステップと、
B.前記生体試料中の少なくとも1つの融合遺伝子の存在下において、増幅産物の形成及び検出が可能な条件下で増幅および検出を行うステップと、
C.融合遺伝子がステップBで検出された場合に、少なくとも1つの融合遺伝子が存在することを判定するステップと、
D.それによって、少なくとも1つの融合遺伝子が存在する場合、前記個体の試料中の少なくとも1つの融合遺伝子の存在はキナーゼ阻害剤療法に対する前記個体の感受性を示すステップと、を含む、方法。 - がんを有する個体のキナーゼ阻害剤療法に対する反応の可能性を判定する方法であって、
A.前記個体に由来する生体試料を、請求項1〜12および15〜19のいずれか一項に記載の組成物と接触させるステップと、
B.前記生体試料中の少なくとも1つの融合遺伝子の存在下において、増幅産物の形成及び検出が可能な条件下で増幅および検出を行うステップと、
C.融合遺伝子がステップBで検出された場合に、少なくとも1つの融合遺伝子が存在することを判定するステップ、および
D.前記個体が前記キナーゼ阻害剤療法に反応しそうであることを判定するステップと、を含む、方法。 - 前記生体試料が、DNAまたはRNAを含む、請求項22または23に記載の方法。
- 前記生体試料が、前記個体の血漿に由来するRNAである、請求項22または23に記載の方法。
- 前記増幅および検出が、定量的逆転写ポリメラーゼ連鎖反応(qRT−PCR)を用いて行われる、請求項22または23に記載の方法。
- 前記キナーゼ阻害剤療法が、アレチニブ、クリゾチニブ、セリチニブ、ロラチニブ、ブリガチニブ、カボザンチニブ、アパチニブ、バンデタニブ、ポナチニブ、レンバチニブ、DS6051b、またはこれらの変異体からなる群から選択される、請求項22〜26のいずれか一項に記載の方法。
- がんを有する個体に由来する生体試料中の少なくとも1つの融合遺伝子の存在を判定する方法であって、
A.前記個体に由来する生体試料を、請求項1〜12および15〜19のいずれか一項に記載の組成物と接触させるステップと、
B.前記生体試料中の少なくとも1つの融合遺伝子の存在下において、増幅産物の形成及び検出が可能な条件下で増幅および検出を行うステップと、
C.融合遺伝子がステップBで検出された場合に、少なくとも1つの融合遺伝子の存在を判定するステップと、を含む、方法。 - 前記生体試料が、DNAまたはRNAを含む、請求項28に記載の方法。
- 前記生体試料が、前記個体の血漿に由来するRNAである、請求項28に記載の方法。
- 前記増幅および検出が、定量的逆転写ポリメラーゼ連鎖反応(qRT−PCR)を用いて行われる、請求項28に記載の方法。
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