JP6817259B2 - 癌の検出のための血漿dna中のサイズ及び数異常の使用 - Google Patents
癌の検出のための血漿dna中のサイズ及び数異常の使用 Download PDFInfo
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Description
本出願は、Loらによって2015年1月13日に出願された「Using Size And Number Aberrations In Plasma DNA For Detecting Cancer」と題する米国特許出願第62/102,867号(代理人整理番号80015−015800US)、及びLoらによって2015年2月3日に出願された「Using Size and Number Aberrations in Plasma DNA for Detecting Cancer」と題する同第62/111,534号(代理人整理番号80015−015801US)に対する優先権を主張し、これらの開示の全体が、あらゆる目的で参照により本明細書に組み込まれる。
本明細書で使用される場合、「生体試料」という用語は、ある対象(例えば、妊婦などのヒト)から取得され、対象となる1つ以上の核酸分子(複数可)を含有する任意の試料を指す。例としては、血漿、唾液、胸水、汗、腹水、胆汁、尿、血清、膵液、便、子宮頚部洗浄水、及び子宮頸部スメア試料が挙げられる。
試料中の数百万または数十億の個々の血漿DNA分子全ての長さを、超並行配列決定を使用して測定することが可能となっている(26、27)。したがって、血漿DNAサイズを、全ゲノム様式かつ単一塩基解像度で研究することができる。このアプローチを使用して、循環DNAのサイズは一般にモノヌクレオソームDNAのサイズに似ていることが示されており、これはアポトーシスを通して血漿DNAが生成され得ることを示す(26、27)。妊婦において、胎児に由来する血漿DNAは、母親に由来するDNAのそれよりも短いことが示されている(26)。循環胎児DNAと循環母方DNAとの間のサイズ差は、母方血漿中の胎児DNAを定量化し、血漿DNAのサイズ分析を通して染色体異数性を検出するための新しい概念的基盤を提供している(28)。更に、移植器官に由来する循環DNAと患者自身の組織に由来する循環DNAとのサイズ分布の差が、実質臓器または骨髄移植のレシピエントで観察されている(27)。
異常領域は、増幅または欠失を含む。増幅とは、領域内のある配列が、それが基準配列内で発生するよりも頻繁に発生するため、その配列が増幅されていることを意味する。増幅は、典型的には、1つの染色体コピー(ハプロタイプ)中のみで発生する。欠失とは、領域内のある配列が基準配列と比較して欠失していることを意味し、二倍体生物について、典型的には1つの染色体コピーのみが欠損を有する。領域は、(互いに分離される)少なくとも2つの座位によって定義することができ、これらの座位のDNA断片を使用して、その領域についての集団的価値を得ることができる。
ある領域の異常は、その領域に由来するDNA断片(分子)の量をカウントすることによって決定することができる。例として、量は、DNA断片の数、DNA断片がオーバーラップする塩基の数、または領域内のDNA断片の他の測定値であり得る。その領域のDNA断片の量は、DNA断片を配列決定して配列読み取りを得、配列読み取りを基準ゲノムに整列させることによって決定することができる。一実施形態において、その領域の配列読み取りの量を別の領域の配列読み取りの量と比較して、過剰提示(増幅)または過小提示(欠失)を決定することができる。別の実施形態において、1つのハプロタイプについて配列読み取りの量を決定し、別のハプロタイプの配列読み取りの量と比較することができる。
図1は、本発明の実施形態に従って、ある染色体領域を、潜在的に増幅を呈するものとして特定する方法100を図示するフローチャートである。方法100及び本明細書に記載される他の方法は、全体的または部分的にコンピュータシステムを使用して実行することができる。
いくつかの実施形態において、染色体は多くの亜染色体領域(例えば、1Mb領域)に分割され得る。この高い解像度は、感度及び特異性を最大化しない可能性がある。他の実施形態は、染色体を2つの腕、すなわち、p及びqに分割し得る。2つの腕の分析は、そのような精細な解像度によって引き起こされるノイズを低減することによって、特異性を改善することができる。染色体腕レベルのzスコア分析の一例が、これより提供される。
いくつかの実施形態は、(増幅または欠失であるかどうかとともに)ある種類の癌の既知の異常領域を使用して、試料中に特定される異常によって関係付けられる潜在的な癌を特定することができる。上記の例において、HCCの既知の異常領域を使用して、HCCの試料をスクリーニングした。このスクリーニングは、(増幅または欠失であるかどうかを含む)特定された異常領域を、既知のセットの異常領域と比較することができる。十分に高い一致が決定されると、その種類の癌が可能性のある試験結果としてフラグ立てされ得る。
図6は、本発明の実施形態に従って、ある生物の生体試料を分析して、生体試料が第1の種類の癌を呈するかどうかを決定する方法600を図示するフローチャートである。生体試料は、正常細胞、及び潜在的に癌に関連付けられる細胞に起源を持つ核酸分子(断片とも呼ばれる)を含む。試料中、これらの分子のうちの少なくともいくつかは無細胞であり得る。
方法600を複数の癌の種類について試験して、正確性を決定した。方法600を既知の癌の種類を有する患者で試験した。更に、使用される閾値は、既知の癌の種類の試料を使用して決定することができる。異なる癌の種類には、異なる閾値が使用され得る。
DNA断片のサイズ分布における統計的に有意な差を使用して、カウントの数と類似した様式で、異常を特定することができる。総(すなわち、腫瘍性プラス非腫瘍性)血漿DNAのサイズ分布が、癌患者において増加することが報告されている(Wang BG,et al.Cancer Res.2003;63:3966−8)。しかしながら、(DNAの総(すなわち、腫瘍プラス非腫瘍)量の代わりに)腫瘍由来DNAを特に研究している場合、腫瘍由来DNA分子のサイズ分布が、非腫瘍細胞に由来する分子のサイズ分布よりも短いことが観察されている(Diehl et al.Proc Natl Acad Sci U S A.2005;102:16368−73)。したがって、循環DNAのサイズ分布を使用して、癌関連染色体異常が存在するかどうかを決定することができる。
図9は、本発明の実施形態に従って、ある生物の生体試料を分析する方法900を図示するフローチャートである。生体試料は、正常細胞、及び潜在的に癌に関連付けられる細胞に起源を持つ核酸分子を含み得る。生体試料中、核酸分子のうちの少なくともいくつかは無細胞であり得る。一態様において、方法900は、第1の染色体の断片のサイズ及び1つ以上の基準染色体の断片のサイズの分離値(例えば、差または比率)に基づいて、配列不均衡の分類を決定することを対象とし得る。
更なる分析のため、我々は、3つの異なるサイズ群、すなわち、150塩基対未満のもの、150〜180塩基対のもの、及び180塩基対超のものの、血漿DNA分子を別々に調査した。150塩基対未満のDNA断片の割合と血漿中の腫瘍DNA画分との間には、正の相関性(ピアソンのr=0.6、p値<0.001)が存在する(図10A)。図10A、10B、及び10Cの腫瘍DNA画分は、対数目盛りで示される。150〜180塩基対のサイズを有するDNA断片の割合と血漿中の腫瘍DNA画分との間には、相関性(r=−0.07、p値=0.95)は観察されなかった(図10B)。180塩基対超のDNAの割合と血漿中の腫瘍DNA画分との間には、負の相関性(r=−0.41、p値<−0.001)が観察された(図10C)。
我々は、超並行配列決定を使用して、全ゲノム様式での単一塩基解像度での血漿DNA試料のサイズプロファイルを研究した。我々は、CAZAを使用して腫瘍由来血漿DNAを特定して、それらの特異的サイズプロファイルを研究した。
図11は、癌患者における血漿DNAサイズ分析の原理の模式図を示す。図11は、段階1110〜2150を示す。段階1110は、血漿中の組織の細胞を示す。上記のように、腫瘍細胞は、様々な領域において増幅及び/または欠失を含み得る。実施例は、ある特定の染色体上で増幅される1つの領域、及び欠失される別の領域を示す。
腫瘍組織及び非腫瘍組織に起源を持つ血漿DNAのサイズプロファイルを比較するために、我々は、CNAを有する染色体腕に由来する血漿DNA断片を分析した。先行研究(34〜36)、及びこの研究における我々の発見に基づくと、HCCに関連付けられる典型的なCNAは、1p及び8pの欠失ならびに1q及び8qの増幅を含む。血漿中53%の腫瘍由来DNAを有するHCC事例(H291)を使用して、原理を説明する。この事例は、血漿中8pの欠失及び8qの増幅を示した。したがって、腫瘍は、8pの欠失した領域よりも、8qの増幅した領域から多くの血漿DNAを放出するだろう。結果として、CNAを有さない領域と比較して、8qは腫瘍由来DNAに比較的富み、8pは腫瘍DNAが比較的枯渇する(換言すると、非腫瘍DNAに比較的富む)だろう。8p及び8qの血漿DNAのサイズプロファイルを、図12Aに示す。8qのサイズプロファイルは、8pのサイズプロファイルの左側にあり、8qの血漿DNAのサイズ分布が8pの血漿DNAのサイズ分布よりも短かったことを示した。8qは腫瘍DNAに富むため、このデータは、腫瘍によって放出されるDNAが、腫瘍に起源を持たないDNAよりも短い傾向があることを示す。
図16は、本発明の実施形態に従って、CAZA及びサイズ分析を実行して、ある生物の生体試料を分析する方法1600を図示するフローチャートである。
癌関連CNAの検出の特異性は、以下の2つの事例に示されるように、血漿DNAサイズ分析によって改善することができる。事例1は、B型肝炎関連硬変症を有する患者であり、事例2はB型肝炎感染の慢性保因者であった。彼らの両方とも、募集時点ではいかなる癌を有することも既知ではなかった。彼らを募集から2年間臨床的に経過観察し、癌は検出されなかった。募集時に2人の対象のそれぞれから静脈血を採取した。血漿DNAを配列決定した。これらの2人の患者のそれぞれにおいて、CNA関与染色体1qが検出された。事例1では、1p及び1qのzスコアはそれぞれ−2.3及び15.5であった。これらの結果は、1qの増幅の解釈と一貫する。血漿DNA断片サイズ分析において、ΔSは−0.019であった。ΔSの負の値は、1pと比較して、1qにおいて短いDNA断片の存在量がより低かったことを示す。カウントに基づく分析が、1qが増幅されたことを示すように、サイズに基づく分析結果は、我々が癌関連CNAについて期待していたものとは逆であった。癌患者において、コピー数増加を有する領域は、増幅を有する領域またはいかなるCNAも有さない領域と比較して、より多くの癌由来の短い断片の存在ために、全体的により短いサイズ分布を示すことが期待される。したがって、この事例におけるサイズ分析は、血漿DNA中に癌関連CNAの存在を示さない。
上記に言及されるように、DNA断片のサイズは癌の段階を示し得る。より後期の段階の癌は、増幅を呈する領域についてより小さな断片を呈する。
HCC患者、HBV保因者、硬変症患者、及び健常な対照の血漿DNAのサイズ分布を、図18及び19に示す。図19において、各個体が異なる色によって表される。一般に、最も顕著なピークは、各対象のサイズ分布プロットの166塩基対で観察された。この観察は、妊婦及び移植レシピエントについての以前の報告(26〜28)と一貫し、これは、循環DNA分子のうちのほとんどがアポトーシスに由来することを示す。興味深いことに、32人の健常な対照のサイズ中央値分布プロファイル(図18の黒色の太線)と比較すると、画分腫瘍DNA濃度を有するHCC患者における血漿DNAのサイズはより長かった。しかしながら、血漿中の腫瘍DNAの増加する画分濃度とともに、血漿DNAのサイズ分布は次第に左に移動した(図18)。
図17は、本発明の実施形態に従って、ある生物の生体試料を分析する方法1700を図示するフローチャートである。生体試料は、正常細胞、及び癌に関連付けられる細胞に起源を持つ核酸分子を含み得る。生体試料中、核酸分子のうちの少なくともいくつかは無細胞である。
図2〜5の結果を得る上で使用される技術を、これより論じる。そのような技術は、上記の他の実施例において使用することができる。
本明細書に言及されるコンピュータシステムのうちのいずれも、いかなる好適な数のサブシステムを利用してもよい。そのようなサブシステムの例を、図32のコンピュータ装置10に示す。いくつかの実施形態において、コンピュータシステムは単一のコンピュータ装置を含み、サブシステムはコンピュータ装置の構成要素であり得る。他の実施形態において、コンピュータシステムは、それぞれがシステムであり、内部構成要素を有する複数のコンピュータ装置を含み得る。コンピュータシステムは、デスクトップコンピュータ及びラップトップコンピュータ、タブレット、携帯電話、ならびに他の携帯デバイスを含み得る。
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Claims (6)
- 生物の生体試料を分析する方法であって、前記生体試料が、正常細胞に起源を持つ核酸分子、及び癌に関連付けられる細胞に起源を持つ核酸分子を含み、前記生体試料中、前記核酸分子のうちの少なくともいくつかが、無細胞核酸分子であり、前記方法が、
前記生体試料中の複数の前記核酸分子のそれぞれについて、
前記核酸分子のサイズを測定すること、及び
前記生物の基準ゲノムにおける前記核酸分子の位置を特定することを行うことと、
前記特定された位置に基づいて、核酸分子の第1の群を第1の染色体領域に由来するものとして特定すること、ここで、前記第1の染色体領域が、複数の第1の座位を含み、
コンピュータシステムによって、核酸分子の前記第1の群のサイズ分布の第1の統計値を算出することと、
癌に関連付けられる細胞に起源を持つ核酸分子の画分を測定することと、
前記測定された画分に基づいて、第1の基準値を選択することと、ここで、当該第1の基準値は、1以上の基準試料からの核酸分子の1以上のサイズ分布に基づく、 前記第1の統計値を前記第1の基準値と比較して、前記生体試料の癌の段階を決定することと、
を含み、
前記の第1の基準値を選択することが、
前記測定された画分が低カットオフ未満であるとき、前記第1の基準値として長いサイズ閾値を選択すること、ここで、前記長いサイズ閾値は、正常よりも長いサイズ分布を特定するように構成され、前記第1の統計値が前記長いサイズ閾値を超えるときに初期段階の癌が決定される、
前記測定された画分が高カットオフを超えるとき、前記第1の基準値として短いサイズ閾値を選択すること、ここで、前記短いサイズ閾値は、正常よりも短いサイズ分布を特定するように構成され、前記第1の統計値が前記短いサイズ閾値未満であるときに後期の癌が決定される、または
前記測定された画分が高カットオフ未満かつ低カットオフ超であるとき、前記第1の基準値として短いサイズ閾値及び第2の基準値として長いサイズ閾値を選択すること、ここで、前記第1の統計値が前記短いサイズ閾値超かつ前記長いサイズ閾値未満であるときに中期段階の癌が決定される、
を含む、方法。 - 前記測定された画分に基づいて、前記第1の基準値を選択することが、前記第1の基準値として長いサイズ閾値を選択することを含む、請求項1に記載の方法。
- 前記測定された画分に基づいて、前記第1の基準値を選択することが、前記第1の基準値として短いサイズ閾値を選択することを含む、請求項1に記載の方法。
- 前記測定された画分に基づいて、前記第1の基準値を選択することが、
前記第1の基準値として短いサイズ閾値及び前記第2の基準値として長いサイズ閾値を選択することを含み、
当該方法が、更に、前記第1の統計値を前記第2の基準値と比較して、前記生体試料の癌の段階を決定することを含む、請求項1に記載の方法。 - コンピュータシステムを制御して、請求項1〜4に記載の方法のうちのいずれかの操作を実行するための複数の命令を記憶するコンピュータ可読媒体を含む、コンピュータプログラム。
- 請求項5に記載のコンピュータプログラムと、
前記コンピュータ可読媒体上に記憶された命令を実行するための1つ以上の処理装置と、を含む、システム。
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