JP7420335B2 - 変異型ヒトDNAポリメラーゼε - Google Patents
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Description
高頻度変異型(hypermutation又はhypermutated)の癌は、通常の癌と比べて、癌特異的変異の変異率が高い癌である。ここで、変異率とは、106塩基(以下、「Mb」ともいう)当たりのアミノ酸残基の変化を伴う変異の数である。高頻度変異型の癌は、通常の癌との変異率の比較によって判断される。変異率は調べる遺伝子の数や種類によって異なり、また、癌の種類によっても異なるが、変異率が相対的に通常の癌より高い場合、高頻度変異型の癌であると判断される。
ヒトDNAポリメラーゼεは、DNA複製酵素であり、野生型DNAポリメラーゼεは配列番号1で示されるアミノ酸配列を有する。ヒトDNAポリメラーゼεのDNA合成活性ドメインは、配列番号1で示されるアミノ酸配列の第624番目~第1145番目に該当し、エキソヌクレアーゼ活性ドメインは、配列番号1で示されるアミノ酸配列の第87番目~第426番目に該当する。
一実施形態に係る核酸は、上述の変異型ヒトDNAポリメラーゼεをコードする核酸(以下、「核酸1」ともいう。)である。核酸1は、イントロンを含むゲノムDNA配列を有する核酸であってもよく、mRNA配列を有する核酸であってもよい。なお、野生型ヒトDNAポリメラーゼε遺伝子のゲノムDNA配列はNCBIアクセッション番号NG_033840である。また、野生型ヒトDNAポリメラーゼεのmRNA配列はNCBIアクセッション番号L09561である。
本実施形態に係る判別方法は、癌を患っているヒト患者において、癌が高頻度変異型の癌であるか判別する方法であって、ヒト患者から採取された癌細胞由来の成分を含むサンプルを用いて、癌細胞に由来するヒトDNAポリメラーゼεのアミノ酸配列の第952番目のアミノ酸残基の変異の有無を決定する工程を有し、当該アミノ酸残基が変異していることが、癌が高頻度変異型の癌であることを示す、方法である。
本実施形態に係る診断方法は、高頻度変異型の癌への罹患を診断する方法であって、ヒト検体から採取された細胞由来の成分を含むサンプルを用いて、細胞に由来するヒトDNAポリメラーゼεのアミノ酸配列の第952番目のアミノ酸残基の変異を検出する工程を有し、当該アミノ酸残基が変異している場合、ヒト検体が高頻度変異型の癌に罹患していると診断する、方法である。
大腸癌患者201症例の癌切除検体ホルマリン固定パラフィン包埋検体を作製し、これを薄切して厚さ20μmの切片を2つ作製した。作製した2つの切片をスライドガラスに貼付したものをDNA抽出用のサンプルとして用いた。
顕微鏡観察用のサンプルをヘマトキシリンエオジンで染色した。染色後のサンプルを、顕微鏡で観察して切片中の癌細胞を多く含む部位を特定した。DNA抽出用のサンプルから、顕微鏡観察用のサンプルで特定した部位を剃刀で削り取り、削り取った部位からDNAを抽出した。DNAの抽出は、BiOstic(登録商標) FFPE Tissue DNA Isolation Kit(商品名)を用いて行った。
大腸癌患者201症例の癌切除検体ホルマリン固定パラフィン包埋検体から抽出したDNAを用いて415遺伝子の癌特異的変異(アミノ酸残基の変異を伴う変異)を次世代シーケンサー(MiSeqシーケンサー,イルミナ社)により分析した。図1に分析結果を示した。
Claims (9)
- 1つ以上のアミノ酸残基の変異を含む変異型ヒトDNAポリメラーゼεであって、
前記アミノ酸残基の変異が、配列番号1で示されるヒトDNAポリメラーゼεのアミノ酸配列の第952番目のロイシン残基が他のアミノ酸残基になる変異を含み、
前記他のアミノ酸残基が、セリン残基である、変異型ヒトDNAポリメラーゼε。 - 請求項1に記載の変異型ヒトDNAポリメラーゼεをコードする核酸。
- 請求項1に記載の変異型ヒトDNAポリメラーゼεをコードする核酸に相補的な核酸。
- 前記他のアミノ酸残基をコードする塩基配列を含む、請求項2に記載の核酸の断片。
- 前記他のアミノ酸残基をコードする塩基配列の相補配列を含む、請求項3に記載の核酸の断片。
- 20~300塩基長の核酸である、請求項4又は5に記載の断片。
- 癌を患っているヒト患者において、癌が高頻度変異型の癌であるか判別する方法であって、
前記ヒト患者から採取された癌細胞由来の成分を含むサンプルを用いて、前記癌細胞に由来する配列番号1で示されるヒトDNAポリメラーゼεのアミノ酸配列の第952番目のアミノ酸残基の変異の有無を決定する工程を有し、
前記アミノ酸残基が変異していることが、前記癌が高頻度変異型の癌であることを示し、
前記アミノ酸残基の変異がL952Sである、方法。 - 前記アミノ酸残基の変異の有無の決定が、ヒトDNAポリメラーゼεのアミノ酸配列の第952番目のアミノ酸残基をコードする塩基配列の変異の検出を含む、請求項7に記載の方法。
- 前記癌が、大腸癌又は直腸癌である、請求項7又は8に記載の方法。
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