JP2019004743A - イリノテカンの治療効果予測方法及びそのためのキット - Google Patents
イリノテカンの治療効果予測方法及びそのためのキット Download PDFInfo
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- JP2019004743A JP2019004743A JP2017122569A JP2017122569A JP2019004743A JP 2019004743 A JP2019004743 A JP 2019004743A JP 2017122569 A JP2017122569 A JP 2017122569A JP 2017122569 A JP2017122569 A JP 2017122569A JP 2019004743 A JP2019004743 A JP 2019004743A
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Abstract
【解決手段】APCDD1L遺伝子におけるrs1980576で特定される遺伝子多型又は当該遺伝子多型と連鎖不平衡にある遺伝子多型を分析し、当該遺伝子多型の遺伝子型に基づいて判定する。
【選択図】なし
Description
(解析対象)
日本人のイリノテカン投与大腸癌(ステージIV)155症例から、イリノテカン減量投与症例、UGT1A1*6(ホモ)、UGT1A1*28(ホモ)及びこれらのコンパウンドヘテロ(compound heterogeneous)症例を除いた症例のうち、治療効果判定を行った140症例及び当該140症例の中のサブポピュレーション66症例(レジメンの統一されたFOLFIRI症例)を解析対象とした。FOLFIRIとは、フルオロウラシルとl-ロイコボリンとを組み合わせた治療にイリノテカンを同時併用する大腸癌に対する標準治療のひとつである。なお、当該140症例は、イリノテカンを含むレジメンにて治療を受けた日本人大腸がん患者である。本実施例におけるレジメンでは、イリノテカンに加えて、フルオロウラシルとl-ロイコボリンとの併用によるFOLFIRIや、カペシタビンとの併用によるXELIRI、S-1との併用によるIRIS、抗EGFR抗体薬(ベバシズマブ、セツキシマブ、パニツムマブ)との併用療法を含んでいる。
各症例からゲノムDNAを次の方法で調製した。まず、EDTA含有チューブに採取した末梢血を加えた。次に、ヨウ化ナトリウム法(Wang et al., Nucleic Acids Res 34:195-201(2014))に基づいて調製した。調製したDNAは、1mM EDTA・2Naを含む10mM Tris-塩酸緩衝液(pH8.0)に溶解し、使用するまで、4℃又は-20℃で保存した。
調製したゲノムDNAを用い、WO2016/132736(PCT/JP2016/000793)に記載と同様の方法でゲノム網羅的解析(WES解析)を行った。すなわち、コントロール群として、UGT1A遺伝子多型(UGT1A1*6、*27、*28、UGT1A7(387T>G、622T>C)、UGT1A9*1b、UGT1A1*60の7箇所)が全て副作用リスクの低いホモ接合型かつイリノテカン副作用の見られなかった症例(n=5)、ケース群には、コントロール群と同じUGT1A遺伝子多型であったにもかかわらず副作用(Grade 3, entire course)がみられた症例(n=5)及び何れかのUGT1A遺伝子多型をヘテロに有するイリノテカン初回投与時から副作用(Grade 4)がみられた症例(n=5)の3つの症例を設定し、ケース・コントロール解析を行った。Validationとして加水分解プローブによるジェノタイピングを行った。遺伝子多型と副作用発生頻度及び奏効率との統計解析にはCochran-Armitage trend testを用いた。
Claims (8)
- 被検者から採取された生体試料中のゲノムDNAに存在するAPCDD1L遺伝子におけるrs1980576で特定される遺伝子多型又は当該遺伝子多型と連鎖不平衡若しくは遺伝的連鎖にある遺伝子多型を分析し、当該遺伝子多型の遺伝子型を判定し、判定した遺伝子型に基づいてイリノテカンによる治療効果を判定する方法。
- 上記rs1980576で特定される遺伝子多型は、配列番号1に示すAPCDD1L遺伝子の塩基配列における186番目における、野生型がアデニンであり変異型がグアニンである一塩基多型であることを特徴とする請求項1記載の方法。
- 上記rs1980576で特定される遺伝子多型が野生型のホモである場合にはイリノテカンの治療効果が高いと判定し、変異型と野生型のヘテロである場合にはイリノテカンの治療効果を有すると判定し、変異型のホモである場合にはイリノテカンの治療効果が低いと判定することを特徴とする請求項1記載の方法。
- 上記rs1980576で特定される遺伝子多型と連鎖不平衡の関係にある遺伝子多型は、rs3946003で特定される一塩基多型であることを特徴とする請求項1記載の方法。
- APCDD1L遺伝子におけるrs1980576で特定される遺伝子多型又は当該遺伝子多型と連鎖不平衡若しくは遺伝的連鎖にある遺伝子多型を含む連続する5〜50塩基の領域とストリンジェントな条件下でハイブリダイズするオリゴヌクレオチドを含む、イリノテカンによる治療効果判定用プローブセット。
- 上記5〜50塩基の領域は、配列番号1に示すAPCDD1L遺伝子の塩基配列における186番目を含むことを特徴とする請求項5記載の治療効果判定用プローブセット。
- 上記rs1980576で特定される遺伝子多型における野生型に対応する野生型プローブと、当該遺伝子多型における変異型に対応する変異型プローブとを含む請求項5記載の治療効果判定用プローブセット。
- 上記rs1980576で特定される遺伝子多型と連鎖不平衡の関係にある遺伝子多型は、rs3946003で特定される一塩基多型であることを特徴とする請求項5記載の治療効果判定用プローブセット。
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