JP2021052629A - 脳腫瘍を検査する方法 - Google Patents
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Abstract
Description
(1)被検体から採取された体液由来試料における、miR-345-3p、miR-208a-5p、miR-188-3p、miR-504-5p、miR-199a-5p、miR-93-3p、miR-328-5p、miR-483-3p、miR-204-3p、miR-411-3p、miR-1251-5p、miR-30c-2-3p、miR-26a-1-3p、miR-27b-3p、miR-338-5p、miR-541-3p、miR-224-3p、miR-143-3p、miR-32-3p、miR-202-5p、miR-296-3p、miR-598-5p、miR-125b-2-3p、miR-20b-3p、miR-181b-2-3p、miR-29b-2-5p、miR-301a-5p、miR-140-3p、miR-122-5p、miR-335-3p、miR-539-5p、miR-374b-5p、miR-144-5p、miR-196a-5p、miR-124-3p、miR-363-5p、miR-376b-5p、miR-367-5p、miR-29a-3p、miR-146a-3p、miR-216a-5p、miR-148a-5p、miR-99a-5p、miR-509-5p、miR-6070、miR-450a-2-3p、miR-4638-3p、miR-20a-3p、miR-646、miR-151a-5p、miR-151b、miR-146a-5p、miR-371a-3p、miR-21-3p、miR-578、miR-4428、miR-5095、miR-193a-3p、miR-4538、miR-492、miR-4482-5p、及びmiR-4768-3pからなる群より選択される少なくとも1種のバイオマーカーを検出する工程、
を含む、検査方法。
を含む、項1に記載の検査方法。
本発明は、その一態様において、脳腫瘍を検査する方法であって、(1)被検体から採取された体液由来試料における、miR-345-3p、miR-208a-5p、miR-188-3p、miR-504-5p、miR-199a-5p、miR-93-3p、miR-328-5p、miR-483-3p、miR-204-3p、miR-411-3p、miR-1251-5p、miR-30c-2-3p、miR-26a-1-3p、miR-27b-3p、miR-338-5p、miR-541-3p、miR-224-3p、miR-143-3p、miR-32-3p、miR-202-5p、miR-296-3p、miR-598-5p、miR-125b-2-3p、miR-20b-3p、miR-181b-2-3p、miR-29b-2-5p、miR-301a-5p、miR-140-3p、miR-122-5p、miR-335-3p、miR-539-5p、miR-374b-5p、miR-144-5p、miR-196a-5p、miR-124-3p、miR-363-5p、miR-376b-5p、miR-367-5p、miR-29a-3p、miR-146a-3p、miR-216a-5p、miR-148a-5p、miR-99a-5p、miR-509-5p、miR-6070、miR-450a-2-3p、miR-4638-3p、miR-20a-3p、miR-646、miR-151a-5p、miR-151b、miR-146a-5p、miR-371a-3p、miR-21-3p、miR-578、miR-4428、miR-5095、miR-193a-3p、miR-4538、miR-492、miR-4482-5p、及びmiR-4768-3pからなる群より選択される少なくとも1種のバイオマーカーを検出する工程、を含む、検査方法(本明細書において、「本発明の検査方法」と示すこともある。)に関する。以下、これについて説明する。
検査対象である脳腫瘍の種類は、特に制限されない。脳腫瘍としては、例えば神経膠腫、髄膜腫、中枢神経系原発悪性リンパ腫、下垂体腺腫、神経鞘腫、頭蓋咽頭腫等が挙げられる。これらの中でも、本発明の検査方法の対象として、好適には、神経膠腫、髄膜腫等が挙げられる。脳腫瘍の各種分類基準における全てのクラス、グレード、ステージの脳腫瘍が検査対象となる。
本発明の検査方法は、一態様として、さらに、(2)前記工程(1)で検出された前記バイオマーカーの量又は濃度に基づいて、前記被検体が脳腫瘍に罹患しているか否かを判定する工程、を含む。該工程2を含む本発明の検査方法によれば、脳腫瘍を判定することが可能となる。
(2a)前記工程(1)で検出された前記BM1A及び/又はBM2Aの量又は濃度がカットオフ値以上である場合に、前記被検体が脳腫瘍に罹患していると判定する工程、
を含むことが好ましい。
(2b)前記工程(1)で検出された前記BM1B及び/又はBM2Bの量又は濃度がカットオフ値以下である場合に、前記被検体が脳腫瘍に罹患していると判定する工程、
を含むことが好ましい。
(2c)前記工程(1)で検出された前記BM1A及び/又はBM2Aの量又は濃度がカットオフ値以上であり、且つ前記工程(1)で検出された前記BM1B及び/又はBM2Bの量又は濃度がカットオフ値以下である場合に、前記被検体が脳腫瘍に罹患していると判定する工程、
を含むことが好ましい。
工程(2)を含む本発明の検査方法により、被検体が脳腫瘍に罹患していると判定された場合、本発明の検査方法に、さらに脳腫瘍の医師による診断を適用する工程を組み合わせることによって、より高い精度で脳腫瘍を診断することができる。また、本発明の検査方法はより正確に脳腫瘍を検出できるので、本発明の検査方法に上記工程を組み合わせることによって、より効率的且つより正確に「脳腫瘍に罹患している」と診断できる。
工程(2)を含む本発明の検査方法により被検体が脳腫瘍に罹患していると判定された場合は本発明の検査方法に対してさらに、或いは上記「2.脳腫瘍のより高い精度での診断」に記載の様に脳腫瘍に罹患していると診断された場合は本発明の検査方法と医師による診断を適用する工程との組合せに対してさらに、(3)脳腫瘍に罹患していると判定又は診断された被検体に対して、該疾患の治療を行う工程を行うことによって、被検体の該疾患を治療することが可能となる。また、本発明の検査方法はより正確に脳腫瘍を検出できるので、本発明の検査方法に対して、或いは本発明の検査方法と医師による診断を適用する工程との組合せに対して工程3を組み合わせることによって、脳腫瘍に罹患している被検体をより効率的に、より確実に治療できる。
本発明は、その一態様において、対象バイオマーカーの検出剤(本明細書において、「本発明の検査薬」と示すこともある。)を含む、脳腫瘍の検査薬(本明細書において、「本発明の検査薬」と示すこともある。)に関する。以下、これについて説明する。
(a)対象バイオマーカーの塩基配列において連続する少なくとも15塩基を有するポリヌクレオチド及び/若しくは当該ポリヌクレオチドに相補的なポリヌクレオチド、並びに
(b)対象バイオマーカーの塩基配列若しくはそれに相補的な塩基配列にストリンジェントな条件下でハイブリダイズする、少なくとも15塩基を有するポリヌクレオチド
からなる群より選択される少なくとも1種が挙げられる。
本発明は、その一態様において、被検物質で処理された動物から採取された体液由来試料における、対象バイオマーカーの量又は濃度を指標とする、脳腫瘍の予防又は治療剤の有効成分のスクリーニング方法(本明細書において、「本発明の有効成分スクリーニング方法」と示すこともある。)に関する。以下、これについて説明する。
本発明は、その一態様において、被検物質で処理された動物から採取された体液由来試料における、対象バイオマーカーの量又は濃度を指標とする、脳腫瘍の誘発性又は増悪性の評価方法(本明細書において、「本発明の毒性評価方法」と示すこともある。)に関する。以下、これについて説明する。
神経膠腫患者の尿62検体および健常者の尿100検体から、miRNAを抽出した。miRNA抽出は、以前開発したナノスケールの棒(ナノワイヤ)を用いて行った。この方法については、国際公開第2015/137427号に記載されている。本法は、従来法に比べ尿中細胞外小胞体を効率よく捕捉することが確認されている。マイクロアレイ解析(東レ社製、miRNA Oligo chip、3D-Gene(登録商標))を行い、健常者と比較し、神経膠腫患者において、発現レベルが1.5倍以上異なり、かつ統計学的に有意差(Wilcoxonの順位和検定にてp値0.05未満)が認められるヒトmiRNA (hsa-miR)を選定した。
脳腫瘍患者(神経膠腫患者及び髄膜種患者の両方を含む)の尿110検体および健常者の尿100検体を対象として、試験例1の方法と同様にしてmiRNA発現量を解析し、バイオマーカーの探索及び判定を行った。なお、本試験例では、データの正規化はglobal normalization法により行い、データの正規化後に0の値を全て1とし、log変換(底2)し、3以下の値は0に切り捨てた。また、本試験例では、L1正則化でmiRNAの絞り込みを行ってから判定式を作成し、その後cross validationも行って判定式の確認をした。本試験例の判定式を以下に示す。
Claims (16)
- 脳腫瘍を検査する方法であって、
(1)被検体から採取された体液由来試料における、miR-345-3p、miR-208a-5p、miR-188-3p、miR-504-5p、miR-199a-5p、miR-93-3p、miR-328-5p、miR-483-3p、miR-204-3p、miR-411-3p、miR-1251-5p、miR-30c-2-3p、miR-26a-1-3p、miR-27b-3p、miR-338-5p、miR-541-3p、miR-224-3p、miR-143-3p、miR-32-3p、miR-202-5p、miR-296-3p、miR-598-5p、miR-125b-2-3p、miR-20b-3p、miR-181b-2-3p、miR-29b-2-5p、miR-301a-5p、miR-140-3p、miR-122-5p、miR-335-3p、miR-539-5p、miR-374b-5p、miR-144-5p、miR-196a-5p、miR-124-3p、miR-363-5p、miR-376b-5p、miR-367-5p、miR-29a-3p、miR-146a-3p、miR-216a-5p、miR-148a-5p、miR-99a-5p、miR-509-5p、miR-6070、miR-450a-2-3p、miR-4638-3p、miR-20a-3p、miR-646、miR-151a-5p、miR-151b、miR-146a-5p、miR-371a-3p、miR-21-3p、miR-578、miR-4428、miR-5095、miR-193a-3p、miR-4538、miR-492、miR-4482-5p、及びmiR-4768-3pからなる群より選択される少なくとも1種のバイオマーカーを検出する工程、
を含む、検査方法。 - (2)前記工程(1)で検出された前記バイオマーカーの量又は濃度に基づいて、前記被検体が脳腫瘍に罹患しているか否かを判定する工程、
を含む、請求項1に記載の検査方法。 - 前記バイオマーカーがmiR-345-3p、miR-208a-5p、miR-188-3p、miR-504-5p、miR-199a-5p、miR-93-3p、miR-328-5p、miR-483-3p、miR-204-3p、miR-411-3p、miR-1251-5p、miR-30c-2-3p、miR-26a-1-3p、miR-27b-3p、miR-338-5p、miR-541-3p、miR-224-3p、miR-143-3p、miR-32-3p、miR-202-5p、miR-296-3p、miR-598-5p、miR-125b-2-3p、miR-20b-3p、miR-181b-2-3p、miR-29b-2-5p、miR-301a-5p、miR-140-3p、miR-122-5p、miR-335-3p、miR-539-5p、miR-374b-5p、miR-144-5p、miR-196a-5p、miR-124-3p、miR-363-5p、miR-376b-5p、miR-367-5p、miR-29a-3p、miR-146a-3p、miR-216a-5p、miR-148a-5p、miR-99a-5p、及びmiR-509-5pからなる群より選択される少なくとも1種である、請求項1又は2に記載の検査方法。
- 前記バイオマーカーがmiR-345-3p、miR-208a-5p、miR-188-3p、miR-504-5p、miR-199a-5p、miR-93-3p、miR-328-5p、及びmiR-483-3pからなる群より選択される少なくとも1種である、請求項1〜3のいずれかに記載の検査方法。
- 前記バイオマーカーが3種以上である、請求項3又は4に記載の検査方法。
- 前記脳腫瘍が神経膠腫である、請求項3〜5のいずれかに記載の検査方法。
- 前記バイオマーカーがmiR-6070、miR-450a-2-3p、miR-4638-3p、miR-20a-3p、miR-646、miR-151a-5p、miR-151b、miR-146a-5p、miR-371a-3p、miR-21-3p、miR-578、miR-4428、miR-5095、miR-193a-3p、miR-4538、miR-492、miR-4482-5p、及びmiR-4768-3pからなる群より選択される少なくとも1種である、請求項1又は2に記載の検査方法。
- 前記バイオマーカーがmiR-6070、miR-450a-2-3p、miR-4638-3p、及びmiR-20a-3pからなる群より選択される少なくとも1種である、請求項1、2及び7のいずれかに記載の検査方法。
- 前記バイオマーカーが3種以上である、請求項7又は8に記載の検査方法。
- 前記体液が尿である、請求項1〜9のいずれかに記載の検査方法。
- 前記体液試料が尿の細胞外小胞である、請求項1〜10のいずれかに記載の検査方法。
- 前記被検体がヒトである、請求項1〜11のいずれかに記載の検査方法。
- miR-345-3p、miR-208a-5p、miR-188-3p、miR-504-5p、miR-199a-5p、miR-93-3p、miR-328-5p、miR-483-3p、miR-204-3p、miR-411-3p、miR-1251-5p、miR-30c-2-3p、miR-26a-1-3p、miR-27b-3p、miR-338-5p、miR-541-3p、miR-224-3p、miR-143-3p、miR-32-3p、miR-202-5p、miR-296-3p、miR-598-5p、miR-125b-2-3p、miR-20b-3p、miR-181b-2-3p、miR-29b-2-5p、miR-301a-5p、miR-140-3p、miR-122-5p、miR-335-3p、miR-539-5p、miR-374b-5p、miR-144-5p、miR-196a-5p、miR-124-3p、miR-363-5p、miR-376b-5p、miR-367-5p、miR-29a-3p、miR-146a-3p、miR-216a-5p、miR-148a-5p、miR-99a-5p、miR-509-5p、miR-6070、miR-450a-2-3p、miR-4638-3p、miR-20a-3p、miR-646、miR-151a-5p、miR-151b、miR-146a-5p、miR-371a-3p、miR-21-3p、miR-578、miR-4428、miR-5095、miR-193a-3p、miR-4538、miR-492、miR-4482-5p、及びmiR-4768-3pからなる群より選択される少なくとも1種のバイオマーカーの検出剤を含む、脳腫瘍の検査薬。
- miR-345-3p、miR-208a-5p、miR-188-3p、miR-504-5p、miR-199a-5p、miR-93-3p、miR-328-5p、miR-483-3p、miR-204-3p、miR-411-3p、miR-1251-5p、miR-30c-2-3p、miR-26a-1-3p、miR-27b-3p、miR-338-5p、miR-541-3p、miR-224-3p、miR-143-3p、miR-32-3p、miR-202-5p、miR-296-3p、miR-598-5p、miR-125b-2-3p、miR-20b-3p、miR-181b-2-3p、miR-29b-2-5p、miR-301a-5p、miR-140-3p、miR-122-5p、miR-335-3p、miR-539-5p、miR-374b-5p、miR-144-5p、miR-196a-5p、miR-124-3p、miR-363-5p、miR-376b-5p、miR-367-5p、miR-29a-3p、miR-146a-3p、miR-216a-5p、miR-148a-5p、miR-99a-5p、miR-509-5p、miR-6070、miR-450a-2-3p、miR-4638-3p、miR-20a-3p、miR-646、miR-151a-5p、miR-151b、miR-146a-5p、miR-371a-3p、miR-21-3p、miR-578、miR-4428、miR-5095、miR-193a-3p、miR-4538、miR-492、miR-4482-5p、及びmiR-4768-3pからなる群より選択される少なくとも1種のバイオマーカーの検出剤を含む、脳腫瘍の検査キット。
- 被検物質で処理された動物から採取された体液由来試料における、miR-345-3p、miR-208a-5p、miR-188-3p、miR-504-5p、miR-199a-5p、miR-93-3p、miR-328-5p、miR-483-3p、miR-204-3p、miR-411-3p、miR-1251-5p、miR-30c-2-3p、miR-26a-1-3p、miR-27b-3p、miR-338-5p、miR-541-3p、miR-224-3p、miR-143-3p、miR-32-3p、miR-202-5p、miR-296-3p、miR-598-5p、miR-125b-2-3p、miR-20b-3p、miR-181b-2-3p、miR-29b-2-5p、miR-301a-5p、miR-140-3p、miR-122-5p、miR-335-3p、miR-539-5p、miR-374b-5p、miR-144-5p、miR-196a-5p、miR-124-3p、miR-363-5p、miR-376b-5p、miR-367-5p、miR-29a-3p、miR-146a-3p、miR-216a-5p、miR-148a-5p、miR-99a-5p、miR-509-5p、miR-6070、miR-450a-2-3p、miR-4638-3p、miR-20a-3p、miR-646、miR-151a-5p、miR-151b、miR-146a-5p、miR-371a-3p、miR-21-3p、miR-578、miR-4428、miR-5095、miR-193a-3p、miR-4538、miR-492、miR-4482-5p、及びmiR-4768-3pからなる群より選択される少なくとも1種のバイオマーカーの量又は濃度を指標とする、脳腫瘍の予防又は治療剤の有効成分のスクリーニング方法。
- 被検物質で処理された動物から採取された体液由来試料体液由来試料における、miR-345-3p、miR-208a-5p、miR-188-3p、miR-504-5p、miR-199a-5p、miR-93-3p、miR-328-5p、miR-483-3p、miR-204-3p、miR-411-3p、miR-1251-5p、miR-30c-2-3p、miR-26a-1-3p、miR-27b-3p、miR-338-5p、miR-541-3p、miR-224-3p、miR-143-3p、miR-32-3p、miR-202-5p、miR-296-3p、miR-598-5p、miR-125b-2-3p、miR-20b-3p、miR-181b-2-3p、miR-29b-2-5p、miR-301a-5p、miR-140-3p、miR-122-5p、miR-335-3p、miR-539-5p、miR-374b-5p、miR-144-5p、miR-196a-5p、miR-124-3p、miR-363-5p、miR-376b-5p、miR-367-5p、miR-29a-3p、miR-146a-3p、miR-216a-5p、miR-148a-5p、miR-99a-5p、miR-509-5p、miR-6070、miR-450a-2-3p、miR-4638-3p、miR-20a-3p、miR-646、miR-151a-5p、miR-151b、miR-146a-5p、miR-371a-3p、miR-21-3p、miR-578、miR-4428、miR-5095、miR-193a-3p、miR-4538、miR-492、miR-4482-5p、及びmiR-4768-3pからなる群より選択される少なくとも1種のバイオマーカーの量又は濃度を指標とする、脳腫瘍の誘発性又は増悪性の評価方法。
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