JP6195147B2 - Isocitrate dehydrogenase mutation detection marker - Google Patents
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本発明は、イソクエン酸脱水素酵素（以下、ＩＤＨということがある。）変異検出用マーカおよびＩＤＨ変異の検出方法に関する。より詳細に、本発明は、脳腫瘍、白血病、大腸がん、胃がん、甲状腺がん、悪性黒色腫などの癌におけるＩＤＨ変異を検出するためのマーカおよび方法に関する。 The present invention relates to an isocitrate dehydrogenase (hereinafter sometimes referred to as IDH) mutation detection marker and an IDH mutation detection method. More specifically, the present invention relates to markers and methods for detecting IDH mutations in cancers such as brain tumors, leukemias, colon cancers, stomach cancers, thyroid cancers, malignant melanomas.
原発性脳腫瘍の中で最も頻度の高い腫瘍をグリオーマ（神経膠腫）という。グリオーマの中で最も悪性度の高いグリオブラストーマの生存期間中央値は、約21.4か月と他の癌腫と比較して極端に悪い。脳腫瘍の網羅的遺伝子解析の結果、ＩＤＨ１に変異がみられないグリオーマでは、ＩＤＨ２のアミノ酸類似体（Ｒ１７２）に影響を及ぼす変異が高頻度に認められたが、ＩＤＨ１，ＩＤＨ２のいずれかが変異したグリオーマは特徴的な遺伝的特性と臨床的特性をもっており、このような変異型のＩＤＨを有する患者は、正常型のＩＤＨを有する患者よりも転帰（変異型31か月、正常型15か月）が優れていたと非特許文献２は報告している。
The most common tumor among primary brain tumors is called glioma. The median survival of glioblastoma, the most aggressive glioma, is about 21.4 months, which is extremely poor compared to other carcinomas. As a result of comprehensive gene analysis of brain tumors, mutations affecting IDH2 amino acid analog (R172) were frequently observed in gliomas in which no mutation was observed in IDH1, but either IDH1 or IDH2 was mutated Glioma has distinct genetic and clinical characteristics, and patients with such a variant IDH have a better outcome than patients with normal IDH (mutant 31 months, normal 15 months) Non-Patent
脳腫瘍、白血病、大腸がん、胃がん、甲状腺がん、悪性黒色腫などの癌において、イソクエン酸脱水素酵素をコードする遺伝子ＩＤＨ１およびＩＤＨ２の変異が見つかっている。変異型ＩＤＨ群のゲノムＤＮＡにおいてＣｐＧサイトの過剰メチル化（hypermethylation）が報告されている（非特許文献５）。ＭＧＭＴ（methyl guanine methyl transferase）プロモータ領域の過剰メチル化によって化学療法感受性増大により予後良好の機序になるとの報告がなされている（非特許文献４）。ＭＧＭＴは抗がん剤により生じるＤＮＡ障害を修復する働きがある。過剰メチル化によってＭＧＭＴの働きが弱まり、抗がん剤が有効になり、予後良好となる。 Mutations in genes IDH1 and IDH2 encoding isocitrate dehydrogenase have been found in cancers such as brain tumors, leukemias, colon cancers, stomach cancers, thyroid cancers, and malignant melanomas. Hypermethylation of CpG sites has been reported in the genomic DNA of mutant IDH groups (Non-patent Document 5). It has been reported that hypermethylation of the MGMT (methyl guanine methyl transferase) promoter region leads to a good prognosis mechanism due to increased sensitivity to chemotherapy (Non-patent Document 4). MGMT works to repair DNA damage caused by anticancer drugs. Hypermethylation weakens the function of MGMT, makes anticancer agents effective, and improves the prognosis.
変異型ＩＤＨは２−ヒドロキシグルタル酸（２ＨＧ）を産生することが知られている（非特許文献１）。産生する２ＨＧの量を測定することによってＩＤＨ変異の有無を検出することができる。２ＨＧの測定法として磁気共鳴分光法を用いた方法が知られている（非特許文献３）。ところが、２ＨＧに由来する化学シフトの位置は他の物質（グルタル酸やグルタミンなど）の化学シフトの位置と重なるので、２ＨＧは明確なピークとして表れず、ＩＤＨ変異検出の信頼性が然程高くないと言われている。 Mutant IDH is known to produce 2-hydroxyglutaric acid (2HG) (Non-patent Document 1). The presence or absence of an IDH mutation can be detected by measuring the amount of 2HG produced. As a method for measuring 2HG, a method using magnetic resonance spectroscopy is known (Non-Patent Document 3). However, since the position of chemical shift derived from 2HG overlaps with the position of chemical shift of other substances (glutaric acid, glutamine, etc.), 2HG does not appear as a clear peak, and the reliability of IDH mutation detection is not so high. It is said.
本発明の課題は、脳腫瘍、白血病、大腸がん、胃がん、甲状腺がん、悪性黒色腫などの疾患における、ＩＤＨ変異を検出するための新規なマーカおよび方法を提供することである。 An object of the present invention is to provide a novel marker and method for detecting an IDH mutation in diseases such as brain tumor, leukemia, colon cancer, stomach cancer, thyroid cancer, malignant melanoma and the like.
本発明者らは、上記課題を解決すべく鋭意研究した結果、下記の形態を包含する本発明を完成するに至った。 As a result of intensive studies to solve the above problems, the present inventors have completed the present invention including the following forms.
〔１〕 トランス−グルタコン酸、シトラコン酸、５−オキソ−テトラヒドロフラン−２−カルボン酸、トリゴネリン、ジヒドロタキステロール、４−アミノ−３−ヒドロキシ酪酸、５−アミノ吉草酸、ホモセリン、イソバレリルカルニチン、Ｎ８−アセチルスペルミジン、オクタノイルカルニチン、ケノデオキシコール酸、およびウルソデオキシコール酸からなる群より選ばれる少なくとも一つを含む
イソクエン酸脱水素酵素変異検出用マーカ。
〔２〕 イソクエン酸脱水素酵素変異が検出される疾患が、脳腫瘍、白血病、大腸がん、胃がん、甲状腺がんおよび悪性黒色腫からなる群より選ばれる少なくとも一つである、〔１〕に記載の検出用マーカ。
[1] trans-glutaconic acid, citraconic acid, 5-oxo-tetrahydrofuran-2-carboxylic acid, trigonelline, dihydrotaxosterol, 4-amino-3-hydroxybutyric acid, 5-aminovaleric acid, homoserine, isovalerylcarnitine, An isocitrate dehydrogenase mutation detection marker comprising at least one selected from the group consisting of N8-acetylspermidine, octanoylcarnitine, chenodeoxycholic acid, and ursodeoxycholic acid.
[2] The disease in which the isocitrate dehydrogenase mutation is detected is at least one selected from the group consisting of brain tumor, leukemia, colon cancer, stomach cancer, thyroid cancer, and malignant melanoma. Detection marker.
〔３〕 トランス−グルタコン酸、シトラコン酸、５−オキソ−テトラヒドロフラン−２−カルボン酸、トリゴネリン、ジヒドロタキステロール、４−アミノ−３−ヒドロキシ酪酸、５−アミノ吉草酸、ホモセリン、イソバレリルカルニチン、Ｎ８−アセチルスペルミジン、オクタノイルカルニチン、ケノデオキシコール酸、およびウルソデオキシコール酸からなる群より選ばれる少なくとも一つを測定することを含む、イソクエン酸脱水素酵素変異の検出方法。 [3] trans-glutaconic acid, citraconic acid, 5-oxo-tetrahydrofuran-2-carboxylic acid, trigonelline, dihydrotaxosterol, 4-amino-3-hydroxybutyric acid, 5-aminovaleric acid, homoserine, isovalerylcarnitine, A method for detecting an isocitrate dehydrogenase mutation, comprising measuring at least one selected from the group consisting of N8-acetylspermidine, octanoylcarnitine, chenodeoxycholic acid, and ursodeoxycholic acid.
〔４〕 イソクエン酸脱水素酵素変異が検出される疾患が、脳腫瘍、白血病、大腸がん、胃がん、甲状腺がんおよび悪性黒色腫からなる群より選ばれる少なくとも一つである、〔３〕に記載の検出方法。
〔５〕 測定を磁気共鳴法にて行う〔３〕に記載の検出方法。
〔６〕 測定を採取した血液の検査で行う〔３〕に記載の検出方法。
[4] The disease in which the isocitrate dehydrogenase mutation is detected is at least one selected from the group consisting of brain tumor, leukemia, colon cancer, stomach cancer, thyroid cancer, and malignant melanoma. Detection method.
[5] The detection method according to [3], wherein the measurement is performed by a magnetic resonance method.
[6] The detection method according to [3], wherein the measurement is performed by examining the collected blood.
本発明のＩＤＨ変異検出用マーカおよびＩＤＨ変異検出方法によれば、磁気共鳴法（ＭＲＩ、ＭＲＳなど）や血液検査などの比較的に侵襲の少ない方法を採用することができ、また、従来の２ＨＧによる検出法に代えてまたは併用することによってＩＤＨ変異検出の信頼性を高めることができる。ＩＤＨ変異を有する癌患者は予後が良好であるので、そのような患者には侵襲の大きい外科的療法の代わりに、放射線療法、免疫療法、化学療法などを行って、患者の精神的または肉体的負担を軽減することができる。 According to the IDH mutation detection marker and IDH mutation detection method of the present invention, a relatively less invasive method such as a magnetic resonance method (MRI, MRS, etc.) or a blood test can be employed. The reliability of IDH mutation detection can be improved by replacing or in combination with the detection method according to. Cancer patients with IDH mutations have a good prognosis, and such patients are treated with radiation therapy, immunotherapy, chemotherapy, etc. instead of highly invasive surgical therapy, and the patient's mental or physical The burden can be reduced.
本発明の一実施形態に係るＩＤＨ変異検出用マーカは、トランス−グルタコン酸（Trans-Glutaconic acid）、シトラコン酸（Citraconic acid）、５−オキソ−テトラヒドロフラン−２−カルボン酸（5-Oxo-2-tetrahydrofurancarboxylic acid）、トリゴネリン（Trigonelline）、ジヒドロタキステロール（Dihydrotachysterol）、４−アミノ−３−ヒドロキシ酪酸（4-Amino-3-hydroxybutyric acid）、５−アミノ吉草酸（5-Aminovaleric acid）、ホモセリン（Homoserine）、イソバレリルカルニチン（Isovalerylcarnitine）、Ｎ８−アセチルスペルミジン（N8-Acetylspermidine）、オクタノイルカルニチン（Octanoylcarnitine）、ケノデオキシコール酸（Chenodeoxycholic acid）、およびウルソデオキシコール酸（Ursodeoxycholic acid）からなる群より選ばれる少なくとも一つを含むものである。 The marker for detecting an IDH mutation according to an embodiment of the present invention includes trans-Glutaconic acid, citraconic acid, 5-oxo-tetrahydrofuran-2-carboxylic acid (5-Oxo-2-). furthercarboxylic acid), Trigonelline, Dihydrotachysterol, 4-Amino-3-hydroxybutyric acid, 5-Aminovaleric acid, Homoserine ), Isovalerylcarnitine, N8-acetylspermidine, octanoylcarnitine, chenodeoxycholic acid, and ursodeoxycholic acid Includes one.
これらの物質のうち、トランス−グルタコン酸（Trans-Glutaconic acid）、シトラコン酸（Citraconic acid）、５−オキソ−テトラヒドロフラン−２−カルボン酸（5-Oxo-2-tetrahydrofurancarboxylic acid）、トリゴネリン（Trigonelline）、およびジヒドロタキステロール（Dihydrotachysterol）は、ＩＤＨ変異によって産生量が有意に増える物質（図４）であり、
４−アミノ−３−ヒドロキシ酪酸（4-Amino-3-hydroxybutyric acid）、５−アミノ吉草酸（5-Aminovaleric acid）、ホモセリン（Homoserine）、イソバレリルカルニチン（Isovalerylcarnitine）、Ｎ８−アセチルスペルミジン（N8-Acetylspermidine）、オクタノイルカルニチン（Octanoylcarnitine）、ケノデオキシコール酸（Chenodeoxycholic acid）、およびウルソデオキシコール酸（Ursodeoxycholic acid）は、ＩＤＨ変異によって産生量が有意に減る物質（図５）である。
Among these substances, trans-Glutaconic acid, citraconic acid, 5-oxo-tetrahydrofurancarboxylic acid, trigonelline, And dihydrotachysterol is a substance (Fig. 4) whose production is significantly increased by IDH mutation,
4-Amino-3-hydroxybutyric acid, 5-aminovaleric acid, homoserine, isovalerylcarnitine, N8-acetylspermidine (N8) -Acetylspermidine, octanoylcarnitine, chenodeoxycholic acid, and ursodeoxycholic acid are substances whose production is significantly reduced by IDH mutation (FIG. 5).
これらの物質からなるマーカは、磁気共鳴法（ＭＲＳ、ＭＲＩなど）によって非侵襲にて測定することができる。また、採取した血液をＣＥ／ＭＳ（キャピラリー電気泳動−質量分析）法、およびＬＣ／ＭＳ（液体クロマトグラフ質量分析）法にて分析することによってもマーカの量を測定することができる。 Markers made of these substances can be measured non-invasively by magnetic resonance methods (MRS, MRI, etc.). The amount of the marker can also be measured by analyzing the collected blood by the CE / MS (capillary electrophoresis-mass spectrometry) method and the LC / MS (liquid chromatograph mass spectrometry) method.
このようにして測定されたマーカの量を、正常型ＩＤＨによる代謝で産生するマーカの量（基準値）と比較し、有意に増加または減少している場合にはＩＤＨが変異していると判定することができる。 The amount of the marker thus measured is compared with the amount (reference value) of the marker produced by metabolism by normal IDH, and if it is significantly increased or decreased, it is determined that IDH is mutated. can do.
まず、細胞解析実験を行い、その結果を網羅的代謝解析した。
（細胞解析実験−メタボローム解析）
正常型IDH1発現プラスミド（IDH1WT-myc-IRES-EGFP）を導入したU87膠芽腫細胞、変異型IDH1発現プラスミド（IDH1R132H-myc-IRES-EGFP）を導入したU87膠芽腫細胞、およびIDH1が空（ＧＦＰ）のプラスミド（myc-IRES-EGFP）を導入したU87膠芽腫細胞を、それぞれ４８時間培養して、ＲＮＡおよび細胞ライセートを調製した。これらから代謝産物を抽出して、ＣＥ／ＭＳ（キャピラリー電気泳動−質量分析）法およびＬＣ／ＭＳ（液体クロマトグラフ質量分析）法を用いて分析を行った。
その結果をメタボローム解析した。その結果の一例を図１に示す。図３にマーカの産生量を示す棒グラフの一例を示す。左から右に、ＧＦＰ、変異型、正常型である。
First, cell analysis experiments were performed, and the results were comprehensively analyzed for metabolism.
(Cell analysis experiment-Metabolome analysis)
U87 glioblastoma cells introduced with normal IDH1 expression plasmid (IDH1 WT -myc-IRES-EGFP), U87 glioblastoma cells introduced with mutant IDH1 expression plasmid (IDH1 R132H -myc -IRES-EGFP), and IDH1 U87 glioblastoma cells into which an empty plasmid (GFP) (myc-IRES-EGFP) was introduced were each cultured for 48 hours to prepare RNA and cell lysate. Metabolites were extracted from these and analyzed using CE / MS (capillary electrophoresis-mass spectrometry) and LC / MS (liquid chromatograph mass spectrometry) methods.
The results were metabolomically analyzed. An example of the result is shown in FIG. FIG. 3 shows an example of a bar graph showing the amount of marker produced. From left to right, GFP, mutant type, and normal type.
次に臨床組織解析実験を行い、その結果を網羅的代謝解析した。
（臨床組織解析実験−メタボローム解析）
ＷＨＯグレードII〜IVの患者から腫瘍組織を摘出し、それらを、それぞれ４８時間培養して、ＲＮＡおよび細胞ライセートを調製した。これらから代謝産物を抽出して、ＣＥ／ＭＳ（キャピラリー電気泳動−質量分析）法およびＬＣ／ＭＳ（液体クロマトグラフ質量分析）法を用いて分析を行った。
その結果をメタボローム解析した。その結果の一例を図２に示す。図４および図５にマーカの代謝産生量を示す棒グラフの一例を示す。左から右に、変異型、正常型である。
Next, clinical tissue analysis experiments were conducted, and the results were comprehensively analyzed for metabolism.
(Clinical tissue analysis experiment-Metabolome analysis)
Tumor tissues were removed from WHO grade II-IV patients and cultured for 48 hours each to prepare RNA and cell lysate. Metabolites were extracted from these and analyzed using CE / MS (capillary electrophoresis-mass spectrometry) and LC / MS (liquid chromatograph mass spectrometry) methods.
The results were metabolomically analyzed. An example of the result is shown in FIG. FIG. 4 and FIG. 5 show an example of a bar graph showing the metabolic production amount of the marker. From left to right, they are mutant and normal.
細胞解析実験からの解析結果と臨床組織解析実験からの解析結果との間で矛盾のないものを抽出した。その結果、正常型ＩＤＨに比べて変異型ＩＤＨは、トランス−グルタコン酸、シトラコン酸、５−オキソ−テトラヒドロフラン−２−カルボン酸、トリゴネリン、およびジヒドロタキステロールの産生量が有意に多くなっていた（図４）。特に、トランス−グルタコン酸およびシトラコン酸の産生量の増加は顕著であった。 The consistent results were extracted between the analysis results from the cell analysis experiment and the analysis results from the clinical tissue analysis experiment. As a result, compared to normal IDH, mutant IDH produced significantly higher amounts of trans-glutaconic acid, citraconic acid, 5-oxo-tetrahydrofuran-2-carboxylic acid, trigonelline, and dihydrotaxosterol ( FIG. 4). In particular, the increase in the production amount of trans-glutaconic acid and citraconic acid was remarkable.
正常型ＩＤＨに比べて変異型ＩＤＨは、４−アミノ−３−ヒドロキシ酪酸、５−アミノ吉草酸、ホモセリン、イソバレリルカルニチン、Ｎ８−アセチルスペルミジン、オクタノイルカルニチン、ケノデオキシコール酸、およびウルソデオキシコール酸の産生量が有意に少なくなっていた（図５）。特に、５−アミノ吉草酸、ホモセリン、およびＮ８−アセチルスペルミジンの産生量の減少が顕著であった。
なお、この解析から、従来から知られている２−ヒドロキシグルタル酸（２ＨＧ）の算出量も、正常型ＩＤＨに比べて変異型ＩＤＨは、増加していることが確かめられた。
Compared to normal IDH, mutant IDH is composed of 4-amino-3-hydroxybutyric acid, 5-aminovaleric acid, homoserine, isovalerylcarnitine, N8-acetylspermidine, octanoylcarnitine, chenodeoxycholic acid, and ursodeoxycholic acid. Was significantly reduced (FIG. 5). In particular, the decrease in the production amount of 5-aminovaleric acid, homoserine, and N8-acetylspermidine was remarkable.
In addition, from this analysis, it was confirmed that the calculated amount of 2-hydroxyglutaric acid (2HG), which is conventionally known, is increased in the mutant IDH as compared with the normal IDH.
網羅的代謝解析によって、さらに、次のようなことが明らかになった。１）解糖系の亢進、TCA回路が抑制され、lactateの上昇傾向が認められた。２）細胞増殖、分裂に必要な材料（アミノ酸、核酸、エネルギー）の低下が認められた。３）脂質代謝は亢進していた。４）酸化ストレスの傾向にあった。 An exhaustive metabolic analysis further revealed the following. 1) Increased glycolysis, TCA cycle was suppressed, and lactate increased. 2) Decreased materials (amino acids, nucleic acids, energy) necessary for cell growth and division were observed. 3) Lipid metabolism was enhanced. 4) There was a tendency of oxidative stress.
また、臨床組織解析実験に協力して頂いた患者のうち、変異型ＩＤＨを有する患者は、正常型ＩＤＨを有する患者に比べて、無増悪生存期間（PFS: Progression-Free Survival）および全生存期間（OS: Overall Survival)がいずれも長かった。結果の一部を表１に示す。 Among patients who participated in clinical tissue analysis experiments, patients with mutant IDH had progression-free survival (PFS) and overall survival compared to patients with normal IDH. (OS: Overall Survival) was long. A part of the results is shown in Table 1.
これらの結果から、本発明の一実施形態に係るマーカを測定することによって、その患者の予後が予測できる。マーカの量によって予後が良好であると考えられる患者には、外科的療法を避け、侵襲の少ない化学療法、免疫療法、放射線療法などを行うという治療方針を立てることができる。 From these results, the prognosis of the patient can be predicted by measuring the marker according to one embodiment of the present invention. For patients who are considered to have a good prognosis due to the amount of marker, it is possible to establish a treatment policy that avoids surgical therapy and performs less invasive chemotherapy, immunotherapy, radiation therapy, and the like.
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