WO2020262429A1 - Cancer biomarker and method for judging onset of cancer - Google Patents

Cancer biomarker and method for judging onset of cancer Download PDF

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WO2020262429A1
WO2020262429A1 PCT/JP2020/024733 JP2020024733W WO2020262429A1 WO 2020262429 A1 WO2020262429 A1 WO 2020262429A1 JP 2020024733 W JP2020024733 W JP 2020024733W WO 2020262429 A1 WO2020262429 A1 WO 2020262429A1
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cancer
ovarian
malignant
lap
tumors
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松本 邦夫
将夫 加藤
友佑 増尾
榮彦 水谷
清住 柴田
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医療法人三栄会
学校法人藤田学園
国立大学法人金沢大学
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  • the biomarker of the present invention can be measured by a known method.
  • an enzymatic method such as the L-leucine-p-nitroanilide method can be preferably used.
  • L-leucine-p-nitroanilide method p-nitro occurs when P-LAP in a sample acts on L-leucine-p-nitroanilide (substrate) to produce L-leucine and p-nitroanilide.
  • the LAP activity value is determined by measuring the rate of increase in absorbance with the formation of anilide.
  • a commercially available leucine aminopeptidase measurement kit can be used.
  • Whether or not a subject has ovarian cancer is determined, for example, with respect to the P-LAP value measured by the L-leucine-p-nitroanilide method, the P-LAP value of the malignant tumor group and the non-malignant tumor group.
  • a determination method in which a cutoff value is set based on the P-LAP value of the above and whether or not the cutoff value is exceeded is used as a determination criterion.
  • the cutoff value may be set in the range of 10 to 30 mU / mL, in the range of 10 to 20 mU / mL, or in the range of 10 to 15 mU / mL.

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Abstract

Provided is a cancer biomarker that comprises placental leucine aminopeptidase in urine. Also provided is a method for judging the onset of ovarian cancer, said method comprising a step for measuring the amount of placental leucine aminopeptidase or the activity of placental leucine aminopeptidase in the urine of a subject.

Description

がんのバイオマーカーおよびがんの発症を判定する方法Cancer biomarkers and methods for determining the onset of cancer
 本発明は、がんのバイオマーカーおよびがんの発症を判定する方法に関するものである。 The present invention relates to a biomarker of cancer and a method for determining the onset of cancer.
 卵巣腫瘍では、超音波検査、必要によりMRI検査を行い、これらの画像診断により卵巣腫瘍であるかそれ以外の腫瘍であるかを区別し、腫瘍の内部構造を詳しく調べて良性か悪性かを推定する。良性または悪性の推定には、画像診断と共に腫瘍マーカー検査が用いられ、腫瘍マーカーの値が非常に高い場合は悪性の可能性が高いとされている。しかし、腫瘍マーカーは良性の内膜症性嚢胞(チョコレート嚢胞)などでも上昇することが知られている。また、卵巣がんの初期には腫瘍マーカーが上昇しないことも多く、卵巣がんの早期発見には不向きとされている。研究の進展と技術の進歩に伴い、卵巣腫瘍の臨床的経過、画像診断および腫瘍マーカーの評価によって、卵巣腫瘍が良性か悪性かその中間型(境界悪性)かについて、相当程度のことがわかるようになってきた。しかし、今でも卵巣がんの確定診断は、手術で卵巣腫瘍を摘出して病理組織検査を行うことにより行われている。 For ovarian tumors, ultrasonography and, if necessary, MRI examinations are performed, and these diagnostic imagings are used to distinguish between ovarian tumors and other tumors, and the internal structure of the tumor is examined in detail to estimate whether it is benign or malignant. To do. Tumor marker tests are used along with diagnostic imaging to estimate benign or malignant, and if the value of the tumor marker is very high, the possibility of malignancy is high. However, tumor markers are also known to be elevated in benign endometriotic cysts (chocolate cysts) and the like. In addition, tumor markers often do not rise in the early stages of ovarian cancer, making them unsuitable for early detection of ovarian cancer. With the progress of research and technology, the clinical course of ovarian tumors, diagnostic imaging and evaluation of tumor markers will show a considerable degree of benign or malignant or intermediate (borderline malignant) ovarian tumors. Has become. However, the definitive diagnosis of ovarian cancer is still made by surgically removing the ovarian tumor and performing a histopathological examination.
 このように、卵巣がんは、手術をしなければ良性か悪性かの判別が難しいがん種の1つである。他臓器のがんの場合、手術前に腫瘍の一部を採取する生検により病理組織検査を行い、悪性(がん)か否かを確定することが多いが、卵巣腫瘍では針を刺すとがん細胞が腹腔内に拡がる危険性があるため、手術前の生検は行われていない。したがって、卵巣腫瘍が良性か、境界悪性か、悪性かを手術前に高感度および高特異度で診断できるバイオマーカーが必要とされている。 In this way, ovarian cancer is one of the cancer types for which it is difficult to distinguish between benign and malignant cancer without surgery. In the case of cancer of other organs, a biopsy that takes a part of the tumor before surgery is often performed to determine whether it is malignant (cancer), but in the case of ovarian tumor, a needle stick is used. Preoperative biopsy has not been done because of the risk of cancer cells spreading into the abdomen. Therefore, there is a need for biomarkers that can diagnose benign, borderline malignant, or malignant ovarian tumors with high sensitivity and specificity prior to surgery.
 ロイシンアミノペプチダーゼ(LAP)は、ペプチドのアミノ末端からロイシンを切り出す活性を有する酵素であり、3種のアイソザイム(細胞質LAP、膜結合性LAP、胎盤性LAP)が知られている。悪性腫瘍において血中LAPが上昇するとの報告があり、また、胎盤性LAP(P-LAP)が腎細胞がんで上昇するとの報告がある。さらに、卵巣組織のP-LAPを、抗体を用いて検出することにより、卵巣がんの発症および予後を評価できることが報告されている(特許文献1)。 Leucine aminopeptidase (LAP) is an enzyme having an activity of excising leucine from the amino terminus of a peptide, and three types of isozymes (cytoplasmic LAP, membrane-binding LAP, and placental LAP) are known. It has been reported that blood LAP is elevated in malignant tumors, and placental LAP (P-LAP) is reported to be elevated in renal cell carcinoma. Furthermore, it has been reported that the onset and prognosis of ovarian cancer can be evaluated by detecting P-LAP of ovarian tissue using an antibody (Patent Document 1).
特表2007-509313Special table 2007-509313
 本発明は、非侵襲的に採取可能な尿中に含まれ、がんの発症および再発を早期に判定可能なバイオマーカーを提供することを課題とする。特に、悪性の卵巣腫瘍と非悪性(良性および境界悪性)の卵巣腫瘍を判別可能な卵巣がんのバイオマーカーを提供すること、および、卵巣がんの発症および再発を早期に判定可能な卵巣がん発症の判定方法を提供することを課題とする。 An object of the present invention is to provide a biomarker contained in urine that can be collected non-invasively and capable of determining the onset and recurrence of cancer at an early stage. In particular, providing biomarkers for ovarian cancer that can distinguish between malignant ovarian tumors and non-malignant (benign and borderline malignant) ovarian tumors, and ovarian cancer that can determine the onset and recurrence of ovarian cancer at an early stage. An object of the present invention is to provide a method for determining the onset of cancer.
 本発明は、上記の課題を解決するために、以下の各発明を包含する。
[1]尿中の胎盤性ロイシンアミノペプチダーゼからなるがんのバイオマーカー。
[2]がんが、卵巣がん、子宮体がん、腎臓がん、前立腺がん、胃がん、膵臓がん、食道がん、絨毛がん、または乳がんである前記[1]に記載のバイオマーカー。
[3]がんが卵巣がんである前記[1]に記載のバイオマーカー。
[4]卵巣がんの発症を判定する方法であって、被験体の尿中の胎盤性ロイシンアミノペプチダーゼ量または胎盤性ロイシンアミノペプチダーゼ活性を測定する工程を含む方法。
[5]被験体が、画像診断において悪性または非悪性の判定が困難な卵巣腫瘍を有する個体である前記[4]に記載の方法。
[6]卵巣がんの発症が、切除手術後の再発である前記[4]に記載の方法。
[7]胎盤性ロイシンアミノペプチダーゼ活性を測定する工程において、被験体の尿をメチオニン存在下でL-ロイシン-p-ニトロアニリドと反応させ、生成したp-ニトロアニリド量を測定する方法を用いる前記[4]~[6]のいずれかに記載の方法。
The present invention includes the following inventions in order to solve the above problems.
[1] A biomarker for cancer consisting of placental leucine aminopeptidase in urine.
[2] The biotechnology according to the above [1], wherein the cancer is ovarian cancer, endometrial cancer, kidney cancer, prostate cancer, stomach cancer, pancreatic cancer, esophageal cancer, choriocarcinoma, or breast cancer. marker.
[3] The biomarker according to the above [1], wherein the cancer is ovarian cancer.
[4] A method for determining the onset of ovarian cancer, which comprises a step of measuring the amount of placental leucine aminopeptidase or the activity of placental leucine aminopeptidase in the urine of a subject.
[5] The method according to the above [4], wherein the subject is an individual having an ovarian tumor whose malignant or non-malignant determination is difficult in diagnostic imaging.
[6] The method according to the above [4], wherein the onset of ovarian cancer is recurrence after excision surgery.
[7] In the step of measuring the placental leucine aminopeptidase activity, the method of reacting the subject's urine with L-leucine-p-nitroanilide in the presence of methionine and measuring the amount of p-nitroanilide produced is used. The method according to any one of [4] to [6].
 本発明により、非侵襲的に採取可能な尿中に含まれるがんのバイオマーカーを提供することができる。本発明のバイオマーカーは、従来の腫瘍マーカーより鋭敏であり、変化が顕著であるため、悪性腫瘍と非悪性腫瘍を判別することができる。本発明のバイオマーカーは、悪性腫瘍と非悪性腫瘍の判別が困難である卵巣がんのバイオマーカーとして非常に有用である。また、本発明のバイオマーカーを用いることにより、卵巣がんの発症および再発を早期に判定可能な卵巣がん発症の判定方法を提供することができる。 INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide a biomarker for cancer contained in urine that can be collected non-invasively. Since the biomarker of the present invention is more sensitive than conventional tumor markers and changes significantly, it is possible to distinguish between malignant tumors and non-malignant tumors. The biomarker of the present invention is very useful as a biomarker for ovarian cancer in which it is difficult to distinguish between a malignant tumor and a non-malignant tumor. In addition, by using the biomarker of the present invention, it is possible to provide a method for determining the onset of ovarian cancer, which can determine the onset and recurrence of ovarian cancer at an early stage.
卵巣腫瘍患者(25例)の尿中P-LAPを測定し、術後病理診断との相関を検討した結果を示す図である。It is a figure which shows the result of having measured the urinary P-LAP of the ovarian tumor patient (25 cases), and examined the correlation with the postoperative pathological diagnosis. 卵巣がん患者の手術前、手術後、再発時の尿中p-LPA、血清CA125および血清CA19-9を測定した結果を示す図である。It is a figure which shows the result of having measured the urinary p-LPA, the serum CA125 and the serum CA19-9 at the time of recurrence before the operation and after the operation of the ovarian cancer patient.
〔バイオマーカー〕
 本発明はがんのバイオマーカーを提供する。本発明のがんのバイオマーカー(以下、「本発明のバイオマーカー」と記す)は、尿中の胎盤性ロイシンアミノペプチダーゼ(以下、「P-LAP」と記す)からなるバイオマーカーである。特許文献1には、卵巣がん患者から分離されたがん組織中のP-LAP量を測定することにより、がんの予後を評価できることが記載されている。しかしP-LAPは蛋白質であり、腎機能が正常であれば尿蛋白は陰性であるため、当業者は尿中のP-LAPを卵巣がんのバイオマーカーとして使用する動機を持ち得ない。さらに、本発明者らは、尿中P-LAPが血清P-LAPより、卵巣がんに対して鋭敏であり、卵巣がんの有無による変化が顕著であることを確認している(実施例参照)。すなわち、尿中のP-LAPを卵巣がんのバイオマーカーに用いることは当業者が容易になし得ることではなく、血清P-LAPより尿中P-LAPがバイオマーカーとして優れているという効果は、容易に予測できない格別顕著な効果である。
[Biomarker]
The present invention provides biomarkers for cancer. The cancer biomarker of the present invention (hereinafter referred to as "biomarker of the present invention") is a biomarker composed of placental leucine aminopeptidase (hereinafter referred to as "P-LAP") in urine. Patent Document 1 describes that the prognosis of cancer can be evaluated by measuring the amount of P-LAP in a cancer tissue isolated from an ovarian cancer patient. However, since P-LAP is a protein and urinary protein is negative if renal function is normal, those skilled in the art cannot have an incentive to use P-LAP in urine as a biomarker for ovarian cancer. Furthermore, the present inventors have confirmed that urinary P-LAP is more sensitive to ovarian cancer than serum P-LAP, and that the change depending on the presence or absence of ovarian cancer is remarkable (Example). reference). That is, it is not easy for a person skilled in the art to use urinary P-LAP as a biomarker for ovarian cancer, and the effect that urinary P-LAP is superior to serum P-LAP as a biomarker is effective. This is a particularly remarkable effect that cannot be easily predicted.
 P-LAPは、以下のがんにおいてもがん組織中に発現していることが報告されている。したがって、尿中P-LAPはこれらのがんのバイオマーカーとしても有用であると考えられる。
・子宮体がん(Shibata K et al. P-LAP/IRAP-induced cell proliferation and glucose uptake in endometrial carcinoma cells via insulin receptor signaling, BMC Cancer 2007, Jan 19; 7:1)
・腎臓がん(Kuriyama M et al. Clinical evaluation of serum placental leucine aminopeptidase (P-LAP) activity in renal cell carcinoma, Nihon Hinyokika Gakkai Zasshi 1987 Jul; 78(7):1220-6.)
・前立腺がん(Lerman B et al. Oxytocin and cancer: An emaerging link. World Journal of Clinical Oncology. 2018 Sep 14; 9(5):74-82.)
・胃がん(Lerman B et al. Oxytocin and cancer: An emaerging link. World Journal of Clinical Oncology. 2018 Sep 14; 9(5):74-82.)
・膵臓がん(Lerman B et al. Oxytocin and cancer: An emaerging link. World Journal of Clinical Oncology. 2018 Sep 14; 9(5):74-82. 、Nagasaka T et al, Immunohistochemical localization of placental leucine aminopeptidase/oxytocinase in normal human placental, fetal and adult tissues, Reproduction Fertility and Development 1997; 9(8):747-53.)
・食道がん(Lerman B et al. Oxytocin and cancer: An emaerging link. World Journal of Clinical Oncology. 2018 Sep 14; 9(5):74-82. 、Nagasaka T et al, Immunohistochemical localization of placental leucine aminopeptidase/oxytocinase in normal human placental, fetal and adult tissues, Reproduction Fertility and Development 1997; 9(8):747-53.)
・絨毛がん(Nagasaka T et al, Immunohistochemical localization of placental leucine aminopeptidase/oxytocinase in normal human placental, fetal and adult tissues, Reproduction Fertility and Development 1997; 9(8):747-53. 、Ino K et al. Expression of placental leucine aminopeptidase and adipocyte-derived leucine aminopeptidase in human normal and malignant invasive trophoblastic cells. Lab Invest. 2003 Dec;83(12):1799-809.)
・乳がん(Jose manuel Martinez-Martos et al. Kidney aminopeptidase activities are related to renal damage in experimental breast cancer, Journal of Clinical and Molecular Medicine. 2018 Doi: 10.15761/JCMM.1000105)
It has been reported that P-LAP is also expressed in cancer tissues in the following cancers. Therefore, urinary P-LAP is considered to be useful as a biomarker for these cancers.
・ Endometrial cancer (Shibata K et al. P-LAP / IRAP-induced cell proliferation and glucose uptake in endometrial carcinoma cells via insulin receptor signaling, BMC Cancer 2007, Jan 19; 7: 1)
・ Kidney cancer (Kuriyama M et al. Clinical evaluation of serum placental leucine aminopeptidase (P-LAP) activity in renal cell carcinoma, Nihon Hinyokika Gakkai Zasshi 1987 Jul; 78 (7): 1220-6.)
・ Prostate cancer (Lerman B et al. Oxytocin and cancer: An emaerging link. World Journal of Clinical Oncology. 2018 Sep 14; 9 (5): 74-82.)
・ Gastric cancer (Lerman B et al. Oxytocin and cancer: An emaerging link. World Journal of Clinical Oncology. 2018 Sep 14; 9 (5): 74-82.)
・ Pancreatic cancer (Lerman B et al. Oxytocin and cancer: An emaerging link. World Journal of Clinical Oncology. 2018 Sep 14; 9 (5): 74-82., Nagasaka T et al, Immunohistochemical localization of placental leucine aminopeptidase / oxytocinase in normal human placental, fetal and adult tissues, Reproduction Fertility and Development 1997; 9 (8): 747-53.)
・ Esophageal cancer (Lerman B et al. Oxytocin and cancer: An emaerging link. World Journal of Clinical Oncology. 2018 Sep 14; 9 (5): 74-82., Nagasaka T et al, Immunohistochemical localization of placental leucine aminopeptidase / oxytocinase in normal human placental, fetal and adult tissues, Reproduction Fertility and Development 1997; 9 (8): 747-53.)
・ Villous cancer (Nagasaka T et al, Immunohistochemical localization of placental leucine aminopeptidase / oxytocinase in normal human placental, fetal and adult tissues, Reproduction Fertility and Development 1997; 9 (8): 747-53., Ino K et al. Expression of placental leucine aminopeptidase and adipocyte-derived leucine aminopeptidase in human normal and malignant invasive trophoblastic cells. Lab Invest. 2003 Dec; 83 (12): 1799-809.)
・ Breast cancer (Jose manuel Martinez-Martos et al. Kidney aminopeptidase activities are related to renal damage in experimental breast cancer, Journal of Clinical and Molecular Medicine. 2018 Doi: 10.15761 / JCMM.1000105)
 本発明のバイオマーカー、すなわち尿中P-LAPは公知の方法により測定することができる。例えば、L-ロイシン-p-ニトロアニリド法などの酵素法を好適に用いることができる。L-ロイシン-p-ニトロアニリド法は、試料中のP-LAPがL-ロイシン-p-ニトロアニリド(基質)に作用してL-ロイシンとp-ニトロアニリドを生成する際に、p-ニトロアニリドの生成に伴う吸光度の増加速度を測定することで、LAP活性値を求めるものである。L-ロイシン-p-ニトロアニリド法により尿中P-LAPを測定する場合、市販のロイシンアミノペプチダーゼ測定キットを使用することができる。 The biomarker of the present invention, that is, urinary P-LAP can be measured by a known method. For example, an enzymatic method such as the L-leucine-p-nitroanilide method can be preferably used. In the L-leucine-p-nitroanilide method, p-nitro occurs when P-LAP in a sample acts on L-leucine-p-nitroanilide (substrate) to produce L-leucine and p-nitroanilide. The LAP activity value is determined by measuring the rate of increase in absorbance with the formation of anilide. When measuring urinary P-LAP by the L-leucine-p-nitroanilide method, a commercially available leucine aminopeptidase measurement kit can be used.
 酵素法により尿中P-LAPを測定する場合、メチオニンの存在下で基質と試料を反応させてもよい。メチオニンの存在により、P-LAP以外のLAP(例えば、細胞質由来のLPA、ミクロソーム由来のLAPなど)の活性を阻害でき、P-LAPに基づく活性を測定することができるからである。メチオニン濃度は特に限定されないが、例えば、1mM~50mMであってもよく、5mM~40mMであってもよく、10mM~30mMであってもよく、15mM~25mMであってもよい。 When measuring urinary P-LAP by the enzymatic method, the substrate and the sample may be reacted in the presence of methionine. This is because the presence of methionine can inhibit the activity of LAPs other than P-LAP (for example, LPA derived from cytoplasm, LAP derived from microsomes, etc.), and the activity based on P-LAP can be measured. The methionine concentration is not particularly limited, but may be, for example, 1 mM to 50 mM, 5 mM to 40 mM, 10 mM to 30 mM, or 15 mM to 25 mM.
 尿中P-LAPの測定法には、ELISA法などのイムノアッセイ法を好適に用いることができる。イムノアッセイ法では、試料と抗P-LAP抗体とを接触させ、試料中のP-LAPと抗P-LAP抗体との複合体を検出することで、尿中P-LAP量を測定することができる。 An immunoassay method such as an ELISA method can be preferably used as a method for measuring P-LAP in urine. In the immunoassay method, the amount of P-LAP in urine can be measured by contacting the sample with the anti-P-LAP antibody and detecting the complex of P-LAP and the anti-P-LAP antibody in the sample. ..
〔卵巣がん発症の判定方法〕
 本発明は、卵巣がん発症の判定方法または卵巣がん発症の判定を補助する方法を提供する。本発明の方法は、医師による卵巣がんの診断を補助することができる。卵巣腫瘍は良性腫瘍、境界悪性腫瘍(良性と悪性の中間的な性質を持つ)および悪性腫瘍(卵巣がん)に分類されるが、悪性腫瘍(卵巣がん)と非悪性腫瘍を、病理組織検査を行わずに判別することは非常に困難である。本発明の方法は、悪性腫瘍(卵巣がん)と非悪性腫瘍を、高い特異度で判別することができるので、非常に有用である。また、本発明の方法は、卵巣がんの発症を早期に判定できるだけでなく、卵巣がんの切除手術後の再発を早期に判定できる点で非常に有用である。
[Method of determining the onset of ovarian cancer]
The present invention provides a method for determining the onset of ovarian cancer or a method for assisting the determination of the onset of ovarian cancer. The method of the present invention can assist a physician in diagnosing ovarian cancer. Ovarian tumors are classified into benign tumors, borderline malignant tumors (having properties intermediate between benign and malignant) and malignant tumors (ovarian cancer). It is very difficult to distinguish without inspection. The method of the present invention is very useful because it can discriminate between malignant tumors (ovarian cancer) and non-malignant tumors with high specificity. In addition, the method of the present invention is very useful in that not only the onset of ovarian cancer can be determined at an early stage, but also the recurrence of ovarian cancer after resection surgery can be determined at an early stage.
 「卵巣腫瘍取扱い規約」(2016年)によれば、卵巣腫瘍は、I.上皮性腫瘍、II.性索間質性腫瘍、III.胚細胞腫瘍、IV.その他の腫瘍に分類され、各々に良性腫瘍、境界悪性腫瘍および悪性腫瘍が含まれる。上皮性腫瘍の良性腫瘍としては、漿液性嚢胞腺腫、粘液性嚢胞腺腫、類内膜腺腫、明細胞腺腫、腺線維腫、表在性乳頭腫、ブレンナー腫瘍、子宮内膜症性嚢胞などが挙げられる。上皮性腫瘍の境界悪性腫瘍としては、漿液性境界悪性腫瘍、粘液性境界悪性腫瘍、類内膜境界悪性腫瘍、明細胞境界悪性腫瘍、境界悪性ブレンナー腫瘍などが挙げられる。上皮性腫瘍の悪性腫瘍としては、低異型度漿液性癌、高異型度漿液性癌、粘液性癌、類内膜癌、明細胞癌、悪性ブレンナー腫瘍、漿液粘液性癌、未分化癌、微小乳頭状パターンを伴う漿液性境界悪性腫瘍などが挙げられる。性索間質性腫瘍の良性腫瘍としては、莢膜細胞腫、セルトリ・間質性腫瘍(高分化型)、硬化性間質性腫瘍、線維腫、ライディク細胞腫、輪状細管を伴う性索腫瘍などが挙げられる。性索間質性腫瘍の境界悪性腫瘍としては、若年型顆粒膜細胞腫、セルトリ・間質細胞腫瘍(中分化型)などが挙げられる。性索間質性腫瘍の悪性腫瘍としては、線維肉腫、セルトリ・間質細胞腫(低分化型)、悪性ステロイド細胞腫瘍、成人型顆粒膜細胞腫などが挙げられる。胚細胞腫瘍の良性腫瘍としては、成熟奇形腫、良性卵巣甲状腺腫瘍、脂腺腺腫などが挙げられる。胚細胞腫瘍の悪性腫瘍としては、悪性転化を伴う成熟奇形腫、卵黄嚢腫瘍、多胎芽腫、胎芽性癌、未分化胚細胞腫、絨毛癌、悪性卵巣甲状腺腫瘍、未熟奇形腫(G1~G3)、カルチノイド腫瘍などが挙げられる。その他の腫瘍の良性腫瘍としては、卵巣網腺腫などが挙げられる。その他の腫瘍の境界悪性腫瘍としては、性腺芽腫(純粋型)などが挙げられる。その他の腫瘍の悪性腫瘍としては、小細胞癌、悪性リンパ腫、二次性(転移性)腫瘍などが挙げられる。 According to the "Ovarian Tumor Handling Regulations" (2016), ovarian tumors are classified as I. Epithelial tumor, II. Sexual cord stromal tumor, III. Embryo cell tumor, IV. It is classified into other tumors, each of which includes benign tumors, borderline malignancies and malignant tumors. Benign tumors of epithelial tumors include serous cystadenoma, mucinous cystadenoma, endometrioid adenoma, clear cell adenoma, adenoma, superficial papilloma, Brenner tumor, endometriotic cyst, etc. Be done. Borderline malignancies of epithelial tumors include serous borderline malignancies, mucinous borderline malignancies, intimal borderline malignancies, clear cell borderline malignancies, borderline malignant Brenner tumors and the like. Malignant tumors of epithelial tumors include low-grade serous cancer, high-grade serous cancer, mucinous cancer, endometrioid cancer, clear cell cancer, malignant Brenner tumor, serous mucinous cancer, undifferentiated cancer, and microscopic Examples include serous borderline malignancies with papillary patterns. Benign tumors of sex cord interstitial tumors include thecoma cell tumor, Sertri / interstitial tumor (well-differentiated type), sclerosing interstitial tumor, fibroma, Rydik cell tumor, and sex cord tumor with cricoid tubules. And so on. Borderline malignancies of sex cord stromal tumors include juvenile granulosa cell tumors and sertoly / stromal cell tumors (moderately differentiated). Examples of malignant tumors of sex cord stromal tumors include fibrosarcoma, Sertri / stromal cell tumor (poorly differentiated type), malignant steroid cell tumor, and adult granulosa cell tumor. Benign tumors of embryonic cell tumors include mature teratomas, benign ovarian thyroid tumors, and sebaceous adenomas. Malignant tumors of germ cell tumors include mature teratomas with malignant transformation, oval sac tumors, multiple germinoma, embryonic cancer, undifferentiated germinoma, choriocarcinoma, malignant ovarian thyroid tumor, and immature teratoma (G1 to G3). ), Cartinoid tumors and the like. Benign tumors of other tumors include ovarian reticular adenomas. Borderline malignancies of other tumors include gonadal blastoma (pure type). Examples of malignant tumors of other tumors include small cell carcinoma, malignant lymphoma, and secondary (metastatic) tumors.
 本発明の方法は、被験体の尿中のP-LAP量またはP-LAP活性を測定する工程を含むものであればよい。被験体は卵巣がんを発症しうる哺乳動物であれば限定されず、ヒト、サル、チンパンジー、イヌ、ネコ、ウシ、ウマ、ブタ、ウサギ、マウス、ラット等が挙げられる。好ましくはヒトである。被験体は、卵巣腫瘍の存在が疑われる個体であってもよく、卵巣腫瘍を有する個体であってもよく、画像診断において悪性または非悪性の判定が困難な卵巣腫瘍を有する個体であってもよい。 The method of the present invention may include a step of measuring the amount of P-LAP or P-LAP activity in the urine of a subject. The subject is not limited as long as it is a mammal capable of developing ovarian cancer, and examples thereof include humans, monkeys, chimpanzees, dogs, cats, cows, horses, pigs, rabbits, mice, and rats. It is preferably human. The subject may be an individual suspected of having an ovarian tumor, an individual having an ovarian tumor, or an individual having an ovarian tumor whose malignant or non-malignant determination is difficult to determine by diagnostic imaging. Good.
 本発明の方法において、尿中のP-LAP量またはP-LAP活性を測定する方法としては、L-ロイシン-p-ニトロアニリド法などの酵素法、ELISA法などのイムノアッセイ法を好適に用いることができる。 In the method of the present invention, as a method for measuring the amount of P-LAP or P-LAP activity in urine, an enzyme method such as the L-leucine-p-nitroanilide method and an immunoassay method such as the ELISA method are preferably used. Can be done.
 被験体が卵巣がんを発症しているか否かの判定は、例えば、L-ロイシン-p-ニトロアニリド法で測定したP-LAP値について、悪性腫瘍群のP-LAP値と非悪性腫瘍群のP-LAP値に基づいてカットオフ値を設定し、当該カットオフ値を超えたかどうかを判定基準とする判定方法などが挙げられる。カットオフ値は10~30mU/mLの範囲に設定してもよく、10~20mU/mLの範囲に設定してもよく、10~15mU/mLの範囲に設定してもよい。 Whether or not a subject has ovarian cancer is determined, for example, with respect to the P-LAP value measured by the L-leucine-p-nitroanilide method, the P-LAP value of the malignant tumor group and the non-malignant tumor group. A determination method in which a cutoff value is set based on the P-LAP value of the above and whether or not the cutoff value is exceeded is used as a determination criterion. The cutoff value may be set in the range of 10 to 30 mU / mL, in the range of 10 to 20 mU / mL, or in the range of 10 to 15 mU / mL.
 なお、卵巣がん以外の様々ながん組織においてもP-LAPの発現は認められる。したがって、本発明の方法は、卵巣がん以外のがんにも適用できる。具体的には、例えば、子宮体がん、腎臓がん、前立腺がん、胃がん、膵臓がん、食道がん、絨毛がん、乳がんなどである。 The expression of P-LAP is also observed in various cancer tissues other than ovarian cancer. Therefore, the method of the present invention can be applied to cancers other than ovarian cancer. Specifically, for example, uterine body cancer, kidney cancer, prostate cancer, stomach cancer, pancreatic cancer, esophageal cancer, choriocarcinoma, breast cancer and the like.
 以下、実施例により本発明を詳細に説明するが、本発明はこれらに限定されるものではない。 Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited thereto.
〔実施例1:卵巣腫瘍患者の尿中P-LAP測定〕
1-1 材料および方法
(1)試料
 画像診断などで良性、悪性の診断が困難な卵巣腫瘍患者(25例)の同意を得て尿を採取し、試料とした。
(2)尿中P-LAP測定方法
 ロイシンアミノペプチダーゼ測定用キット(株式会社セロテック)を使用した。具体的には、第一試薬160μLおよび第二試薬40μLをチューブに加え、L-メチオニンを終濃度20mMになるように添加し、尿を4μL加え、37℃で5分間インキュベートした。分光光度計を用いて405nmの吸光度を測定した。
(3)病理診断
 上記25例の卵巣腫瘍患者については、その後手術を行い、卵巣腫瘍を摘出して病理組織検査によって、良性、悪性の診断を行った。
[Example 1: Measurement of P-LAP in urine of a patient with ovarian tumor]
1-1 Materials and methods (1) Samples Urine was collected with the consent of ovarian tumor patients (25 patients) whose benign or malignant diagnosis was difficult by diagnostic imaging, and used as samples.
(2) Urinary P-LAP measurement method A leucine aminopeptidase measurement kit (Cerotech Co., Ltd.) was used. Specifically, 160 μL of the first reagent and 40 μL of the second reagent were added to the tube, L-methionine was added to a final concentration of 20 mM, 4 μL of urine was added, and the mixture was incubated at 37 ° C. for 5 minutes. The absorbance at 405 nm was measured using a spectrophotometer.
(3) Pathological diagnosis The above 25 patients with ovarian tumor were subsequently operated on, and the ovarian tumor was removed and histopathological examination was performed to make a benign or malignant diagnosis.
(4)結果
 結果を図1および表1に示した。25例中10例が悪性、15例が良性~境界悪性(非悪性)であった。悪性腫瘍患者の尿中P-LAP(平均値:43.4mU/mL)は、非悪性腫瘍患者の尿中P-LAP(平均値:6.8mU/mL)より顕著に高値であった。カットオフ値を15mU/mLに設定すれば、感度90%、特異度100%であった。なお、良性~境界悪性15例の内訳は、チョコレート嚢腫7例、成熟奇形腫2例、粘液性嚢胞腺腫2例、線維腫1例、粘液性境界悪性腫瘍2例、漿液性境界悪性腫瘍1例であった。悪性腫瘍10例の内訳は、明細胞がん4例、内膜がん2例、粘液性がん1例、漿液性がん2例、未分化がん1例であった。
(4) Results The results are shown in Fig. 1 and Table 1. Of the 25 cases, 10 were malignant and 15 were benign to borderline malignant (non-malignant). The urinary P-LAP (mean value: 43.4 mU / mL) of malignant tumor patients was significantly higher than that of urinary P-LAP (mean value: 6.8 mU / mL) of non-malignant tumor patients. When the cutoff value was set to 15 mU / mL, the sensitivity was 90% and the specificity was 100%. The breakdown of 15 cases of benign to borderline malignancy is chocolate cyst 7 cases, mature teratoma 2 cases, mucinous cystadenoma 2 cases, fibroma 1 case, mucinous borderline malignant tumor 2 cases, serous borderline malignant tumor 1 case. Met. The breakdown of 10 malignant tumors was clear cell cancer in 4, intimal cancer in 2, mucinous cancer in 1, serous cancer in 2, and undifferentiated cancer in 1.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
(5)血清P-LAP測定
 上記25例中5例(良性2例、悪性3例)については、血清中のP-LAPを測定した。測定方法は上記(2)と同じである。結果を表2に示した。悪性腫瘍患者と良性腫瘍患者の血清P-LAP値に差は認められなかった。
(5) Serum P-LAP measurement In 5 of the above 25 cases (benign 2 cases, malignant 3 cases), serum P-LAP was measured. The measuring method is the same as (2) above. The results are shown in Table 2. There was no difference in serum P-LAP levels between malignant tumor patients and benign tumor patients.
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
〔実施例2:卵巣がん患者の手術前、手術後、再発時の尿中P-LPAの推移〕
 卵巣がん患者の手術前、手術後、再発時の尿中p-LPAを測定した。同時に、腫瘍マーカーである血清CA125および血清CA19-9を測定した。この患者は、手術は2018年5月9日に手術を行い、同年5月22日に手術後の測定を行い翌23日に退院した。その後、同年5月31日に再発が確認された。
[Example 2: Transition of urinary P-LPA before, after, and at the time of recurrence of ovarian cancer patients]
Urinary p-LPA was measured before, after, and at the time of recurrence of ovarian cancer patients. At the same time, tumor markers serum CA125 and serum CA19-9 were measured. This patient underwent surgery on May 9, 2018, measured after surgery on May 22, 2018, and was discharged on the following day. After that, recurrence was confirmed on May 31, the same year.
 結果を図2に示した。尿中P-LPAは、手術前が163mU/mL、手術後が8mU/mL、再発時が152mU/mLであった。従来の腫瘍マーカーであるCA125およびCA19-9も手術後に濃度が下がり、再発時には濃度の上昇が認められたが、手術後の低下率および再発時の上昇率は尿中P-LPAのほうが顕著であった。つまり、尿中P-LPAのほうが従来の腫瘍マーカーより、鋭敏にがん細胞の存在を反映できることが示された。この結果から、尿中P-LPAは、手術で切除した卵巣がんの再発を判定するためのマーカーとして有用であることが明らかになった。 The results are shown in Fig. 2. Urinary P-LPA was 163 mU / mL before the operation, 8 mU / mL after the operation, and 152 mU / mL at the time of recurrence. Conventional tumor markers CA125 and CA19-9 also decreased in concentration after surgery and increased in concentration at the time of recurrence, but the rate of decrease after surgery and the rate of increase at the time of recurrence were more remarkable in urinary P-LPA. there were. In other words, it was shown that urinary P-LPA can more sensitively reflect the presence of cancer cells than conventional tumor markers. From this result, it was clarified that urinary P-LPA is useful as a marker for determining the recurrence of surgically resected ovarian cancer.
 なお本発明は上述した各実施形態および実施例に限定されるものではなく、請求項に示した範囲で種々の変更が可能であり、異なる実施形態にそれぞれ開示された技術的手段を適宜組み合わせて得られる実施形態についても本発明の技術的範囲に含まれる。また、本明細書中に記載された学術文献および特許文献の全てが、本明細書中において参考として援用される。 The present invention is not limited to the above-described embodiments and examples, and various modifications can be made within the scope of the claims, and the technical means disclosed in the different embodiments may be appropriately combined. The obtained embodiments are also included in the technical scope of the present invention. In addition, all the academic and patent documents described in the present specification are incorporated herein by reference.

Claims (7)

  1.  尿中の胎盤性ロイシンアミノペプチダーゼからなるがんのバイオマーカー。 A cancer biomarker consisting of placental leucine aminopeptidase in urine.
  2.  がんが、卵巣がん、子宮体がん、腎臓がん、前立腺がん、胃がん、膵臓がん、食道がん、絨毛がん、または乳がんである請求項1に記載のバイオマーカー。 The biomarker according to claim 1, wherein the cancer is ovarian cancer, endometrial cancer, kidney cancer, prostate cancer, stomach cancer, pancreatic cancer, esophageal cancer, choriocarcinoma, or breast cancer.
  3.  がんが卵巣がんである請求項1に記載のバイオマーカー。 The biomarker according to claim 1, wherein the cancer is ovarian cancer.
  4.  卵巣がんの発症を判定する方法であって、被験体の尿中の胎盤性ロイシンアミノペプチダーゼ量または胎盤性ロイシンアミノペプチダーゼ活性を測定する工程を含む方法。 A method for determining the onset of ovarian cancer, which includes a step of measuring the amount of placental leucine aminopeptidase or the activity of placental leucine aminopeptidase in the urine of a subject.
  5.  被験体が、画像診断において悪性または非悪性の判定が困難な卵巣腫瘍を有する個体である請求項4に記載の方法。 The method according to claim 4, wherein the subject is an individual having an ovarian tumor whose malignant or non-malignant determination is difficult in diagnostic imaging.
  6.  卵巣がんの発症が、切除手術後の再発である請求項4に記載の方法。 The method according to claim 4, wherein the onset of ovarian cancer is recurrence after excision surgery.
  7.  胎盤性ロイシンアミノペプチダーゼ活性を測定する工程において、被験体の尿をメチオニン存在下でL-ロイシン-p-ニトロアニリドと反応させ、生成したp-ニトロアニリド量を測定する方法を用いる請求項4~6のいずれかに記載の方法。 In the step of measuring the placental leucine aminopeptidase activity, a method of reacting a subject's urine with L-leucine-p-nitroanilide in the presence of methionine and measuring the amount of p-nitroanilide produced is used. The method according to any one of 6.
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