WO2015182580A1 - Procédé de détection de métastase du cancer colorectal - Google Patents

Procédé de détection de métastase du cancer colorectal Download PDF

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WO2015182580A1
WO2015182580A1 PCT/JP2015/065029 JP2015065029W WO2015182580A1 WO 2015182580 A1 WO2015182580 A1 WO 2015182580A1 JP 2015065029 W JP2015065029 W JP 2015065029W WO 2015182580 A1 WO2015182580 A1 WO 2015182580A1
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colorectal cancer
metastasis
marker
ceacam1
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PCT/JP2015/065029
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Japanese (ja)
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毅 朝長
秀明 久米
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国立研究開発法人 医薬基盤・健康・栄養研究所
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/62—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating the ionisation of gases, e.g. aerosols; by investigating electric discharges, e.g. emission of cathode
    • G01N27/622—Ion mobility spectrometry
    • G01N27/623—Ion mobility spectrometry combined with mass spectrometry
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer

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  • the present invention relates to a method for detecting metastasis of colorectal cancer. More specifically, the present invention relates to a method for detecting colorectal cancer with metastasis by measuring the amount of a specific marker in a sample, and a kit used for the method.
  • Patent Document 1 RNA whose expression level is changed in the blood of patients with colorectal cancer is listed, and RNA derived from CD177 is disclosed as one of them.
  • Patent Document 2 reports that expression of CEACAM1 is reduced in the right and left tumors of the large intestine as a result of analyzing the expressed gene based on information such as the position of the sample derived from the large intestine tissue.
  • Non-patent document 1 reports the expression pattern of CEACAM1 gene and the progression of colorectal cancer.
  • An object of the present invention is to provide a method for detecting colon cancer metastasis simply and accurately, and a kit used in the method.
  • the present invention relates to the following [1] to [6].
  • [1] In a body fluid sample derived from a subject, the amount of at least one protein selected from the group consisting of CEACAM8, CEACAM1, CD177, and C5AR1 is measured, and the measured value is used as an index.
  • a method for detecting metastasis of colorectal cancer comprising a step of comparing the measured value and the reference value in the step, wherein the case where the measured value is recognized to be larger than the reference value is an indicator of the presence of metastasis of colorectal cancer .
  • Treatment evaluation method [4] A kit for detecting metastasis of colorectal cancer, comprising an antibody against one or more proteins selected from the group consisting of CEACAM8, CEACAM1, CD177, and C5AR1, or a fragment thereof.
  • [5] Use as a marker for colorectal cancer with metastasis of one or more proteins selected from the group consisting of CEACAM8, CEACAM1, CD177, and C5AR1.
  • Metastasis of colorectal cancer comprising detecting one or more proteins selected from the group consisting of CEACAM8, CEACAM1, CD177, and C5AR1 from a body fluid sample derived from a subject. A method of providing information on suspected colorectal cancer metastasis.
  • the presence or absence of colorectal cancer metastasis can be easily and accurately determined by the method or kit of the present invention.
  • the method or kit of the present invention makes it possible to specifically detect metastasis of colorectal cancer.
  • FIG. 1 is a diagram showing colorectal cancer marker candidates.
  • FIG. 2 shows the results of confirming the expression level of each marker in the extracted membrane vesicle fraction for each of the healthy group, the colon cancer patient group without metastasis, and the colon cancer patient group with metastasis.
  • FIG. 3 is a diagram showing the results of confirming the expression levels of markers derived from exosomes for individual specimens of a healthy group, a colon cancer patient group without metastasis, and a colon cancer patient group with metastasis. .
  • the method of the present invention is a method for detecting colorectal cancer metastasis in a subject, and may be affected by colorectal cancer with metastasis by measuring the amount of a specific marker in a body fluid sample. It is characterized by judging sex. Therefore, the present invention is also a method for providing information for detecting metastasis of colorectal cancer. Specifically, in a body fluid sample derived from a subject, a step of measuring the amount of a specific marker described later, and a measured value in the step are compared with a reference value, where the measured value in the subject is a reference value And when the subject is found to be larger than the colon cancer, the subject is judged to have colon cancer metastasized or suffering from metastasized colon cancer.
  • proteins to be measured in the present invention include CEACAM8, CEACAM1, CD177, and C5AR1.
  • CEACAM8 in the present specification refers to human-derived CEACAM8 (Carcinoembryonic antigen-related cell adhesion molecule 8) protein (GenBank accession No. P31997), which has the amino acid sequence shown in SEQ ID NO: 1. Although it is a 349-residue polypeptide, it may be a mutant or a fragment of a wild-type and / or mutant protein.
  • CEACAM1 in the present specification refers to human-derived CEACAM1 (Carcinoembryonic antigen-related cell adhesion molecule 1) protein (GenBank Accession No. P13688), which has the amino acid sequence shown in SEQ ID NO: 2. Although it is a polypeptide of 526 residues, it may be a mutant or a fragment of a wild-type and / or mutant protein.
  • CD177 refers to a human-derived CD177 protein (GenBank Accession No. Q8N6Q3), and the wild type is a 437-residue polypeptide having the amino acid sequence shown in SEQ ID NO: 3. This mutant or a fragment of a wild type and / or mutant type protein may be used.
  • C5AR1 refers to a human-derived C5AR1 protein (GenBank Accession No. P21730), which is a 350-residue polypeptide having the amino acid sequence shown in SEQ ID NO: 4 for the wild type. This mutant or a fragment of a wild type and / or mutant type protein may be used.
  • the present invention shows that there are more proteins in body fluid samples of metastatic colorectal cancer patients than in healthy individuals and colorectal cancer patients without metastasis.
  • the inventors have found the present invention for the first time and have completed the present invention (hereinafter, these four kinds of proteins may be collectively referred to as the marker of the present invention).
  • these four kinds of proteins may be collectively referred to as the marker of the present invention.
  • the marker of the present invention As described above, among CEACAM1 and CD177 among the markers of the present invention, there is a report on the relationship with colorectal cancer, but it can be detected with a sample derived from exosomes and the relationship with the presence or absence of metastasis. Until now, it has not been verified.
  • Patent Document 2 reports that the expression level of CEACAM1 decreases when suffering from colorectal cancer, and the tendency is different from the findings of the present inventors. Further, according to Non-Patent Document 1, it is reported that there is no significant difference in the expression pattern of CEACAM1 in each stage of colorectal cancer patients.
  • the method for identifying the marker of the present invention as a marker protein for colorectal cancer with metastasis will be described in detail in Examples below, but will be briefly described below.
  • a protein that produces a fluctuation signal is isolated and identified by a known proteomic technique. , Selected as a candidate protein.
  • these proteins were verified as follows. Specifically, the colon cancer patient group is divided into two groups according to the presence or absence of metastasis, and the body fluid samples of the healthy group, the colon cancer patient group without metastasis, and the colon cancer patient group with metastasis are obtained. As a result of comparison between groups of the amount of the candidate protein, the marker of the present invention was identified. In addition, the judgment of the presence or absence of metastasis in the colon cancer patient group was performed by image diagnosis.
  • colon cancer has metastasized or colon cancer metastasis means that primary cells of colon cancer migrate and reach other parts of the body to form cancer, or It means that it can be formed.
  • metalastatic colorectal cancer refers to primary colorectal cancer in which primary cells of colorectal cancer form or may have metastatic focus in other parts of the body. That's it. At this time, the degree of metastasis or the state of metastasis is not particularly limited.
  • Cold cancer without metastasis refers to colorectal cancer in which metastasis is not formed.
  • the method of the present invention specifically includes a protein amount measurement step (step A) and a colon cancer metastasis determination step (step B). Below, each process in this invention is demonstrated in detail.
  • Step A refers to a step of measuring the amount of one or more proteins selected from the group consisting of CEACAM8, CEACAM1, CD177, and C5AR1 in a body fluid sample derived from a subject.
  • body fluid sample used in the present specification, for example, blood, urine, saliva, milk, nasal discharge, cerebrospinal fluid and the like are exemplified, but blood is preferred.
  • blood can be whole blood, serum, and plasma.
  • the method for collecting and preparing the body fluid sample is not particularly limited, and can be performed according to a known method.
  • the marker of the present invention is also detected from an exosome or membrane vesicle fraction prepared from a body fluid sample, it can be used as a measurement target after preparing these. It is known that both the membrane vesicle fraction and the exosome can be obtained by aggregating a body fluid sample by ultracentrifugation or the like. In addition, since exosomes are vesicular granules and antigens that are specifically expressed (for example, CD9, CD63, CD147, EPCAM, etc.) are known, immunoprecipitation using an antibody that can specifically bind to these antigens. It is known that it can be captured (for example, International Publication No. 2013/099925).
  • the measurement of the marker of the present invention can be performed according to a known method. Specifically, for example, a mass spectrometric method and a method using an antibody capable of specifically recognizing a marker to be measured are preferable examples.
  • mass spectrometry examples include mass spectrometry using a MALDI (matrix-assisted laser desorption / ionization) mass spectrometer, an ESI (electrospray ionization) mass spectrometer, and the like. It may be a method to do. Of these, the LC-MS method using an ESI mass spectrometer is preferred.
  • MALDI matrix-assisted laser desorption / ionization
  • ESI electrospray ionization
  • Examples of methods using antibodies include Western blotting, radioimmunoassay (RIA), enzyme immunoassay (ELISA, EIA), luminescence immunoassay, and fluorescence immunoassay (exoscreen). Law).
  • the antibody used in such a method has the characteristic that the marker of the present invention can be detected or captured with good sensitivity and specificity.
  • Such an antibody can be prepared by a method well known to those skilled in the art.
  • a monoclonal antibody or a fragment thereof can be preferably used.
  • the monoclonal antibody or a fragment thereof can be used after labeling or solid-phase according to a generally known method.
  • the “monoclonal antibody fragment” means a fragment that is a part of the monoclonal antibody and has a specific binding property to the target protein in the same manner as the monoclonal antibody.
  • Specific examples include Fab, F (ab ′) 2 , Fab ′, single chain antibody (scFv), disulfide stabilized antibody (dsFv), dimerized V region fragment (Diabody), and CDR-containing peptides. be able to.
  • the marker amount can be measured.
  • the following process B is performed using the obtained measured value.
  • Step B is a step of determining (or evaluating) colon cancer metastasis in vitro based on the amount of the marker obtained in Step A.
  • the determination method when the amount of the marker of the subject is statistically significant compared to the reference value, the colorectal cancer has metastasized or is suffering from colorectal cancer with metastasis.
  • the method of determining (or evaluating) is mentioned.
  • “determining” refers to evaluating metastasis of colorectal cancer or morbidity of colorectal cancer with metastasis based on the measurement result obtained by the detection method of the present invention. It is intended not to include judgment by a physician.
  • the “reference value” can be, for example, a measurement value of the marker amount in a healthy person.
  • the amount of marker contained in a sample (positive sample) confirmed to be derived from a plurality of colorectal cancer patients with metastases and a plurality of healthy individuals (or from colorectal cancer patients without metastases) is measured and compared, and based on the result, a value that can distinguish the positive sample and the negative sample with the highest probability is obtained.
  • Healthy person means an individual who is not affected by at least colon cancer (with or without metastasis), preferably a healthy individual. Further, the healthy person needs to be the same species as the subject. For example, when the subject to be detected is a human (subject), the healthy person must also be a human (hereinafter referred to as “healthy person” in this specification).
  • the physical condition of a healthy person is preferably the same as or close to that of the subject. For example, in the case of a human, the physical condition corresponds to race, sex, age, height, weight, and the like.
  • the body fluid sample derived from a healthy person is preferably the same type of sample as the body fluid sample derived from the subject.
  • the body fluid sample derived from the healthy person is also preferably blood.
  • the amount of the marker in the body fluid sample of the healthy person is preferably measured by the same method as the method for measuring the amount of the marker in the body fluid sample of the subject described in the above step.
  • the amount of the marker in the bodily fluid sample of the healthy person can be newly measured every time the amount of the marker in the bodily fluid sample of the subject is measured, but the amount of the marker measured in advance can also be used.
  • the amount of a marker in various physical conditions of a healthy person is measured in advance and the value is input to a computer and stored in a database, the physical condition of the subject can be input to the computer, This is convenient because the amount of marker of a healthy person who has the optimal physical condition for comparison with the subject can be used immediately.
  • “Statistically significant” includes, for example, a case where the risk value (significance level) of the obtained value is less than 5%, 1%, or 0.1%. Therefore, “statistically significant” for the measured value means that there is a significant difference between the two when the quantitative difference between the markers obtained from the subject and the healthy subject is statistically processed, And it means that the amount of the marker of the subject is relatively large compared to that of the healthy subject. For example, the amount of the marker in the body fluid sample corresponds to a case where the subject is twice or more, preferably 3 times or more, more preferably 4 times or more, most preferably 5 times or more that of a healthy person. If the quantitative difference is 3 times or more, the reliability is high, and it can be said that there is a significant statistical amount.
  • the test method for statistical processing is not particularly limited as long as a known test method capable of determining the presence or absence of significance is appropriately used. For example, Student's t test or multiple comparison test can be used.
  • the subject is evaluated as having colon cancer metastasized or suffering from colon cancer with metastasis.
  • the stage of colorectal cancer that is the subject of the present invention is not particularly limited, and ranges from early stage cancer to end stage cancer.
  • the colorectal cancer metastasis detection method of the present invention includes a mode in which a marker in a body fluid sample is measured using a mass spectrometer and a mode in which an antibody is used to measure immunologically. According to the method of the present invention, it is possible not only to determine whether or not a subject suffers from colorectal cancer with metastasis, or whether or not colorectal cancer metastasis has occurred. Enables identification of healthy individuals or colorectal cancer patients with metastasis from those with no metastasis.
  • the marker amount of the healthy subject is set to the marker amount before treatment of the subject, and the marker amount after treatment is set to If the amount of marker after treatment is shown to be reduced by comparing with the amount of marker in the subject, it is judged that the treatment is likely to be effective in the treatment of metastatic colorectal cancer be able to. Therefore, the present invention also measures the marker amount of the present invention before and after receiving cancer treatment, and determines that the treatment is effective when the value after treatment is smaller than that before treatment. It is possible to provide an evaluation method characterized by The evaluation of the treatment of “colorectal cancer with metastasis” herein includes evaluating the treatment of cancer at the metastasis destination in addition to the treatment of colorectal cancer that is the primary lesion.
  • a kit for detecting colon cancer metastasis (colorectal cancer with metastasis) (hereinafter, also referred to as “colorectal cancer metastasis detection kit”) is provided.
  • Colorectal cancer metastasis detection kit is used to evaluate the presence or absence of metastatic colorectal cancer, the degree of morbidity or the improvement or degree of improvement, or the presence or absence of colorectal cancer metastasis, It is used directly or indirectly to screen candidate substances useful for the prevention, amelioration or treatment of colorectal cancer metastasis.
  • the kit of this embodiment is a marker of the present invention whose expression varies in a body fluid sample, preferably blood, serum, plasma, membrane vesicle fraction, or exosome, in relation to the onset of colorectal cancer.
  • a body fluid sample preferably blood, serum, plasma, membrane vesicle fraction, or exosome.
  • an antibody or a fragment thereof or a chemically modified derivative thereof is included.
  • These antibodies may be bound to a solid phase carrier.
  • Others include, for example, labeled secondary antibodies, as well as substrates necessary for label detection, carriers, washing buffers, sample diluents, enzyme substrates, reaction stop solutions, purified proteins as standards, instructions for use, etc. You may go out.
  • the antibody or fragment thereof that can recognize the marker of the present invention is as described above.
  • kits can be used as long as they use an antibody (for example, Western blot method, ELISA method, exoscreen method, etc.) when measuring the protein amount of the marker of the present invention in a body fluid sample.
  • an antibody for example, Western blot method, ELISA method, exoscreen method, etc.
  • the body fluid sample is an exosome
  • a protein not derived from the exosome may be simultaneously detected by the antibody.
  • kit of the present invention for example, when the amount of protein of the marker of the present invention present in the blood sample of a healthy subject and a subject is measured, and there is a significant difference between the expression levels of both, A determination and / or diagnosis of cancer metastasis can be made.
  • Example 1 Selection of biomarker candidate membrane protein using tissue
  • a membrane fraction prepared from a benign tumor of the large intestine and a colon cancer patient (including “no metastasis” and “with metastasis”) according to a conventional method is subjected to the isobaric tags for relative and absolute quantification method (hereinafter referred to as “iTRAQ (registered trademark)”).
  • iTRAQ relative and absolute quantification method
  • Proteome analysis by the “Applied Biosystems” method). Proteins were identified from the fluctuation signals seen here, and proteome analysis was performed by the Selected Reaction Monitoring method (hereinafter referred to as “SRM method”) with higher quantitative accuracy for further verification (results not shown).
  • SRM method Selected Reaction Monitoring method
  • SI peptide a stable isotope-labeled peptide identified by the proteome analysis by the iTRAQ method is mixed and used as an internal standard. The quantitative accuracy was improved.
  • Example 2 (Confirmation of candidate protein expression in membrane vesicle fraction in mixed blood) Next, a total of 3 specimens: a sample mixed with the serum of 4 healthy subjects, a sample mixed with the serum of 4 colorectal cancer patients without metastasis, and a sample mixed with the serum of 4 colorectal cancer patients with metastasis A membrane vesicle fraction was prepared for the specimen, and the expression level of the candidate protein selected in Example 1 was examined. The presence or absence of colorectal cancer metastasis was confirmed by pathological findings and laparoscopic findings.
  • the membrane vesicle fraction was prepared by the following method. Specifically, 550 ⁇ L of PBS was added to 100 ⁇ L of serum, centrifuged at 2,000 ⁇ g and 4 ° C. for 30 minutes, and then filtered using a 0.22 ⁇ m spin column. Then, after ultracentrifugation at 100,000 ⁇ g and 4 ° C. for 90 minutes, the precipitate was washed with PBS, and ultracentrifugated again at 100,000 ⁇ g and 4 ° C for 90 minutes. Further, the precipitate was washed with PBS containing 50 mM DTT, and the precipitate after ultracentrifugation at 100,000 ⁇ g and 4 ° C. for 90 minutes was obtained as a membrane vesicle fraction.
  • the obtained membrane vesicle fraction was solubilized with Phase Transfer Surfactant solution (hereinafter referred to as “PTS solution”) containing surfactants (deoxycholic acid and lauroyl sarcosine acid), digested with trypsin, and then added with ethyl acetate.
  • PTS solution Phase Transfer Surfactant solution
  • surfactants deoxycholic acid and lauroyl sarcosine acid
  • the TSQ ⁇ vantage mass spectrometer manufactured by Thermo Fisher Scientific Co., Ltd.
  • SRM method proteome analysis is performed. It was.
  • Example 3 (Confirmation of candidate protein expression in membrane vesicle fraction in blood in individual specimen)
  • the candidate proteins extracted in Example 2 were verified and further refined using individual serum samples.
  • the test used sera from 20 healthy individuals, 18 patients with stage 1 or stage 2 colorectal cancer who had no metastasis, and 19 patients with stage 4 colorectal cancer with metastasis.
  • a membrane vesicle fraction was prepared in the same manner as in Example 2, and the membrane fraction corresponding to 40 ⁇ L of serum was solubilized with a PTS solution containing a surfactant (deoxycholic acid and lauroyl sarcosine acid). After digestion with trypsin, ethyl acetate was added to remove the surfactant.
  • the SI peptide was added here, and the proteome analysis by SRM method was performed.
  • the SI peptide used here was a stable isotope-labeled peptide (purchased from Greiner) of a peptide sequence (trypsin digested fragment) specific to each protein based on amino acid sequence information.
  • candidates that did not show the same change as the result of the mixed sample in individual samples or candidates detected only in some samples were excluded. The results are shown in FIG. The significant difference test in the figure was performed according to the Mann-Whitney U test test.
  • CEACAM1, CEACAM8, CD177, and C5AR1 were significantly increased in colorectal cancer patients with metastasis compared to healthy subjects. This shows that it is possible to detect colon cancer with metastasis by measuring CEACAM1, CEACAM8, CD177, and C5AR1 present in the membrane vesicle fraction in blood. Furthermore, CEACAM1, CEACAM8, CD177, and C5AR1 show a tendency to increase in patients with metastatic colorectal cancer compared to those with no metastasis, and among them CEACAM1, CEACAM8, and CD177 There was a significant increase.
  • Example 4 (Confirmation of candidate protein expression in exosomes) CD63 was employed as an exosome marker protein, and exosomes were prepared from serum by immunoprecipitation using an anti-CD63 antibody and examined for the expression of candidate proteins. Sera from two healthy subjects, two Stage 1 or Stage 2 colorectal cancer patients with no metastasis, and two Stage 4 colorectal cancer patients with metastasis were provided for the study. As the anti-CD63 antibody, Anti CD63 for Exosome Isolation (Cosmo Bio) was used.
  • a serum membrane vesicle fraction using an antibody was prepared as follows. After adding 100 ⁇ L of PBS to 100 ⁇ L of serum, a resin having an anti-CD63 antibody covalently bonded to the magnetic beads was added and allowed to react overnight at 4 ° C. Exosomes were prepared by removing non-specific binders by washing several times with PBS.
  • the obtained exosome was solubilized with a PTS solution containing surfactants (deoxycholic acid and lauroyl sarcosine acid), digested with trypsin, and then ethyl acetate was added to remove the surfactant.
  • the CEACAM1, CEACAM8, CD177, and C5AR1 SI peptides used in Example 3 were added as internal standard peptides to the trypsin-digested sample, and then measured by the SRM method using a TSQ vantage mass spectrometer and subjected to proteomic analysis. At this time, the membrane vesicle fraction prepared by ultracentrifugation was also measured at the same time and used as a comparative control. The results are shown in FIG.
  • CD63-IP-SRM is a sample obtained by treating exosomes immunoprecipitated with an anti-CD63 antibody by the SRM method, and Centrifugation-SRM indicates each sample treated by the SRM method by ultracentrifugation.
  • CEACAM1, CEACAM8, CD177, and C5AR1 were also expressed in exosomes, and their amounts showed the same tendency as those of membrane vesicle fractions prepared by ultracentrifugation. .
  • the method of the present invention allows the sample provider to determine whether or not there is a high possibility of colorectal cancer with metastasis or whether or not colorectal cancer has metastasized. This is useful because the sample provider can take measures to prevent the progression of colorectal cancer.
  • Sequence number 1 of a sequence table is an amino acid sequence of CEACAM8 protein.
  • Sequence number 2 of a sequence table is an amino acid sequence of CEACAM1 protein.
  • Sequence number 3 of a sequence table is an amino acid sequence of CD177 protein.
  • Sequence number 4 of a sequence table is an amino acid sequence of C5AR1 protein.

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Abstract

L'invention concerne un procédé de détection de métastase de cancer colorectal, caractérisé par la mesure de la quantité d'au moins un type de protéine choisi parmi un groupe comprenant CEACAM8, CEACAM1, CD177, et C5AR1 et l'utilisation de cette valeur de mesure en tant qu'indicateur, dans un échantillon de liquide corporel obtenu d'un sujet. En résultat de ce procédé, une détermination peut être effectuée pour savoir s'il y a une probabilité élevée qu'un fournisseur d'échantillon ait un cancer colorectal métastatique ou si le cancer colorectal est métastasé. Ce procédé est utile car le fournisseur d'échantillon peut de ce fait prendre des mesures pour prévenir la progression du cancer colorectal.
PCT/JP2015/065029 2014-05-28 2015-05-26 Procédé de détection de métastase du cancer colorectal WO2015182580A1 (fr)

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EP3647788A4 (fr) * 2017-06-30 2021-07-14 National Institutes of Biomedical Innovation, Health and Nutrition Biomarqueur pour la détection du cancer colorectal
KR102596374B1 (ko) 2017-06-30 2023-10-30 고쿠리츠 켄큐 카이하츠 호진 이야쿠 키반 켄코 에이요 켄큐쇼 대장암을 검출하기 위한 바이오마커
JP2020016532A (ja) * 2018-07-25 2020-01-30 国立大学法人 熊本大学 質量分析用のペプチド試料の調製方法
JP7203407B2 (ja) 2018-07-25 2023-01-13 国立大学法人 熊本大学 質量分析用のペプチド試料の調製方法
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