WO2022075773A1 - Biomarqueur pour le diagnostic du cancer du pancréas et utilisation associée - Google Patents

Biomarqueur pour le diagnostic du cancer du pancréas et utilisation associée Download PDF

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WO2022075773A1
WO2022075773A1 PCT/KR2021/013796 KR2021013796W WO2022075773A1 WO 2022075773 A1 WO2022075773 A1 WO 2022075773A1 KR 2021013796 W KR2021013796 W KR 2021013796W WO 2022075773 A1 WO2022075773 A1 WO 2022075773A1
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pancreatic cancer
alpha
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isoform
protein
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윤승배
송미영
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가톨릭대학교 산학협력단
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    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
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    • 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
    • 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
    • G01N33/57407—Specifically defined cancers
    • G01N33/57438—Specifically defined cancers of liver, pancreas or kidney
    • 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
    • G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
    • 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
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • 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
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers

Definitions

  • the present invention relates to a biomarker for diagnosing pancreatic cancer and its use, and more particularly, to a marker composition for diagnosing pancreatic cancer, a composition for diagnosing pancreatic cancer, a diagnostic kit, and a method for providing information for diagnosing pancreatic cancer.
  • Pancreatic cancer is a malignant tumor originating from the pancreas, and it is known that the 5-year survival rate is less than 10% because most patients are found to have advanced cancer. Although the incidence of pancreatic cancer in Korea ranks eighth, cancer-related deaths account for just after lung cancer, liver cancer, stomach cancer, and colorectal cancer. Symptoms of pancreatic cancer include symptoms found in various pancreatic diseases, and abdominal pain, anorexia, weight loss, and jaundice are the most common symptoms. Jaundice occurs in most cases.
  • Korean Patent Application Laid-Open No. 2009-0003308 discloses a method for diagnosing pancreatic cancer by detecting the expression level of REG4 protein in an individual's blood sample
  • Korean Patent Publication No. 2012-0009781 provides information necessary for diagnosing pancreatic cancer in an individual
  • an analysis method for measuring the expression level of XIST RNA in cancer tissues isolated from individuals is disclosed in Korean Patent Publication No. 2007-0119250, a novel gene LBFL313 family that is differently expressed in human pancreatic cancer tissues compared to normal human pancreatic tissues.
  • US Patent Publication No. 2011/0294136 discloses a method for diagnosing pancreatic cancer using biomarkers such as keratin 8 protein.
  • biomarkers such as keratin 8 protein
  • the present inventors collected plasma from normal persons and pancreatic cancer patients in order to discover a genetic marker capable of diagnosing pancreatic cancer, and separated exosomes therefrom to analyze exosome proteins,
  • the present invention was completed based on the discovery of a gene whose expression was significantly increased only in pancreatic cancer patients compared to normal persons.
  • the present invention provides MAN1A1 (Mannosyl-oligosaccharide 1,2-alpha-mannosidase IA; NCBI accession number: NM_005907.4), ENPEP (Glutamyl aminopeptidase; NM_001977.4), CD14 (Monocyte differentiation antigen CD14; NM_000591.4) , NM_001040021.3, NM_001174104.2, NM_001174105.2), MARF1 (Meiosis regulator and mRNA stability factor 1; NM_014647.4, NM_001184998.2, NM_001184999.2) and PIGR (Polymeric immunoglobulin receptor; NM_002644.4) containing It provides a marker composition for diagnosing pancreatic cancer, comprising the mRNA of the gene or the protein encoded by the gene.
  • the present invention provides MAN1A1 (Mannosyl-oligosaccharide 1,2-alpha-mannosidase IA; NCBI accession number: NM_005907.4), ENPEP (Glutamyl aminopeptidase; NM_001977.4), CD14 (Monocyte differentiation antigen CD14; NM_000591).
  • MAN1A1 Mannosyl-oligosaccharide 1,2-alpha-mannosidase IA; NCBI accession number: NM_005907.4
  • ENPEP Glutamyl aminopeptidase; NM_001977.4
  • CD14 Monocyte differentiation antigen CD14; NM_000591.
  • NM_001040021.3 NM_001174104.2, NM_001174105.2
  • MARF1 Meiosis regulator and mRNA stability factor 1; NM_014647.4, NM_001184998.2, NM_001184999.2
  • PIGR Polymeric immunoglobulin receptor
  • MAN1A1 Mannosyl-oligosaccharide 1,2-alpha-mannosidase IA; NCBI accession number: NM_005907.4), ENPEP (Glutamyl aminopeptidase; NM_001977.4), CD14 (Monocyte Differentiation antigen CD14; NM_002644.4) provides an information providing method for diagnosing pancreatic cancer, including measuring the level of mRNA of a gene or a protein encoded from the gene.
  • the present invention provides MAN1A1 (Mannosyl-oligosaccharide 1,2-alpha-mannosidase IA; NCBI accession number: NM_005907.4), ENPEP (Glutamyl aminopeptidase; NM_001977.4), CD14 ( Monocyte differentiation antigen CD14; NM_000591.4, NM_001040021.3, NM_001174104.2, NM_001174105.2), MARF1 (Meiosis regulator and mRNA stability factor 1; NM_014647.4, NM_001184998.2, NM_001184999.2) and PIGR (Polymeric immunoglobulin receptor) ; NM_002644.4) provides a marker composition for diagnosing pancreatic cancer, including mRNA of a gene or a protein encoded by the gene.
  • MAN1A1 Mannosyl-oligosaccharide 1,2-alpha-mannosidase IA; NCBI accession number: NM_00
  • the marker composition is HIST1H2AB (Histone H2A type 1-B/E; NM_003513.3), CLCA1 (Calcium-activated chloride channel regulator 1; NM_001285.4), LACRT (Extracellular glycoprotein lacritin; NM_033277) .2), LTBP1 (Isoform 4 of Latent-transforming growth factor beta-binding protein 1; UniProtKB accession number: Q14766-4), OSTF1 (Osteoclast-stimulating factor 1; NM_012383.5), GP9 (Platelet glycoprotein IX) ; NM_000174.5), PSMA3 (Proteasome subunit alpha type-3; NM_002788.4, NM_152132.3), MME (Neprilysin; NM_000902.5, NM_007288.3, NM_007289.4, NM_007287.4, NM_001354642.2, NM_00135
  • NAP1L1 Nucleosome assembly protein 1-like 1; NM_139207.5, NM_004537.7, NM_001330231.2, NM_001307924.3, NM_001330232.2
  • AMY2A Pancreatic alpha-amylase; NM_000699.3
  • TPM1 Tropomyosin alpha -1 chain; NM_001018005.2, NM_001018007.2, NM_001018004.2, NM_001018006.2, NM_000366.6, NM_001018008.2, NM_001018020.2, NM_001301244.2, NM_001301289.2, NM_001330344.2, NM_0013303411.
  • NM_001286665.2 group consisting of NM_001286665.2, NM_001286666.2, NM_001286667.2, NM_001330517.2
  • ANPEP Aminopeptidase N; NM_001150.3
  • LAMP2 Isoform LAMP-2C of Lysosome-associated membrane glycoprotein 2; NM_001122606.1
  • It may further include mRNA of one or more genes selected from or a protein encoded by the gene.
  • the present invention provides MAN1A1 (Mannosyl-oligosaccharide 1,2-alpha-mannosidase IA; NCBI accession number: NM_005907.4), ENPEP (Glutamyl aminopeptidase; NM_001977.4), CD14 (Monocyte differentiation antigen CD14; NM_000591).
  • MAN1A1 Mannosyl-oligosaccharide 1,2-alpha-mannosidase IA; NCBI accession number: NM_005907.4
  • ENPEP Glutamyl aminopeptidase; NM_001977.4
  • CD14 Monocyte differentiation antigen CD14; NM_000591.
  • NM_001040021.3 including NM_001174104.2, NM_001174105.2
  • MARF1 Meiosis regulator and mRNA stability factor 1; NM_014647.4, NM_001184998.2, NM_001184999.2
  • PIGR Polymeric immunoglobulin receptor; NM_002644.4
  • the composition for diagnosing pancreatic cancer is HIST1H2AB (Histone H2A type 1-B/E; NM_003513.3), CLCA1 (Calcium-activated chloride channel regulator 1; NM_001285.4), LACRT (Extracellular glycoprotein lacritin; NM_033277.2), LTBP1 (Isoform 4 of Latent-transforming growth factor beta-binding protein 1; UniProtKB accession number: Q14766-4), OSTF1 (Osteoclast-stimulating factor 1; NM_012383.5), GP9 (Platelet glycoprotein) IX; NM_000174.5), PSMA3 (Proteasome subunit alpha type-3; NM_002788.4, NM_152132.3), MME (Neprilysin; NM_000902.5, NM_007288.3, NM_007289.4, NM_007287.4, NM_001354642.2, NM
  • NAP1L1 Nucleosome assembly protein 1-like 1; NM_139207.5, NM_004537.7, NM_001330231.2, NM_001307924.3, NM_001330232.2
  • AMY2A Pancreatic alpha-amylase; NM_000699.3
  • TPM1 Tropomyosin alpha -1 chain; NM_001018005.2, NM_001018007.2, NM_001018004.2, NM_001018006.2, NM_000366.6, NM_001018008.2, NM_001018020.2, NM_001301244.2, NM_001301289.2, NM_001330344.2, NM_0013303411.
  • NM_001286665.2 group consisting of NM_001286665.2, NM_001286666.2, NM_001286667.2, NM_001330517.2
  • ANPEP Aminopeptidase N; NM_001150.3
  • LAMP2 Isoform LAMP-2C of Lysosome-associated membrane glycoprotein 2; NM_001122606.1
  • It may further comprise an agent for measuring the mRNA level of one or more genes selected from or a protein encoded by the gene.
  • the composition can diagnose pancreatic cancer early.
  • MAN1A1 Mannosyl-oligosaccharide 1,2-alpha-mannosidase IA; NCBI accession number: NM_005907.4), ENPEP (Glutamyl aminopeptidase; NM_001977.4), CD14 (Monocyte Differentiation antigen CD14; NM_002644.4) provides an information providing method for diagnosing pancreatic cancer, including measuring the level of mRNA of a gene or a protein encoded from the gene.
  • the method comprises HIST1H2AB (Histone H2A type 1-B/E; NM_003513.3), CLCA1 (Calcium-activated chloride channel regulator 1; NM_001285.4), LACRT (Extracellular glycoprotein lacritin; NM_033277.
  • LTBP1 (Isoform 4 of Latent-transforming growth factor beta-binding protein 1; UniProtKB accession number: Q14766-4), OSTF1 (Osteoclast-stimulating factor 1; NM_012383.5), GP9 (Platelet glycoprotein IX; NM_000174.5), PSMA3 (Proteasome subunit alpha type-3; NM_002788.4, NM_152132.3), MME (Neprilysin; NM_000902.5, NM_007288.3, NM_007289.4, NM_007287.4, NM_001354642.2, NM_001354643.1) ), UGP2 (UTP-glucose-1-phosphate uridylyltransferase; NM_006759.4, NM_001001521.2), ANK1 (Isoform Er13 of Ankyrin-1; UniProtKB accession number: P16157-14), ACSL1 (Long-L
  • NAP1L1 Nucleosome assembly protein 1-like 1; NM_139207.5, NM_004537.7, NM_001330231.2, NM_001307924.3, NM_001330232.2
  • AMY2A Pancreatic alpha-amylase; NM_000699.3
  • TPM1 Tropomyosin alpha -1 chain; NM_001018005.2, NM_001018007.2, NM_001018004.2, NM_001018006.2, NM_000366.6, NM_001018008.2, NM_001018020.2, NM_001301244.2, NM_001301289.2, NM_001330344.2, NM_0013303411.
  • NM_001286665.2 group consisting of NM_001286665.2, NM_001286666.2, NM_001286667.2, NM_001330517.2
  • ANPEP Aminopeptidase N; NM_001150.3
  • LAMP2 Isoform LAMP-2C of Lysosome-associated membrane glycoprotein 2; NM_001122606.1
  • It may further comprise the step of measuring the mRNA level of one or more genes selected from or a protein encoded from the gene.
  • the biological sample may be exosomes derived from blood or plasma.
  • the mRNA level is determined by next generation sequencing (NGS), polymerase chain reaction (PCR), reverse transcription polymerase chain reaction (RT-PCR), real-time polymerase chain reaction ( Real-time PCR), RNase protection assay (RPA), microarray, and northern blotting (northern blotting) can be measured through one or more methods selected from the group consisting of.
  • NGS next generation sequencing
  • PCR polymerase chain reaction
  • RT-PCR reverse transcription polymerase chain reaction
  • Real-time PCR real-time polymerase chain reaction
  • RNase protection assay RNase protection assay
  • microarray and northern blotting (northern blotting) can be measured through one or more methods selected from the group consisting of.
  • the protein level is determined by western blotting, radioimmunoassay (RIA), radioimmunodiffusion, enzyme immunoassay (ELISA), immunoprecipitation. , flow cytometry, immunofluorescence, ouchterlony, complement fixation assay, and at least one method selected from the group consisting of a protein chip can be measured through
  • the present inventors analyzed the protein in exosomes isolated from plasma of normal people and pancreatic cancer patients, and discovered a gene with significantly increased expression in pancreatic cancer patients compared to normal people as biomarkers for diagnosing pancreatic cancer. It is expected to be used effectively in clinical practice.
  • 1 to 35 are analysis of the expression level of proteins in exosomes isolated from plasma of normal people and pancreatic cancer patients, and the bars shown in the figure represent the quantitative protein amounts of each sample, among which the blue bar is the average value of each group sample. and standard deviation (x-axis of all graphs is Quan Channels, left is PC or EPC, right is control, y-axis is Abundance [a.u.], 10 per division).
  • FIG. 1 shows the results of confirming the expression level of MAN1A1 (Mannosyl-oligosaccharide 1,2-alpha-mannosidase IA; NCBI accession number: NM_005907.4) in exosome proteins isolated from plasma of normal people and pancreatic cancer patients. That is, Figure 1a shows the results of normal people and pan-pancreatic cancer patients, and Figure 1b shows the results of normal people and early-pancreatic cancer patients.
  • MAN1A1 Mannosyl-oligosaccharide 1,2-alpha-mannosidase IA
  • Figure 2 shows the results of confirming the expression level of ENPEP (Glutamyl aminopeptidase; NCBI accession number: NM_001977.4) in exosome proteins isolated from plasma of normal people and pancreatic cancer patients
  • Figure 2a shows normal people
  • Figure 2b shows the results of patients with pancreatic cancer (Pan-pancreatic cancer), normal people and early-shows the results of patients with early pancreatic cancer.
  • FIG. 3 shows the results of confirming the expression level of CD14 (Monocyte differentiation antigen CD14; NM_000591.4, NM_001040021.3, NM_001174104.2, NM_001174105.2) in exosome proteins isolated from plasma of normal people and pancreatic cancer patients
  • Figure 3a shows the results of normal people and pan-pancreatic cancer (Pan-pancreatic cancer) patients
  • Figure 3b shows the results of normal people and early-pancreatic cancer (Early pancreatic cancer) patients.
  • Figure 4 shows the expression level of MARF1 (Meiosis regulator and mRNA stability factor 1; NCBI accession number: NM_014647.4, NM_001184998.2, NM_001184999.2) in exosome proteins isolated from plasma of normal people and pancreatic cancer patients. The confirmed results are shown.
  • MARF1 Meiosis regulator and mRNA stability factor 1; NCBI accession number: NM_014647.4, NM_001184998.2, NM_001184999.2
  • PIGR Polymeric immunoglobulin receptor
  • HIST1H2AB Histone H2A type 1-B/E; NM_003513.3
  • FIG. 7 shows the results of confirming the expression level of CLCA1 (Calcium-activated chloride channel regulator 1; NCBI accession number: NM_001285.4) in exosome proteins isolated from plasma of normal people and pancreatic cancer patients
  • FIG. 7a is a normal person and pan-pancreatic cancer (Pan-pancreatic cancer) patient results
  • Figure 7b is a normal person and early - shows the results of pancreatic cancer (Early pancreatic cancer) patients.
  • LACRT Extracellular glycoprotein lacritin; NCBI accession number: NM_033277.2
  • LTBP1 (Isoform 4 of Latent-transforming growth factor beta-binding protein 1; UniProtKB accession number: Q14766-4) in exosome proteins isolated from plasma of normal people and pancreatic cancer patients; is shown.
  • OSTF1 Ostoclast-stimulating factor 1; NCBI accession number: NM_012383.5
  • GP9 Platinum glycoprotein IX; NCBI accession number: NM_000174.5
  • exosome proteins isolated from plasma of normal people and pancreatic cancer patients show the results of confirming the expression level of GP9 (Platelet glycoprotein IX; NCBI accession number: NM_000174.5) in exosome proteins isolated from plasma of normal people and pancreatic cancer patients.
  • FIG. 12 shows the results of confirming the expression level of PSMA3 (Proteasome subunit alpha type-3; NCBI accession number: NM_002788.4, NM_152132.3) in exosome proteins isolated from plasma of normal people and pancreatic cancer patients.
  • Figure 12a shows the results of normal people and pan-pancreatic cancer patients
  • Figure 12b shows the results of normal people and early-pancreatic cancer patients.
  • MME (Neprilysin; NCBI accession number: NM_000902.5, NM_007288.3, NM_007289.4, NM_007287.4, NM_001354642.2, NM_001354643) proteins in exosomes isolated from plasma of normal people and pancreatic cancer patients. 1) shows the result of confirming the expression level.
  • Figure 14 shows the results of confirming the expression level of UGP2 (UTP-glucose-1-phosphate uridylyltransferase; NCBI accession number: NM_006759.4, NM_001001521.2) in the protein in the exosome isolated from the plasma of normal people and pancreatic cancer patients. it has been shown
  • ANK1 Isoform Er13 of Ankyrin-1; UniProtKB accession number: P16157-14
  • FIG. 16 shows ACSL1 (Long-chain-fatty-acid-CoA ligase 1; NCBI accession number: NM_001995.5, NM_001286708.2, NM_001381877.1, Expression of NM_001381878.1, NM_001381879.1, NM_001381880.1, NM_001381881.1, NM_001381882.1, NM_001381883.1, NM_001286710.2, NM_001381884.1, NM_001381885.1, NM_001381886.1, NM_001381887.1, NM_001286711.2) expression
  • FIG. 16a shows the results of normal people and pan-pancreatic cancer patients
  • FIG. 16b shows the results of normal people and early-pancreatic cancer patients.
  • FIG. 17 shows the results of confirming the expression level of AHSG (Alpha-2-HS-glycoprotein; NCBI accession number: NM_001622.4) in exosome proteins isolated from plasma of normal people and pancreatic cancer patients
  • FIG. 17a Figure 17b shows the results of normal people and pan-pancreatic cancer patients
  • Fig. 17b shows the results of normal people and early-pancreatic cancer patients.
  • VASP Vasodilator-stimulated phosphoprotein
  • Figure 19 shows the result of confirming the expression level of F10 (Coagulation factor X; NCBI accession number: NM_000504.4, NM_001312674.2, NM_001312675.2) in the protein in the exosome isolated from the plasma of normal people and pancreatic cancer patients will be.
  • F10 Coagulation factor X; NCBI accession number: NM_000504.4, NM_001312674.2, NM_001312675.2
  • Figure 20 shows the result of confirming the expression level of PSMB3 (Proteasome subunit beta type-3; NCBI accession number: NM_002795.4) in exosome proteins isolated from plasma of normal people and pancreatic cancer patients
  • Figure 20a is Figure 20b shows the results of normal people and pan-pancreatic cancer patients, and normal people and early-pancreatic cancer patients.
  • MMRN1 Multimerin-1; NCBI accession number: NM_007351.3
  • HABP2 Hyaluronan-binding protein 2; NCBI accession number: NM_004132.5, NM_001177660.3
  • LAMB1 Laminin subunit beta-1; NCBI accession number: NM_002291.3
  • MMP9 Microx metalloproteinase-9; NCBI accession number: NM_004994.3
  • NAP1L1 Nucleosome assembly protein 1-like 1; NCBI accession number: NM_139207.5, NM_004537.7, NM_001330231.2, NM_001307924.3, NM_001330232.2 shows the results of confirming the expression level
  • FIG. 25a shows the results of normal people and pan-pancreatic cancer patients
  • FIG. 25b shows the results of normal people and early-pancreatic cancer patients. will be.
  • Figure 26 shows the results of confirming the expression level of AMY2A (Pancreatic alpha-amylase; NCBI accession number: NM_000699.3) in exosome proteins isolated from plasma of normal people and pancreatic cancer patients.
  • Figure 26b shows the results of normal people and early-pancreatic cancer (Early pancreatic cancer) patients.
  • TPM1 Tropomyosin alpha-1 chain; NCBI accession number: NM_001018005.2, NM_001018007.2, NM_001018004.2, NM_001018006.2, NM_000366 in exosome proteins isolated from plasma of normal people and pancreatic cancer patients.
  • FIG. 27a shows the results of normal people and pan-pancreatic cancer patients.
  • FIG. 27b shows normal people and early-pancreatic cancer patients. shows the results of
  • Figure 28 shows the results of confirming the expression level of CANX (Isoform 2 of Calnexin; NCBI accession number: NM_001363994.1) in the protein in the exosomes isolated from the plasma of normal people and pancreatic cancer patients
  • Figure 28a is normal and Pan-pancreatic cancer (Pan-pancreatic cancer) patient results
  • Figure 28b shows the results of normal people and early-pancreatic cancer (Early pancreatic cancer) patients.
  • FIG. 29 shows GP2 (Pancreatic secretory granule membrane major glycoprotein GP2; NCBI accession number: NM_001007240.3, NM_001502.4, NM_001007241.3, NM_001007242.3) in exosome proteins isolated from plasma of normal people and pancreatic cancer patients. Shows the results of confirming the expression level, and FIG. 29a shows the results of normal people and pan-pancreatic cancer patients, and FIG. 29b shows the results of normal people and early-pancreatic cancer patients.
  • HLA-C HLA class I histocompatibility antigen, C alpha chain; NCBI accession number: NM_002117.6, NM_001243042.1
  • Figure 31 shows the expression level of PCCA (Propionyl-CoA carboxylase alpha chain, mitochondrial; NCBI accession number: NM_000282.4, NM_001127692.3, NM_001178004.2) in exosome proteins isolated from plasma of normal people and pancreatic cancer patients. shows the results of checking .
  • PCCA Propionyl-CoA carboxylase alpha chain, mitochondrial; NCBI accession number: NM_000282.4, NM_001127692.3, NM_001178004.2
  • Figure 32 shows the results of confirming the expression level of CHDR2 (Cadherin-related family member 2; NCBI accession number: NM_001171976.2, NM_017675.5) in the protein in the exosome isolated from the plasma of normal people and pancreatic cancer patients .
  • Figure 33 shows POSTN (Periostin; NCBI accession) number: NM_006475.3, NM_001135934.2, NM_001135935.2, NM_001135936.2, NM_001286665.2, NM_001286666 in exosome proteins isolated from plasma of normal persons and pancreatic cancer patients. 2, NM_001286667.2, NM_001330517.2) shows the results of checking the expression level.
  • ANPEP Aminopeptidase N; NCBI accession number: NM_001150.3
  • LAMP2 immunoglobulin-2C of Lysosome-associated membrane glycoprotein 2; NCBI accession number: NM_001122606.1
  • the present inventors collected plasma from normal persons and pancreatic cancer patients, separated exosomes from them, and analyzed the exosome proteins. As a result, compared to normal persons, expression was significantly expressed only in pancreatic cancer patients. The present invention was completed based on the discovery of this increasing gene.
  • the present invention provides MAN1A1 (Mannosyl-oligosaccharide 1,2-alpha-mannosidase IA; NCBI accession number: NM_005907.4), ENPEP (Glutamyl aminopeptidase; NM_001977.4), CD14 (Monocyte differentiation antigen CD14; NM_000591).
  • MAN1A1 Mannosyl-oligosaccharide 1,2-alpha-mannosidase IA; NCBI accession number: NM_005907.4
  • ENPEP Glutamyl aminopeptidase; NM_001977.4
  • CD14 Monocyte differentiation antigen CD14; NM_000591.
  • NM_001040021.3 NM_001174104.2, NM_001174105.2
  • MARF1 Meiosis regulator and mRNA stability factor 1; NM_014647.4, NM_001184998.2, NM_001184999.2
  • PIGR Polymeric immunoglobulin receptor
  • the marker composition is HIST1H2AB (Histone H2A type 1-B/E; NM_003513.3), CLCA1 (Calcium-activated chloride channel regulator 1; NM_001285.4), LACRT (Extracellular glycoprotein lacritin; NM_033277.2) , LTBP1 (Isoform 4 of Latent-transforming growth factor beta-binding protein 1; UniProtKB accession number: Q14766-4), OSTF1 (Osteoclast-stimulating factor 1; NM_012383.5), GP9 (Platelet glycoprotein IX; NM_000174.
  • HIST1H2AB Histone H2A type 1-B/E; NM_003513.3
  • CLCA1 Calcium-activated chloride channel regulator 1; NM_001285.4
  • LACRT Extracellular glycoprotein lacritin; NM_033277.2
  • LTBP1 Isoform 4 of Latent-transforming growth factor beta-binding protein 1; Uni
  • PSMA3 Proteasome subunit alpha type-3; NM_002788.4, NM_152132.3
  • MME Neprilysin; NM_000902.5, NM_007288.3, NM_007289.4, NM_007287.4, NM_001354642.2, NM_001354643.1
  • UGP2 UGP2
  • UGP2 UGP2
  • UGP2 UGP2
  • UGP2 UGP2
  • UGP2 UGP2
  • UGP2 UGP2
  • UGP2 UGP2
  • ANK1 Isoform Er13 of Ankyrin-1; UniProtKB accession number: P16157-14
  • ACSL1 Long-chain-fatty-acid -CoA ligase 1;NM_001995.5, NM_001286708.2, NM_001381877.1, NM_001381878.1, NM_001381879.1, NM_001381880.1, NM_001381881.1, NM_00
  • NAP1L1 Nucleosome assembly protein 1-like 1; NM_139207.5, NM_004537.7, NM_001330231.2, NM_001307924.3, NM_001330232.2
  • AMY2A Pancreatic alpha-amylase; NM_000699.3
  • TPM1 Tropomyosin alpha -1 chain; NM_001018005.2, NM_001018007.2, NM_001018004.2, NM_001018006.2, NM_000366.6, NM_001018008.2, NM_001018020.2, NM_001301244.2, NM_001301289.2, NM_001330344.2, NM_0013303411.
  • NM_001286665.2 group consisting of NM_001286665.2, NM_001286666.2, NM_001286667.2, NM_001330517.2
  • ANPEP Aminopeptidase N; NM_001150.3
  • LAMP2 Isoform LAMP-2C of Lysosome-associated membrane glycoprotein 2; NM_001122606.1
  • It may further include mRNA of one or more genes selected from or a protein encoded by the gene.
  • pancreatic cancer refers to an aggressive characteristic in which pancreatic cells divide and grow ignoring normal growth limits, an invasive characteristic that penetrates into surrounding tissues, and a metastatic (metastatic) characteristic that spreads to other parts of the body.
  • Metastatic refers to diseases caused by cells with characteristics.
  • Diagnosis in a broad sense means judging the actual condition of a patient's disease in all aspects. The content of the judgment is the name of the disease, etiology, type, severity, detailed mode of the disease, and the presence or absence of complications. Diagnosis in the present invention is to determine whether or not cancer is onset and the level of progression.
  • the present inventors identified the use of a specific gene according to the present invention as a novel marker for diagnosing pancreatic cancer through specific examples.
  • AHSG, VASP, F10, PSMB3, MMRN1, HABP2, LAMB1, MMP9, NAP1L1, AMY2A, TPM1, CANX, GP2, HLA-C, PCCA, CDHR2, POSTN, ANPEP and LAMP2 was significantly increased.
  • the present invention provides MAN1A1 (Mannosyl-oligosaccharide 1,2-alpha-mannosidase IA; NCBI accession number: NM_005907.4), ENPEP (Glutamyl aminopeptidase; NM_001977.4), CD14 (Monocyte differentiation) antigen CD14; NM_000591.4, NM_001040021.3, NM_001174104.2, NM_001174105.2), MARF1 (Meiosis regulator and mRNA stability factor 1; NM_014647.4, NM_001184998.2, NM_001184999.2) and PIGR (Polymeric immunoglobulin receptor; NM_002644) .4) provides a composition for diagnosing pancreatic cancer and a kit for diagnosing pancreatic cancer comprising the composition, comprising an agent for measuring the level of mRNA or protein encoded by the gene comprising the gene.
  • MAN1A1 Mannosyl-oligosaccharide 1,2-
  • the composition for diagnosing pancreatic cancer is HIST1H2AB (Histone H2A type 1-B/E; NM_003513.3), CLCA1 (Calcium-activated chloride channel regulator 1; NM_001285.4), LACRT (Extracellular glycoprotein lacritin; NM_033277.2) ), LTBP1 (Isoform 4 of Latent-transforming growth factor beta-binding protein 1; UniProtKB accession number: Q14766-4), OSTF1 (Osteoclast-stimulating factor 1; NM_012383.5), GP9 (Platelet glycoprotein IX; NM_000174) .5), PSMA3 (Proteasome subunit alpha type-3; NM_002788.4, NM_152132.3), MME (Neprilysin; NM_000902.5, NM_007288.3, NM_007289.4, NM_007287.4, NM_001354642.2, NM
  • NAP1L1 Nucleosome assembly protein 1-like 1; NM_139207.5, NM_004537.7, NM_001330231.2, NM_001307924.3, NM_001330232.2
  • AMY2A Pancreatic alpha-amylase; NM_000699.3
  • TPM1 Tropomyosin alpha -1 chain; NM_001018005.2, NM_001018007.2, NM_001018004.2, NM_001018006.2, NM_000366.6, NM_001018008.2, NM_001018020.2, NM_001301244.2, NM_001301289.2, NM_001330344.2, NM_0013303411.
  • NM_001286665.2 group consisting of NM_001286665.2, NM_001286666.2, NM_001286667.2, NM_001330517.2
  • ANPEP Aminopeptidase N; NM_001150.3
  • LAMP2 Isoform LAMP-2C of Lysosome-associated membrane glycoprotein 2; NM_001122606.1
  • It may further comprise an agent for measuring the mRNA level of one or more genes selected from or a protein encoded by the gene.
  • the composition can diagnose pancreatic cancer early.
  • the kit for prediction of the present invention consists of one or more other component compositions, solutions or devices suitable for the analysis method.
  • the kit of the present invention contains genomic DNA derived from a sample to be analyzed, a primer set specific for the marker gene of the present invention, an appropriate amount of a DNA polymerase, a dNTP mixture, a PCR buffer, and water to perform PCR. It may be a kit comprising
  • the PCR buffer solution may contain KCl, Tris-HCl and MgCl 2 .
  • components necessary for performing electrophoresis that can confirm whether or not the PCR product is amplified may be additionally included in the kit of the present invention.
  • the kit of the present invention may be a kit including essential elements necessary for performing RT-PCR.
  • the RT-PCR kit includes a test tube or other suitable container, reaction buffer, deoxynucleotides (dNTPs), enzymes such as Taq-polymerase and reverse transcriptase, DNase, RNase inhibitors, DEPC -Water (DEPC-water), sterile water, etc. may be included.
  • dNTPs deoxynucleotides
  • enzymes such as Taq-polymerase and reverse transcriptase
  • DNase DNase
  • RNase inhibitors DEPC -Water
  • sterile water etc.
  • a primer pair specific for a gene used as a quantitative control may be included.
  • the kit of the present invention may be a kit including essential elements necessary for performing a DNA chip.
  • the DNA chip kit may include a substrate to which cDNA corresponding to a gene or fragment thereof is attached as a probe, and the substrate may include cDNA corresponding to a quantitative structural gene or fragment thereof.
  • the kit of the present invention may be in the form of a microarray having a substrate on which the marker gene of the present invention is immobilized.
  • the kit of the present invention may be a kit characterized in that it includes essential elements necessary for performing ELISA.
  • the ELISA kit includes an antibody specific for a marker protein, and an agent for measuring the protein level.
  • the ELISA kit may include a reagent capable of detecting an antibody that has formed an "antigen-antibody complex", for example, a labeled secondary antibody, chromopores, an enzyme, and a substrate thereof.
  • an antibody specific for the quantitative control protein may be included.
  • MAN1A1 Mannosyl-oligosaccharide 1,2-alpha-mannosidase IA; NCBI accession number: NM_005907.4
  • ENPEP Glutamyl aminopeptidase; NM_001977.
  • CD14 Monocyte differentiation antigen CD14; NM_000591.4, NM_001040021.3, NM_001174104.2, NM_001174105.2
  • MARF1 Meiosis regulator and mRNA stability factor 1; NM_014647.4, NM_001184998.2, NM_001184999.2
  • PIGR Polymeric immunoglobulin receptor; NM_002644.4
  • the method is HIST1H2AB (Histone H2A type 1-B/E; NM_003513.3), CLCA1 (Calcium-activated chloride channel regulator 1; NM_001285.4), LACRT (Extracellular glycoprotein lacritin; NM_033277.2), LTBP1 (Isoform 4 of Latent-transforming growth factor beta-binding protein 1; UniProtKB accession number: Q14766-4), OSTF1 (Osteoclast-stimulating factor 1; NM_012383.5), GP9 (Platelet glycoprotein IX; NM_000174.5) ), PSMA3 (Proteasome subunit alpha type-3; NM_002788.4, NM_152132.3), MME (Neprilysin; NM_000902.5, NM_007288.3, NM_007289.4, NM_007287.4, NM_001354642.2, NM_001354643.1), UGP
  • NAP1L1 Nucleosome assembly protein 1-like 1; NM_139207.5, NM_004537.7, NM_001330231.2, NM_001307924.3, NM_001330232.2
  • AMY2A Pancreatic alpha-amylase; NM_000699.3
  • TPM1 Tropomyosin alpha -1 chain; NM_001018005.2, NM_001018007.2, NM_001018004.2, NM_001018006.2, NM_000366.6, NM_001018008.2, NM_001018020.2, NM_001301244.2, NM_001301289.2, NM_001330344.2, NM_0013303411.
  • NM_001286665.2 group consisting of NM_001286665.2, NM_001286666.2, NM_001286667.2, NM_001330517.2
  • ANPEP Aminopeptidase N; NM_001150.3
  • LAMP2 Isoform LAMP-2C of Lysosome-associated membrane glycoprotein 2; NM_001122606.1
  • It may further comprise the step of measuring the mRNA level of one or more genes selected from or a protein encoded from the gene.
  • the term “information providing method for diagnosing pancreatic cancer” used in the present invention provides objective basic information necessary for diagnosing pancreatic cancer as a preliminary step for diagnosis, and the clinical judgment or opinion of a doctor is excluded.
  • the subject-derived biological sample may include tissues, cells, whole blood, blood, saliva, sputum, cerebrospinal fluid and urine, preferably blood or plasma, and more preferably plasma-derived exosomes.
  • the present invention is not limited thereto.
  • the mRNA level is determined by next generation sequencing (NGS), polymerase chain reaction (PCR), reverse transcription polymerase chain reaction (RT-PCR), real-time polymerase chain reaction (Real-time PCR), RNase protection assay (RNase protection assay; RPA), microarray (microarray), and may be measured through one or more methods selected from the group consisting of northern blotting (northern blotting), but is not limited thereto.
  • NGS next generation sequencing
  • PCR polymerase chain reaction
  • RT-PCR reverse transcription polymerase chain reaction
  • Real-time PCR real-time polymerase chain reaction
  • RPA RNase protection assay
  • microarray microarray
  • the protein level was determined by western blotting, radioimmunoassay (RIA), radioimmunodiffusion, enzyme immunoassay (ELISA), immunoprecipitation, flow cytometry, and immunity. It may be measured by at least one method selected from the group consisting of immunofluorescence, ouchterlony, complement fixation assay, and protein chip, but is limited thereto it's not going to be
  • Plasma samples from normal and pancreatic cancer patients are collected in BD Vacutainer Plastic K2EDTA Tube (BD, Cat.no 367525), and plasma is separated by centrifugation within 2 hours at 2,500 rpm and 4°C for 20 minutes. The supernatant plasma was aliquoted into Protein LoBind Tubes (Eppendorf, Cat.no 0030108116) by 500 ⁇ l and stored at -80°C.
  • Plasma samples were centrifuged at 3,000 g and 4 °C for 15 minutes to remove cells and cell debris in the plasma. Then, 250 ⁇ l of Exo2D TM for Protein assay (EXOSOMEplus) was added to 500 ⁇ l of plasma sample at a 2:1 ratio to separate exosomes based on the Aqueous Two-Phase System, and then, HaltTM Protease and Phosphatase Inhibitor Cocktail, EDTA-Free ( The exosome samples were prepared by resuspending the exosomes in 200 ⁇ l of PBS with the addition of Thermo scientific). Samples were stored at -80 °C until analysis.
  • EXOSOMEplus Exo2D TM for Protein assay
  • exosome protein 20 ⁇ g was mixed with SDS loading buffer and then electrophoresed using 10% Sodium Dodecyl Sulfate Polyacrylamide Gel Eletrophoresis (SDS-PAGE) technique to separate proteins according to molecular weight size. After immersing the electrophoresed gel in InstantBlue (Coomassie blue stanning) reagent and staining at room temperature for 15 minutes, protein detection and distribution were first checked.
  • InstantBlue Concentrassie blue stanning
  • 80 ⁇ l of 50 mM TEAB buffer was added and centrifuged at 1,000 g for 60 seconds.
  • 80 ⁇ l of 0.2% FA was added and centrifuged at 1,000 g for 60 seconds.
  • 80 ⁇ l of elution buffer (50% ACN, 0.2% FA) was added, centrifuged at 4,000 g for 60 seconds, and the eluted sample was freeze-dried.
  • Protein peptide samples prepared through the digestion process were analyzed for proteomic bodies using Q Exactive Plus LC-MS/MS System mass spectrometer (Thermo Scientific). Each sample was measured in duplicate, and the data generated by the instrument was analyzed using Proteome Discoverer TM 2.2 (Thermo Scientific) software for database search, comprehensive protein and peptide identification, characterization and quantitative analysis and statistical analysis. was carried out.

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Abstract

La présente invention concerne un biomarqueur pour le diagnostic du cancer du pancréas et une utilisation associée et, plus particulièrement, une composition de marqueur pour diagnostiquer un cancer du pancréas, une composition et un kit de diagnostic pour diagnostiquer un cancer du pancréas, et un procédé pour fournir des informations pour diagnostiquer un cancer du pancréas. Suite à l'analyse d'une protéine dans des exosomes isolés à partir du plasma d'individus normaux et de patients atteints d'un cancer du pancréas, les inventeurs de la présente invention ont découvert des gènes dont l'expression augmentait significativement chez des patients atteints d'un cancer du pancréas par comparaison avec des individus normaux. Ainsi, les gènes devraient pouvoir être utilisés efficacement dans la pratique clinique en tant que biomarqueurs utiles dans le diagnostic du cancer du pancréas.
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JP5863074B2 (ja) * 2012-05-18 2016-02-16 日東紡績株式会社 膵臓癌を検出するためのマーカー
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