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WO2004011945A2 - Marqueurs moleculaires de carcinome cholangiocellulaire - Google Patents

Marqueurs moleculaires de carcinome cholangiocellulaire Download PDF

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Publication number
WO2004011945A2
WO2004011945A2 PCT/EP2003/008243 EP0308243W WO2004011945A2 WO 2004011945 A2 WO2004011945 A2 WO 2004011945A2 EP 0308243 W EP0308243 W EP 0308243W WO 2004011945 A2 WO2004011945 A2 WO 2004011945A2
Authority
WO
WIPO (PCT)
Prior art keywords
sequence
ccc
iii
genes
nucleic acid
Prior art date
Application number
PCT/EP2003/008243
Other languages
German (de)
English (en)
Other versions
WO2004011945A3 (fr
Inventor
Sabine Debuschewitz
Jürgen Jobst
Stephan Kaiser
Original Assignee
Sabine Debuschewitz
Jobst Juergen
Stephan Kaiser
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from PCT/EP2002/008305 external-priority patent/WO2003010336A2/fr
Application filed by Sabine Debuschewitz, Jobst Juergen, Stephan Kaiser filed Critical Sabine Debuschewitz
Priority to EP03771105A priority Critical patent/EP1525477A2/fr
Priority to AU2003253329A priority patent/AU2003253329A1/en
Publication of WO2004011945A2 publication Critical patent/WO2004011945A2/fr
Publication of WO2004011945A3 publication Critical patent/WO2004011945A3/fr

Links

Classifications

    • 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
    • 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
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • 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
    • 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
    • C12Q2600/112—Disease subtyping, staging or classification
    • 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
    • C12Q2600/136—Screening for pharmacological compounds

Definitions

  • the present invention relates to molecular markers that occur in cholangiolar carcinoma (CCC).
  • CCC cholangiolar carcinoma
  • the invention further relates to a CCC-specific cluster as a unique diagnostic agent for CCC.
  • the invention further relates to the discrimination of CCC and HCC (liver cell carcinoma).
  • Cholangiocellular carcinoma is a carcinoma that originates from the cells of the bile ducts, the cholangiocytes.
  • the CCC is therefore a carcinoma of the bile ducts, mostly an adenocarcinoma and thus localized in the liver and in the laxative bile ducts.
  • HCC liver cell carcinoma
  • hepatocytes, bile duct cells are the cellular origin of the CCC.
  • nucleic acid which (i) is shown in Table I, in Table II, in Table III or in Table IV, (ii) a sequence from (i) in the context of the degeneration of the genetic code (iii) has a partial sequence of a sequence from (i) or / and (ii) with a length of at least 25, preferably at least 50 and more preferably at least 100 nucleotides, (iv) with a sequence from (i), (ii ) or / and (iii) hybridizes under stringent conditions or / and (v) has a sequence complementary to a sequence from (i), (ii), (iii) or / and (iv), or one encoded by such a nucleic acid Polypeptide as a target for cholangiolar carcinoma (CCC).
  • CCC cholangiolar carcinoma
  • a stringent hybridization according to the present invention is preferably present if, after washing for 1 hour with 1 ⁇ SSC and 0.1% SDS at 50 ° C., preferably at 55 ° C., more preferably at 62 ° C. and most preferably at 68 ° C and more preferably for 1 hour with 0.2 x SSC and 0.1% SDS at 50 ° C, preferably at 55 ° C, more preferably a positive hybridization signal is observed at 62 ° C and most preferably at 68 ° C.
  • the genes identified in the context of the present invention represent effective targets and, in particular, suitable markers for CCC.
  • the genes in Table IA and / or the genes in Table IIA are particularly preferably used, in which an increase or decrease in expression in 100% of the investigated Patient has been identified. For many applications, however, it is already sufficient to use at least one gene from Table IIIA, ie genes in which increased expression has been found in at least 80% of the patients examined.
  • genes are preferably used which, compared to non-cancerous or normal liver cells, by a factor of are at least 1, 5 down or up regulated, more preferably by a factor of at least 2, even more preferably by a factor of at least 3 and most preferably by a factor of at least 4.
  • the genes found according to the invention are preferably combined into groups which are specific for CCC and allow a clear differentiation from CCC to other cells, including other pathologically changed cells.
  • the genes shown in Tables I, II, III and IV are preferably used for the detection or / and for the diagnosis and / or for the prognosis of CCC.
  • the identified groups of genes can also be used to identify clear identifying features for the discrimination against different (liver) tumors.
  • a CCC - specific pattern for the diagnosis of CCC positive tissue samples compared to other tissue samples of the liver was identified by cluster analysis.
  • At least 20, in particular at least 40 genes are used with which particularly good differentiation can be achieved, namely the genes in Table IA, in particular genes Nos. 1 to 14 in Table IA and the genes in Table IIA in particular genes Nos. 1 to 34 in Table NA.
  • at least 10 are preferably upregulated and at least 10 downregulated genes were used, whereby a cluster analysis enables a 100% differentiation between tumor liver tissue and non-malignant liver tissue.
  • all genes listed in Tables I, II and III are used. With these 143 differentially expressed genes, a clear assignment (tumor to non-tumor) is possible due to the expression homogeneity of the CCC.
  • genes listed in Tables IB and NB are used and in a further preferred embodiment the genes listed in Tables IA and IIA, i.e. all genes up or down regulated in 100% of cases.
  • nucleic acids provided as targets according to the invention or their amount, for example the amount expressed in a cell can be determined by means of suitable assays and thus used for the diagnosis of CCC.
  • probes are preferably provided or formed which bind to the nucleic acids shown in the tables.
  • sequences complementary to the specified genes or complementary sequence sections can be used.
  • clusters to discriminate between different tumors of the liver for example benign-malignant or malignant-malignant (liver carcinoma or metastases of colon cancer-CCC) or clusters to differentiate between different stages of individual tumors, the genes from Tables I to IV being used in each case where a particularly clear or particularly consistent change can be observed.
  • These differentiations are often difficult or impossible to achieve today using the methods currently available.
  • cholangiocellular carcinoma which originates from the cells of the bile ducts, the cholangiocytes, there is also HCC in the liver, which originates from the "real" liver cells, the hepatocytes, as a carcinoma.
  • HCC cholangiocellular carcinoma
  • a diagnostic agent which uses at least one, in particular at least 5, more preferably at least 10 and up to all of the genes shown in Tables IB, IIB, IIIB and IV which are specific for CCC as a target , It is preferred to use at least 1, more preferably at least 5 and even more preferably at least 10 of the genes shown in Tables IB, IIB and / or IIIB, in particular the genes shown in Tables IB and / or IIB. Most preferably, a differentiation is made between CCC and HCC with all 42 genes shown in Tables IB, IIB and IIIB. The genes shown in Tables IB, IIB, IIIB and IV can also be used to distinguish the CCC from normal tissue or non-malignant tissue.
  • the presence of a consistent pattern of genetic changes in the CCC offers the possibility of examining various stages, causes or / and subgroups of the CCC with regard to specific genetic patterns. For example, an indication of the probability of developing a malignant tumor from previously damaged tissue can be given here (prognosis). Such a pattern also offers the possibility of clearly differentiating in the histological differentiation between tumor cells and non-malignant transformed cells. In this way, a diagnosis that is largely independent of the investigator can be made (gene cluster analysis - genome pathology, gene profile pathology).
  • overexpressed genes can act as significantly more specific and - if they appear in the early stages of tumor development - more sensitive tumor markers than the previously known and used ones.
  • the selected genes can also be used as a coupling site for potential therapeutic targets.
  • the invention it is also possible to differentiate between different forms or subgroups of CCC. Since surgical therapy is more promising in early tumor stages, early prognostic parameters for CCC, as provided by the genes according to the invention and in particular the cluster analyzes according to the invention, are essential for successful therapy. In addition, according to the invention, targeted screening of risk groups can be carried out using the data provided here. Also to be emphasized is the possibility of providing a serum marker for the development of a CCC and the possibility of an anti-CCC vaccine based on the data presented here for the risk groups mentioned.
  • Another advantage that can be obtained with the present invention is that with the genes provided according to the invention one Risk group diagnosis can be carried out. For this purpose, for example, patients are examined and divided into corresponding risk groups based on the overexpressed or underexpressed genes.
  • fetal-expressed genes are of particular interest as tumor markers.
  • Genes that code for receptors and oncogenes as well as genes involved in the cell cycle (cdc) and signal transduction elements are particularly suitable for therapeutic approaches.
  • the invention thus encompasses gene sequences as a diagnostic detection method and as potential therapeutic targets in connection with a CCC as well as a CCC-specific cluster from e.g. 143 genes (indicator genes - genome pathology) as a unique diagnostic tool.
  • the economic benefits result on the one hand, for example, from the use of the expression pattern as a detection method for molecular tumor identification (specific serum markers, specific gene clusters, immunohistochemical markers), on the other hand those genes that are suitable for therapeutic approaches for molecular therapies such as Gene therapy and / or tumor vaccination are considered, checked accordingly and used for the development of therapy.
  • the invention further relates to a method for diagnosing CCC, in which the amount of at least one nucleic acid, more preferably of at least 2 nucleic acids, even more preferably of at least 5 nucleic acids in a sample, which is shown in Table I, II, III or / and IV are shown or a protein encoded thereof is determined.
  • the invention further relates to a method for the therapy of CCC, in which the amount of at least one nucleic acid shown in Table I, II, II or / and IV or a protein encoded therein is influenced.
  • the influencing can comprise an increase or decrease in the amount, for example by adding the at least one nucleic acid or a protein encoded thereby (in particular in the case of downregulated genes of Tables II or / and III) or by intercepting genes produced in excess or proteins encoded thereby, for example by means of antisense molecules or suitable antibodies (in particular in the case of up-regulated genes of Tables I or / and IV).
  • the invention further comprises a CCC-specific cluster or an expression profile associated with CCC, which comprises at least 5, in particular at least 10 and up to all of the genes Tables IA, IIA and / or IIIA.
  • genes identified by means of gene chip analysis are shown in the tables.
  • the database access numbers of the genes and the name of the genes or the polypeptide or EST number coded by them are given in the tables.
  • Table IA shows genes that are specifically upregulated in human CCC compared to non-cancerous liver cells in 100% of the examined patients by at least twice. The extent of the up-regulation is also indicated.
  • Table IB shows those genes from Table IA which are differentially expressed in the CCC compared to human primary HCC in 100% of the CCC patients examined.
  • Table IIB again shows the genes that are differentially expressed in the CCC compared to human primary HCC in 100% of the CCC patients.
  • Table INA shows genes that are specifically down-regulated in 80% of the patients in the CCC compared to non-cancerous liver cells.
  • Table IIIB shows the genes that are differentially expressed in the CCC compared to the HCC in 80% of the CCC patients.
  • Table IV shows genes that are upregulated in the CCC and are not differentially regulated in the HCC.
  • the gene expression analyzes are a selection of the significantly over- (red tones) and under-expressed (green tones) genes (applied vertically) from the respective tissue samples (shown horizontally).
  • FIG. 1 shows a gene cluster analysis of a CCC in comparison to non-malignant tissue based on 143 genes from Tables IA, IIA and INA.
  • Each track in the figure shows a tissue sample, the individual color pixels per track each a gene or a hybridization signal.
  • CCC tumor tissue (TU) or non-malignant tissue (NG) are plotted in the individual tracks.
  • a red color pixel means that the corresponding gene in the sample is overexpressed, a green color pixel that the corresponding gene is underexpressed.
  • 143 genes were used, which allowed the strongest differential differentiation between the two tissues. The aim of the investigation was to obtain the clearest possible differentiation between tumor tissue and non-malignant tissue in the simplest possible way. It can be clearly seen from FIG. 1 that a distinction between the different cell types is possible in a simple manner, even for a layperson or untrained personnel.
  • RNA liver cancer tissue
  • Table 1 B differentially expressed genes in CCC versus HCC in 100% of the patients
  • NM_006944 secreted phosphoprotein 2, 24kD -3, 27 AF323990 cytosolic beta-glucosidase -3,
  • alpha polypeptide 1 (3-oxo-5 alpha-steroid delta 4-dehydrogenase alpha 1) -2.5 93AJ277280 hepcidin antimicrobial peptide -2.5 94 D16350 SA hypertension-associated homolog (rat) -2.4 95J02639 serine (or cysteine) proteinase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 5 -2.2
  • cytochrome P450 subfamily VIIA (cholesterol 7 alpha-monooxygenase), polypeptides 1 -6.2
  • AI003579 solute carrier family 6 neurotransmitter transporter, GABA
  • GABA neurotransmitter transporter
  • member 1 -3.8
  • 22AI478172 homogentisate 1, 2-dioxygenase (homogentisate oxidase) -3.8 23 AF232009 peroxisomal trans 2-enoyl CoA reductase; putative short chain alcohol dehydrogenase -3.7 24X06399 cytochrome P450, subfamily IIB (phenobarbital-inducible), polypeptide 6 -3.6 25 BC002477 KIAA1630 protein -3.6 26X04300 cytochrome P450, subfamily I (aromatic compound-inducible), polypeptide 1 -3.3
  • HCC hepatocellular carcinoma
  • CCC cholangiocellular carcinoma
  • Consensus includes Homo sapiens ELISC-1 mRNA, partial cds 3,4
  • Consensus includes ribosomal protein L13a 2.8
  • Consensus includes Homo sapiens clone 23570 mRNA sequence 2.0
  • Consensus includes Human DNA sequence from clone LA16-358B7 on chromosome 16 1, 8
  • Consensus includes ... protein-coupled receptor, family C, group 5, member B 1, 6

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Organic Chemistry (AREA)
  • Urology & Nephrology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pathology (AREA)
  • Analytical Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Oncology (AREA)
  • Hematology (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Hospice & Palliative Care (AREA)
  • Physics & Mathematics (AREA)
  • Biotechnology (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Microbiology (AREA)
  • General Physics & Mathematics (AREA)
  • Medicinal Chemistry (AREA)
  • Biophysics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Food Science & Technology (AREA)
  • Cell Biology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne des marqueurs moléculaires qui apparaissent en cas de carcinome cholangiocellulaire (CCC). Ces marqueurs comprennent notamment des séquences de gènes ou des peptides codés par ces séquences, dont l'expression est régulée vers le haut ou vers le bas en cas de CCC concernant des cellules hépatiques non malignes ou normales. La présente invention concerne également l'utilisation de ces séquences pour diagnostiquer et/ou traiter un CCC et pour cribler et identifier de nouvelles substances actives pour le CCC. En outre, cette invention concerne un groupe spécifique au CCC se présentant sous forme d'agent diagnostique unique de CCC. Cette invention concerne également la discrimination de CCC et CHC (carcinome hépato-cellulaire).
PCT/EP2003/008243 2002-07-25 2003-07-25 Marqueurs moleculaires de carcinome cholangiocellulaire WO2004011945A2 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP03771105A EP1525477A2 (fr) 2002-07-25 2003-07-25 Marqueurs moleculaires de carcinome cholangiocellulaire
AU2003253329A AU2003253329A1 (en) 2002-07-25 2003-07-25 Molecular markers for cholangiolar carcinoma

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PCT/EP2002/008305 WO2003010336A2 (fr) 2001-07-25 2002-07-25 Marqueurs moleculaires lies a un carcinome hepatocellulaire
EPPCT/EP02/08305 2002-07-25

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WO2004011945A2 true WO2004011945A2 (fr) 2004-02-05
WO2004011945A3 WO2004011945A3 (fr) 2004-06-03

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AU (1) AU2003253329A1 (fr)
WO (1) WO2004011945A2 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008000126A (ja) * 2006-05-24 2008-01-10 Kanazawa Univ 遺伝子発現プロファイルによるｃ型肝硬変及び肝癌の検出
WO2012076723A1 (fr) * 2010-12-10 2012-06-14 Mosaiques Diagnostics And Therapeutics Ag Procédé et marqueur pour le diagnostic d'un rétrécissement des voies biliaires et d'un cholangiocarcinome à partir de la bile

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002022746A (ja) * 2000-07-12 2002-01-23 Kyokuho Yagita 癌の早期診断法

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002022746A (ja) * 2000-07-12 2002-01-23 Kyokuho Yagita 癌の早期診断法

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DE LAS MULAS J MARTIN ET AL: "Immunohistochemical evaluation of canine primary liver carcinomas: Distribution of alpha-fetoprotein, carcinoembryonic antigen, keratins and vimentin." RESEARCH IN VETERINARY SCIENCE, Bd. 59, Nr. 2, 1995, Seiten 124-127, XP009018425 ISSN: 0034-5288 *
KAWAI HIROSHI F ET AL: "alpha-Fetoprotein-producing hepatoma cell lines share common expression profiles of genes in various categories demonstrated by cDNA microarray analysis." HEPATOLOGY, Bd. 33, Nr. 3, M{rz 2001 (2001-03), Seiten 676-691, XP009018388 ISSN: 0270-9139 *
PATENT ABSTRACTS OF JAPAN Bd. 2002, Nr. 05, 3. Mai 2002 (2002-05-03) & JP 2002 022746 A (YAGITA KYOKUHO), 23. Januar 2002 (2002-01-23) *
RONCALLI MASSIMO ET AL: "Expression of new phenotypic markers in cholangiocarcinoma and putative precursor lesions." JOURNAL OF SURGICAL ONCOLOGY, Nr. SUPPL. 3, 1993, Seiten 173-174, XP009018389 First International Conference on Hepatobiliary Tumours;Milan, Italy; August 30-September 2, 1992 ISSN: 0022-4790 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008000126A (ja) * 2006-05-24 2008-01-10 Kanazawa Univ 遺伝子発現プロファイルによるｃ型肝硬変及び肝癌の検出
WO2012076723A1 (fr) * 2010-12-10 2012-06-14 Mosaiques Diagnostics And Therapeutics Ag Procédé et marqueur pour le diagnostic d'un rétrécissement des voies biliaires et d'un cholangiocarcinome à partir de la bile

Also Published As

Publication number Publication date
AU2003253329A1 (en) 2004-02-16
WO2004011945A3 (fr) 2004-06-03
EP1525477A2 (fr) 2005-04-27

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