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WO2018189215A1 - Procédé de prédiction du temps de survie d'un patient souffrant d'un carcinome hépatocellulaire - Google Patents

Procédé de prédiction du temps de survie d'un patient souffrant d'un carcinome hépatocellulaire Download PDF

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Publication number
WO2018189215A1
WO2018189215A1 PCT/EP2018/059229 EP2018059229W WO2018189215A1 WO 2018189215 A1 WO2018189215 A1 WO 2018189215A1 EP 2018059229 W EP2018059229 W EP 2018059229W WO 2018189215 A1 WO2018189215 A1 WO 2018189215A1
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Prior art keywords
hcc
hccs
expression level
genes
patient
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PCT/EP2018/059229
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English (en)
Inventor
Orlando Musso
Florian ROHART
Kim-Anh LE CAO
Romain DESERT
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INSERM (Institut National de la Santé et de la Recherche Médicale)
Université De Rennes 1
The University Of Queensland
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Publication of WO2018189215A1 publication Critical patent/WO2018189215A1/fr

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    • 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
    • C12Q2600/118—Prognosis of disease development
    • 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 method for predicting the survival time of a patient suffering from an hepatocellular carcinoma (HCC) comprising: i) determining, in a sample obtained from the patient, the expression level of the genes selected in the group consisting in AGXT, FETUB, GLS2, GNMT, SLC10A1 and SLC22A7; ii) comparing the expression level of the genes determined at step i) with their predetermined reference values and iii) providing a good prognosis when the expression levels determined at step i) are higher than their predetermined reference values, or providing a bad prognosis when the expression level determined at step i) are lower than their predetermined reference values.
  • HCC hepatocellular carcinoma
  • HCC Hepatocellular carcinoma
  • HCCs Treatment allocation for early-stage HCCs might be improved by identifying homogeneous molecular subclasses with predictable outcomes.
  • (2, 3) The molecular landscape of HCCs is emerging as a result of global gene expression analyses and the discovery of crucial driver tumor mutations.
  • (1, 2) At present, HCCs are split into two molecular classes, each representing 50% of tumors: proliferative and nonproliferative HCCs.
  • Proliferative HCCs include two subclasses enriched in WNT/TGFB signals and stem/progenitor cell markers, respectively.(l, 2) Among non-proliferative HCCs, half of the tumors form a homogeneous subclass with a high rate of activating ⁇ -catenin (CTNNBl) exon 3 mutations. (2, 4-6) These tumors are well-differentiated, (2, 4-8) but patient survival rates do not differ from HCCs carrying wild-type CTNNBl. The rest of nonproliferative HCCs carry wild-type CTNNB1,(5) but no evidence to date allowed them to qualify as a homogeneous HCC subclass.
  • CTNNBl ⁇ -catenin
  • the inventors established 1) a first signature consisting of 5 genes which is suitable for predicting ⁇ -catenin mutations and 2) a second signature of at least 6 genes which is also suitable for predicting the survival time of a patient suffering from a specific subclass of HCC (Periportal-type HCCs).
  • the present invention relates to a method for predicting the survival time of a patient suffering from hepatocellular carcinoma (HCC) comprising: i) determining, in a sample obtained from the patient, the expression level of the genes selected in the group consisting in AGXT, FETUB, GLS2, GNMT, SLC10A1 and SLC22A7; ii) comparing the expression level of the genes determined at step i) with their predetermined reference values and iii) providing a good prognosis when the expression levels determined at step i) are higher than their predetermined reference values, or providing a bad prognosis when the expression level determined at step i) are lower than their predetermined reference values.
  • HCC hepatocellular carcinoma
  • a first aspect of the invention relates to a method for predicting the survival time of a patient suffering from an hepatocellular carcinoma (HCC) comprising: i) determining, in a sample obtained from the patient, the expression level of the genes selected in the group consisting in AGXT, FETUB, GLS2, GNMT, SLC10A1 and SLC22A7; ii) comparing the expression level of the genes determined at step i) with their predetermined reference values and iii) providing a good prognosis when the expression levels determined at step i) are higher than their predetermined reference values, or providing a bad prognosis when the expression level determined at step i) are lower than their predetermined reference values.
  • HCC hepatocellular carcinoma
  • the invention relates to a method for predicting the survival time of a patient suffering from an hepatocellular carcinoma (HCC) comprising: i) determining, in a sample obtained from the patient, the expression level of the genes selected in AGXT, FETUB, GLS2, GNMT, SLC10A1 and SLC22A7; ii) comparing the expression level of the genes determined at step i) with their predetermined reference values and iii) providing a good prognosis when the expression levels determined at step i) are higher than their predetermined reference values, or providing a bad prognosis when the expression level determined at step i) are lower than their predetermined reference values.
  • HCC hepatocellular carcinoma
  • the measurement of the expression level of at least one gene in the group consisting of OTC and SLC27A5 may be added to the method for predicting the survival time of a patient suffering from a hepatocellular carcinoma.
  • the invention relates to a method for predicting the survival time of a patient suffering from an hepatocellular carcinoma comprising i) determining in a sample obtained from the patient the expression level of the genes selected in the group consisting in AGXT, FETUB, GLS2, GNMT, SLC10A1, SLC22A7 and OTC ii) comparing the expression level of the genes determined at step i) with their predetermined reference values and iii) providing a good prognosis when the expression level determined at step i) are higher than their predetermined reference values, or providing a bad prognosis when the expression level determined at step i) are lower than their predetermined reference values.
  • the invention relates to to a method for predicting the survival time of a patient suffering from an hepatocellular carcinoma comprising i) determining in a sample obtained from the patient the expression level of the genes selected in AGXT, FETUB, GLS2, GNMT, SLC10A1, SLC22A7 and OTC ii) comparing the expression level of the genes determined at step i) with their predetermined reference values and iii) providing a good prognosis when the expression level determined at step i) are higher than their predetermined reference values, or providing a bad prognosis when the expression level determined at step i) are lower than their predetermined reference values.
  • the invention relates to a method for predicting the survival time of a patient suffering from an hepatocellular carcinoma comprising i) determining in a sample obtained from the patient the expression level of the genes selected in the group consisting in AGXT, FETUB, GLS2, GNMT, SLC10A1, SLC22A7 and SLC27A5 ii) comparing the expression level of the genes determined at step i) with their predetermined reference values and iii) providing a good prognosis when the expression level determined at step i) are higher than their predetermined reference values, or providing a bad prognosis when the expression level determined at step i) are lower than their predetermined reference values.
  • the invention in another aspect, relates to a method for predicting the survival time of a patient suffering from an hepatocellular carcinoma comprising i) determining in a sample obtained from the patient the expression level of the genes selected in the group consisting in AGXT, FETUB, GLS2, GNMT, SLC10A1, SLC22A7, OTC and SLC27A5 ii) comparing the expression level of the genes determined at step i) with their predetermined reference values and iii) providing a good prognosis when the expression level determined at step i) are higher than their predetermined reference values, or providing a bad prognosis when the expression level determined at step i) are lower than their predetermined reference values.
  • Another aspect of the invention relates to a method for predicting the overall survival of a patient suffering from an hepatocellular carcinoma comprising i) determining in a sample obtained from the patient the expression level of the genes selected in the group consisting in AGXT, FETUB, GLS2, GNMT, SLC10A1 and SLC22A7 ii) comparing the expression level of the genes determined at step i) with their predetermined reference values and iii) providing a good prognosis when the expression level determined at step i) are higher than their predetermined reference values, or providing a bad prognosis when the expression level determined at step i) are lower than their predetermined reference values.
  • Another aspect of the invention relates to a method for predicting the overall survival of a patient suffering from an hepatocellular carcinoma comprising i) determining in a sample obtained from the patient the expression level of the genes selected in the group consisting in AGXT, FETUB, GLS2, GNMT, SLC10A1, SLC22A7 and OTC ii) comparing the expression level of the genes determined at step i) with their predetermined reference values and iii) providing a good prognosis when the expression level determined at step i) are higher than their predetermined reference values, or providing a bad prognosis when the expression level determined at step i) are lower than their predetermined reference values.
  • Another aspect of the invention relates to a method for predicting the overall survival of a patient suffering from an hepatocellular carcinoma comprising i) determining in a sample obtained from the patient the expression level of the genes selected in the group consisting in AGXT, FETUB, GLS2, GNMT, SLC10A1, SLC22A7 and SLC27A5 ii) comparing the expression level of the genes determined at step i) with their predetermined reference values and iii) providing a good prognosis when the expression level determined at step i) are higher than their predetermined reference values, or providing a bad prognosis when the expression level determined at step i) are lower than their predetermined reference values.
  • Another aspect of the invention relates to a method for predicting the overall survival of a patient suffering from an hepatocellular carcinoma comprising i) determining in a sample obtained from the patient the expression level of the genes selected in the group consisting in AGXT, FETUB, GLS2, GNMT, SLC10A1, SLC22A7, OTC and SLC27A5 ii) comparing the expression level of the genes determined at step i) with their predetermined reference values and iii) providing a good prognosis when the expression level determined at step i) are higher than their predetermined reference values, or providing a bad prognosis when the expression level determined at step i) are lower than their predetermined reference values.
  • Another aspect of the invention relates to a method for predicting the disease-free- survival of a patient suffering from an hepatocellular carcinoma comprising i) determining in a sample obtained from the patient the expression level of the genes selected in the group consisting in AGXT, FETUB, GLS2, GNMT, SLC10A1 and SLC22A7 ii) comparing the expression level of the genes determined at step i) with their predetermined reference values and iii) providing a good prognosis when the expression level determined at step i) are higher than their predetermined reference values, or providing a bad prognosis when the expression level determined at step i) are lower than their predetermined reference values.
  • Another aspect of the invention relates to a method for predicting the disease-free- survival of a patient suffering from an hepatocellular carcinoma comprising i) determining in a sample obtained from the patient the expression level of the genes selected in the group consisting in AGXT, FETUB, GLS2, GNMT, SLC10A1, SLC22A7 and OTC ii) comparing the expression level of the genes determined at step i) with their predetermined reference values and iii) providing a good prognosis when the expression level determined at step i) are higher than their predetermined reference values, or providing a bad prognosis when the expression level determined at step i) are lower than their predetermined reference values.
  • Another aspect of the invention relates to a method for predicting the disease-free- survival of a patient suffering from an hepatocellular carcinoma comprising i) determining in a sample obtained from the patient the expression level of the genes selected in the group consisting in AGXT, FETUB, GLS2, GNMT, SLC10A1, SLC22A7 and SLC27A5 ii) comparing the expression level of the genes determined at step i) with their predetermined reference values and iii) providing a good prognosis when the expression level determined at step i) are higher than their predetermined reference values, or providing a bad prognosis when the expression level determined at step i) are lower than their predetermined reference values.
  • Another aspect of the invention relates to a method for predicting the disease-free- survival of a patient suffering from an hepatocellular carcinoma comprising i) determining in a sample obtained from the patient the expression level of the genes selected in the group consisting in AGXT, FETUB, GLS2, GNMT, SLC10A1, SLC22A7, OTC and SLC27A5 ii) comparing the expression level of the genes determined at step i) with their predetermined reference values and iii) providing a good prognosis when the expression level determined at step i) are higher than their predetermined reference values, or providing a bad prognosis when the expression level determined at step i) are lower than their predetermined reference values.
  • a second aspect of the invention relates to a method for predicting at least a mutation of the CTNNB1 gene in a patient suffering from hepatocellular carcinoma comprising i) determining in a sample obtained from the patient the expression level of the genes selected in the group consisting in HAL, VNN1, ODAM, GLUL and LGR5; ii) computing a CTNNB1 mutation score conceived by the inventors thanks to these expression levels of the genes and; iii) comparing said CTNNBl mutation score determined at step ii) with its predetermined reference value to determine if there is at least a mutation on the CTNNBl gene or no mutation on the CTNNBl gene.
  • the invention relates to a method for predicting at least a mutation of the CTNNBl gene in a patient suffering from hepatocellular carcinoma comprising i) determining in a sample obtained from the patient the expression level of the genes selected in the group consisting in HAL, VNN1, ODAM, GLUL and LGR5; ii) computing a CTNNBl mutation score conceived by the inventors, as follows:
  • Identifying a CTNNBl mutation in a hepatocellular carcinoma indicates that the patient suffering from this cancer will have a Perivenous-type HCC. Identifying this subclass of HCC is clinically relevant because: (i) this subclass of liver cancer is characterized by activation of the ⁇ -catenin signalling pathway that could be treated by specific inhibitors of this pathway (see for example the patent applications WO2011088127, US7803783 or WO2004032838); (ii) overall survival and disease-free survival rates of patients suffering from HCCs carrying CTNNBl mutations will probably be less favourable than those of patients suffering from Periportal-type HCCs, but more favourable than those of patients suffering from STEM-type HCCs.
  • OS Overall survival
  • DFS Disease-free survival
  • the term "Good Prognosis” denotes a significantly more favourable probability of survival after patient treatment in the group of patients defined as “good prognosis” compared with the group of patients defined as “bad prognosis”.
  • sample denotes, blood, peripheral-blood, serum, plasma, and liver tissues obtained by HCC biopsy, HCC resection or liver resection specimens.
  • patient refers to an individual who is being managed for liver disease and who is susceptible to develop an HCC at any stage of this disease.
  • HCCs can be proliferative and non- proliferative HCCs.
  • Proliferative HCCs include two subclasses enriched in WNT/TGFB signals and stem/progenitor cell markers, respectively.
  • Non-proliferative HCCs can be periportal or perivenous HCCs, as defined by the inventors.
  • HCC can be a "ECM-type HCC” (for Cancer Extracellular Matrix) or an or a STEM-type HCCs (see for example Hoshida , cancer research 2009).
  • AGXT refers to the gene of "Alanine-Glyoxylate
  • FETUB refers to the gene of "Fetuin B”. The sequence of said gene can be found under the Ensembl accession number ENSG00000090512.
  • GLS2 refers to the gene of "Glutaminase 2".
  • the sequence of said gene can be found under the Ensembl accession number ENSG00000135423.
  • GNMT refers to the gene of "Glycine N-methyltransferase”. The sequence of said gene can be found under the Ensembl accession number ENSG00000124713.
  • SLC 10A 1 refers to the gene of "Solute Carrier Family 10
  • the sequence of said gene can be found under the Ensembl accession number ENSG00000100652.
  • SLC22A7 refers to the gene of "Solute carrier family 22 member 7".
  • the sequence of said gene can be found under the Ensembl accession number ENSG00000137204.
  • OTC refers to the gene of "Ornithine Carbamoyltransferase". The sequence of said gene can be found under the Ensembl accession number ENSG00000036473.
  • SLC27A5 refers to the gene of "Solute Carrier Family 27 Member 5 Canal
  • the sequence of said gene can be found under the Ensembl accession number ENSG00000083807.
  • HAL refers to the gene of "Histidine ammonia-lyase”. The sequence of said gene can be found under the Ensembl accession number ENSG00000084110.
  • VNN1 refers to the gene of "Vanin 1".
  • the sequence of said gene can be found under the Ensembl accession number ENSG00000112299.
  • ODAM refers to the gene of "Odontogenic ameloblast- associated protein".
  • the sequence of said gene can be found under the Ensembl accession number ENSG00000109205.
  • GLUL refers to the gene of "Glutamine synthetase”. The sequence of said gene can be found under the Ensembl accession number ENSG00000135821.
  • LGR5 refers to the gene of "Leucine-rich repeat-containing G-protein coupled receptor 5".
  • the sequence of said gene can be found under the Ensembl accession number ENSG00000139292.
  • CNNB1 or " ⁇ -catenin gene” refers to the gene which encode for the protein ⁇ -catenin.
  • the sequence of said gene can be found under the Ensembl accession number ENSG00000168036.
  • Measuring the expression level of the genes listed above can be done by measuring the gene expression level of these genes and can be performed by a variety of techniques well known in the art.
  • the expression level of a gene may be determined by determining the quantity of mRNA.
  • Methods for determining the quantity of mRNA are well known in the art.
  • the nucleic acid contained in the samples e.g., cell or tissue prepared from the patient
  • the extracted mRNA is then detected by hybridization (e. g., Northern blot analysis, in situ hybridization) and/or amplification (e.g., RT-PCR).
  • LCR ligase chain reaction
  • TMA transcription- mediated amplification
  • SDA strand displacement amplification
  • NASBA nucleic acid sequence based amplification
  • Nucleic acids having at least 10 nucleotides and exhibiting sequence complementarity or homology to the mRNA of interest herein find utility as hybridization probes or amplification primers. It is understood that such nucleic acids need not be identical, but are typically at least about 80% identical to the homologous region of comparable size, more preferably 85% identical and even more preferably 90-95% identical. In certain embodiments, it will be advantageous to use nucleic acids in combination with appropriate means, such as a detectable label, for detecting hybridization.
  • the nucleic acid probes include one or more labels, for example to permit detection of a target nucleic acid molecule using the disclosed probes.
  • a nucleic acid probe includes a label (e.g., a detectable label).
  • a "detectable label” is a molecule or material that can be used to produce a detectable signal that indicates the presence or concentration of the probe (particularly the bound or hybridized probe) in a sample.
  • a labeled nucleic acid molecule provides an indicator of the presence or concentration of a target nucleic acid sequence (e.g., genomic target nucleic acid sequence) (to which the labeled uniquely specific nucleic acid molecule is bound or hybridized) in a sample.
  • a label associated with one or more nucleic acid molecules can be detected either directly or indirectly.
  • a label can be detected by any known or yet to be discovered mechanism including absorption, emission and/ or scattering of a photon (including radio frequency, microwave frequency, infrared frequency, visible frequency and ultra-violet frequency photons).
  • Detectable labels include colored, fluorescent, phosphorescent and luminescent molecules and materials, catalysts (such as enzymes) that convert one substance into another substance to provide a detectable difference (such as by converting a colorless substance into a colored substance or vice versa, or by producing a precipitate or increasing sample turbidity), haptens that can be detected by antibody binding interactions, and paramagnetic and magnetic molecules or materials.
  • detectable labels include fluorescent molecules (or fluorochromes).
  • fluorescent molecules or fluorochromes
  • Numerous fluorochromes are known to those of skill in the art, and can be selected, for example from Life Technologies (formerly Invitrogen), e.g., see, The Handbook— A Guide to Fluorescent Probes and Labeling Technologies).
  • fluorophores that can be attached (for example, chemically conjugated) to a nucleic acid molecule (such as a uniquely specific binding region) are provided in U.S. Pat. No.
  • fluorophores include thiol-reactive europium chelates which emit at approximately 617 mn (Heyduk and Heyduk, Analyt. Biochem. 248:216-27, 1997; J. Biol. Chem. 274:3315-22, 1999), as well as GFP, LissamineTM, diethylaminocoumarin, fluorescein chlorotriazinyl, naphthofluorescein, 4,7-dichlororhodamine and xanthene (as described in U.S. Pat. No. 5,800,996 to Lee et al.) and derivatives thereof.
  • fluorophores known to those skilled in the art can also be used, for example those available from Life Technologies (Invitrogen; Molecular Probes (Eugene, Oreg.)) and including the ALEXA FLUOR® series of dyes (for example, as described in U.S. Pat. Nos. 5,696,157, 6, 130, 101 and 6,716,979), the BODIPY series of dyes (dipyrrometheneboron difluoride dyes, for example as described in U.S. Pat. Nos.
  • a fluorescent label can be a fluorescent nanoparticle, such as a semiconductor nanocrystal, e.g., a QUANTUM DOTTM (obtained, for example, from Life Technologies (QuantumDot Corp, Invitrogen Nanocrystal Technologies, Eugene, Oreg.); see also, U.S. Pat. Nos. 6,815,064; 6,682,596; and 6,649, 138).
  • Semiconductor nanocrystals are microscopic particles having size-dependent optical and/or electrical properties.
  • Semiconductor nanocrystals that can he coupled to a variety of biological molecules (including dNTPs and/or nucleic acids) or substrates by techniques described in, for example, Bruchez et al., Science 281 :20132016, 1998; Chan et al., Science 281:2016-2018, 1998; and U.S. Pat. No. 6,274,323. Formation of semiconductor nanocrystals of various compositions are disclosed in, e.g., U.S. Pat. Nos.
  • semiconductor nanocrystals can he produced that emit light of different colors hased on their composition, size or size and composition.
  • quantum dots that emit light at different wavelengths based on size (565 mn, 655 mn, 705 mn, or 800 mn emission wavelengths), which are suitable as fluorescent labels in the probes disclosed herein are available from Life Technologies (Carlshad, Calif.).
  • Additional labels include, for example, radioisotopes (such as 3 H), metal chelates such as DOTA and DPTA chelates of radioactive or paramagnetic metal ions like Gd3+, and liposomes.
  • Detectable labels that can he used with nucleic acid molecules also include enzymes, for example horseradish peroxidase, alkaline phosphatase, acid phosphatase, glucose oxidase, beta-galactosidase, beta-glucuronidase, or beta-lactamase.
  • enzymes for example horseradish peroxidase, alkaline phosphatase, acid phosphatase, glucose oxidase, beta-galactosidase, beta-glucuronidase, or beta-lactamase.
  • an enzyme can he used in a metallographic detection scheme.
  • SISH silver in situ hyhridization
  • Metallographic detection methods include using an enzyme, such as alkaline phosphatase, in combination with a water-soluble metal ion and a redox-inactive substrate of the enzyme. The substrate is converted to a redox-active agent by the enzyme, and the redoxactive agent reduces the metal ion, causing it to form a detectable precipitate.
  • Metallographic detection methods also include using an oxido-reductase enzyme (such as horseradish peroxidase) along with a water soluble metal ion, an oxidizing agent and a reducing agent, again to form a detectable precipitate.
  • an oxido-reductase enzyme such as horseradish peroxidase
  • Probes made using the disclosed methods can be used for nucleic acid detection, such as ISH procedures (for example, fluorescence in situ hybridization (FISH), chromo genie in situ hybridization (CISH) and silver in situ hybridization (SISH)) or comparative genomic hybridization (CGH).
  • ISH procedures for example, fluorescence in situ hybridization (FISH), chromo genie in situ hybridization (CISH) and silver in situ hybridization (SISH)
  • CGH comparative genomic hybridization
  • ISH In situ hybridization
  • a sample containing target nucleic acid sequence e.g., genomic target nucleic acid sequence
  • a metaphase or interphase chromosome preparation such as a cell or tissue sample mounted on a slide
  • a labeled probe specifically hybridizable or specific for the target nucleic acid sequence (e.g., genomic target nucleic acid sequence).
  • the slides are optionally pretreated, e.g., to remove paraffin or other materials that can interfere with uniform hybridization.
  • the sample and the probe are both treated, for example by heating to denature the double stranded nucleic acids.
  • the probe (formulated in a suitable hybridization buffer) and the sample are combined, under conditions and for sufficient time to permit hybridization to occur (typically to reach equilibrium).
  • the chromosome preparation is washed to remove excess probe, and detection of specific labeling of the chromosome target is performed using standard techniques.
  • a biotinylated probe can be detected using fluorescein-labeled avidin or avidin- alkaline phosphatase.
  • fluorochrome detection the fluorochrome can be detected directly, or the samples can be incubated, for example, with fluorescein isothiocyanate (FITC)- conjugated avidin.
  • FITC fluorescein isothiocyanate
  • FrfC signal can be effected, if necessary, by incubation with biotin-conjugated goat antiavidin antibodies, washing and a second incubation with FITC- conjugated avidin.
  • samples can be incubated, for example, with streptavidin, washed, incubated with biotin-conjugated alkaline phosphatase, washed again and pre-equilibrated (e.g., in alkaline phosphatase (AP) buffer).
  • AP alkaline phosphatase
  • Numerous reagents and detection schemes can be employed in conjunction with FISH, CISH, and SISH procedures to improve sensitivity, resolution, or other desirable properties.
  • probes labeled with fluorophores including fluorescent dyes and QUANTUM DOTS®
  • fluorophores including fluorescent dyes and QUANTUM DOTS®
  • the probe can be labeled with a nonfluorescent molecule, such as a hapten (such as the following non- limiting examples: biotin, digoxigenin, DNP, and various oxazoles, pyrrazoles, thiazoles, nitroaryls, benzofurazans, triterpenes, ureas, thioureas, rotenones, coumarin, courmarin-based compounds, Podophyllotoxin, Podophyllotoxin-based compounds, and combinations thereof), ligand or other indirectly detectable moiety.
  • a hapten such as the following non- limiting examples: biotin, digoxigenin, DNP, and various oxazoles, pyrrazoles, thiazoles, nitroaryls, benzofurazans, triterpenes, ureas, thioureas, rotenones, coumarin, courmarin-based compounds, Podophyllotoxin,
  • Probes labeled with such non-fluorescent molecules (and the target nucleic acid sequences to which they bind) can then be detected by contacting the sample (e.g., the cell or tissue sample to which the probe is bound) with a labeled detection reagent, such as an antibody (or receptor, or other specific binding partner) specific for the chosen hapten or ligand.
  • a labeled detection reagent such as an antibody (or receptor, or other specific binding partner) specific for the chosen hapten or ligand.
  • the detection reagent can be labeled with a fluorophore (e.g., QUANTUM DOT®) or with another indirectly detectable moiety, or can be contacted with one or more additional specific binding agents (e.g., secondary or specific antibodies), which can be labeled with a fluorophore.
  • the probe, or specific binding agent (such as an antibody, e.g., a primary antibody, receptor or other binding agent) is labeled with an enzyme that is capable of converting a fluorogenic or chromogenic composition into a detectable fluorescent, colored or otherwise detectable signal (e.g., as in deposition of detectable metal particles in SISH).
  • the enzyme can be attached directly or indirectly via a linker to the relevant probe or detection reagent. Examples of suitable reagents (e.g., binding reagents) and chemistries (e.g., linker and attachment chemistries) are described in U.S. Patent Application Publication Nos. 2006/0246524; 2006/0246523, and 2007/ 01 17153.
  • multiplex detection schemes can he produced to facilitate detection of multiple target nucleic acid sequences (e.g., genomic target nucleic acid sequences) in a single assay (e.g., on a single cell or tissue sample or on more than one cell or tissue sample).
  • a first probe that corresponds to a first target sequence can he labelled with a first hapten, such as biotin, while a second probe that corresponds to a second target sequence can be labelled with a second hapten, such as DNP.
  • the bound probes can he detected by contacting the sample with a first specific binding agent (in this case avidin labelled with a first fluorophore, for example, a first spectrally distinct QUANTUM DOT®, e.g., that emits at 585 mn) and a second specific binding agent (in this case an anti-DNP antibody, or antibody fragment, labelled with a second fluorophore (for example, a second spectrally distinct QUANTUM DOT®, e.g., that emits at 705 mn).
  • a first specific binding agent in this case avidin labelled with a first fluorophore, for example, a first spectrally distinct QUANTUM DOT®, e.g., that emits at 585 mn
  • a second specific binding agent in this case an anti-DNP antibody, or antibody fragment, labelled with a second fluorophore (for example, a second spectrally distinct QUANTUM DOT®,
  • Probes typically comprise single-stranded nucleic acids of between 10 to 1000 nucleotides in length, for instance of between 10 and 800, more preferably of between 15 and 700, typically of between 20 and 500.
  • Primers typically are shorter single- stranded nucleic acids, of between 10 to 25 nucleotides in length, designed to perfectly or almost perfectly match a nucleic acid of interest, to be amplified.
  • the probes and primers are "specific" to the nucleic acids they hybridize to, i.e. they preferably hybridize under high stringency hybridization conditions (corresponding to the highest melting temperature Tm, e.g., 50 % formamide, 5x or 6x SCC.
  • SCC is a 0.15 M NaCl, 0.015 M Na-citrate).
  • the nucleic acid primers or probes used in the above amplification and detection method may be assembled as a kit.
  • a kit includes consensus primers and molecular probes.
  • a preferred kit also includes the components necessary to determine if amplification has occurred.
  • the kit may also include, for example, PCR buffers and enzymes; positive control sequences, reaction control primers; and instructions for amplifying and detecting the specific sequences.
  • the methods of the invention comprise the steps of providing total RNAs extracted from cumulus cells and subjecting the RNAs to amplification and hybridization to specific probes, more particularly by means of a quantitative or semiquantitative RT-PCR.
  • the expression level is determined by DNA chip analysis.
  • DNA chip or nucleic acid microarray consists of different nucleic acid probes that are chemically attached to a substrate, which can be a microchip, a glass slide or a micro sphere- sized bead.
  • a microchip may be constituted of polymers, plastics, resins, polysaccharides, silica or silica-based materials, carbon, metals, inorganic glasses, or nitrocellulose.
  • Probes comprise nucleic acids such as cDNAs or oligonucleotides that may be about 10 to about 60 base pairs.
  • a sample from a test subject optionally first subjected to a reverse transcription, is labelled and contacted with the microarray in hybridization conditions, leading to the formation of complexes between target nucleic acids that are complementary to probe sequences attached to the microarray surface.
  • the labelled hybridized complexes are then detected and can be quantified or semi-quantified. Labelling may be achieved by various methods, e.g. by using radioactive or fluorescent labelling.
  • Many variants of the microarray hybridization technology are available to the man skilled in the art (see e.g. the review by Hoheisel, Nature Reviews, Genetics, 2006, 7:200-210).
  • the expression level is determined by metabolic imaging (see for example Yamashita T et al., Hepatology 2014, 60: 1674-1685 or Ueno A et al., Journal of hepatology 2014, 61: 1080-1087).
  • Expression level of a gene may be expressed as absolute expression level or normalized expression level.
  • expression levels are normalized by correcting the absolute expression level of a gene by comparing its expression to the expression of a gene that is not a relevant for determining the cancer stage of the patient, e.g., a housekeeping gene that is constitutively expressed.
  • Suitable genes for normalization include housekeeping genes such as the actin gene ACTB, ribosomal 18S gene, GUSB, PGK1, TFRC, GAPDH, GUSB, TBP and ABL1. This normalization allows the comparison of the expression level in one sample, e.g., a patient sample, to another sample, or between samples from different sources.
  • Predetermined reference values used for comparison may comprise "cut-off or "threshold" values that may be determined as described herein.
  • Each reference (“cut-off) value for the genes' expression may be predetermined by carrying out a method comprising the steps of
  • the expression level of the genes has been assessed for 100 HCC samples from 100 patients.
  • the 100 samples are ranked according to their expression level.
  • Sample 1 has the highest expression level and sample 100 has the lowest expression level.
  • a first grouping provides two subsets: on one side sample Nr 1 and on the other side the 99 other samples.
  • the next grouping provides on one side samples 1 and 2 and on the other side the 98 remaining samples etc., until the last grouping: on one side samples 1 to 99 and on the other side sample Nr 100.
  • Kaplan Meier curves are prepared for each of the 99 groups of two subsets. Also for each of the 99 groups, the p value between both subsets was calculated.
  • the reference value is selected such as the discrimination based on the criterion of the minimum p value is the strongest.
  • the expression level corresponding to the boundary between both subsets for which the p value is minimum is considered as the reference value. It should be noted that the reference value is not necessarily the median value of expression levels.
  • the reference value (cut-off value) may be used in the present method to discriminate HCC samples and therefore the corresponding patients.
  • Kaplan-Meier curves of percentage of survival as a function of time are commonly used to measure the fraction of patients living for a certain amount of time after treatment and are well known by the person skilled in the art.
  • Such predetermined reference values of expression level may be determined for any gene defined above.
  • Another aspect of the invention relates to a chemotherapeutic compound for use in the treatment of HCC in a patient with a bad prognosis as described above.
  • chemotherapeutic compounds may be selected in the group consisting in: fludarabine, gemcitabine, capecitabine, methotrexate, taxol, taxotere, mercaptopurine, thioguanine, hydroxyurea, cytarabine, cyclophosphamide, ifosfamide, nitrosoureas, platinum complexes such as cisplatin, carboplatin and oxaliplatin, mitomycin, dacarbazine, procarbizine, etoposide, teniposide, campathecins, bleomycin, doxorubicin, idarubicin, daunorubicin, dactinomycin, plicamycin, mitoxantrone, L-asparaginase, doxorubicin, epimbicm, 5-fluorouracil, taxanes such as docetaxel and paclitaxel, leucovorin,
  • additional anticancer agents may be selected from, but are not limited to, one or a combination of the following class of agents: alkylating agents, plant alkaloids, DNA topoisomerase inhibitors, anti-folates, pyrimidine analogs, purine analogs, DNA antimetabolites, taxanes, podophyllotoxin, hormonal therapies, retinoids, photosensitizers or photodynamic therapies, angiogenesis inhibitors, antimitotic agents, isoprenylation inhibitors, cell cycle inhibitors, actinomycins, bleomycins, anthracyclines, MDR inhibitors and Ca2+ ATPase inhibitors.
  • a more aggressive chemo therapeutic compound may be used to treat patient with bad prognosis.
  • This compound may be the sorafenib for example..
  • HCC patients with good prognosis may benefit from potentially curative therapies that include but may not be limited to tumor resection, local tumor ablation and liver transplantation.
  • therapies include but may not be limited to tumor resection, local tumor ablation and liver transplantation.
  • the choice among these alternatives will greatly depend on the functional reserve of the liver, tumor accessibility and localization in the liver, donor liver availability and the intrinsic aggressiveness of the tumor, which can be predicted using different methods to predict survival time in patients with HCC. (See for example: Sapisochin G, Bruix J. Liver transplantation for hepatocellular carcinoma: outcomes and novel surgical approaches. Nature reviews. Gastroenterology & hepatology 2017;14:203-217).
  • resection of the HCC in the patient with bad prognosis may be done to diminish tumor burden and to provide the best supportive care to the patient.
  • resection of the HCC in the patient with good prognosis may be done to avoid tumor progression while the patient is in the waiting list for liver transplantation.
  • resection of the HCC in the patient with good prognosis may be done to downstage the patient in such a way that they meet transplantation criteria.
  • local ablation of the HCC in the patient with good prognosis may be done to avoid tumor progression while the patient is in the waiting list for liver transplantation.
  • local ablation of the HCC in the patient with good prognosis may be done to downstage the patient in such a way that they meet transplantation criteria.
  • Tumor ablation techniques comprise, but are not limited to, techniques based on radiofrequency, microvawe, alcohol or acetic acid percutaneous injection.
  • a transplantation of a liver may be realized to treat the patient with good prognosis.
  • the transplantation has more chances to be successful than a transplantation in a patient with a bad prognosis.
  • the genes of the invention are in a particular interest to help clinicians to have the best therapeutic answer for the patient.
  • Another aspect of the invention relates to a therapeutic composition
  • a therapeutic composition comprising a chemotherapeutic compound for use in the treatment of HCC in a patient with a bad prognosis as described above.
  • Any therapeutic agent of the invention may be combined with pharmaceutically acceptable excipients, and optionally sustained-release matrices, such as biodegradable polymers, to form therapeutic compositions.
  • “Pharmaceutically” or “pharmaceutically acceptable” refers to molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to a mammal, especially a human, as appropriate.
  • a pharmaceutically acceptable carrier or excipient refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • compositions for example, the route of administration, the dosage and the regimen naturally depend upon the condition to be treated, the severity of the illness, the age, weight, and sex of the patient, etc.
  • compositions of the invention can be formulated for a topical, oral, intranasal, parenteral, intraocular, intravenous, intramuscular, intrathecal or subcutaneous administration and the like.
  • the pharmaceutical compositions contain vehicles which are pharmaceutically acceptable for a formulation capable of being injected (like lipiodol, gelfoam, ivalon).
  • vehicles which are pharmaceutically acceptable for a formulation capable of being injected (like lipiodol, gelfoam, ivalon).
  • These may be in particular isotonic, sterile, saline solutions (monosodium or disodium phosphate, sodium, potassium, calcium or magnesium chloride and the like or mixtures of such salts), or dry, especially freeze-dried compositions which upon addition, depending on the case, of sterilized water or physiological saline, permit the constitution of injectable solutions.
  • the doses used for the administration can be adapted as a function of various parameters, and in particular as a function of the mode of administration used, of the relevant pathology, or alternatively of the desired duration of treatment.
  • FIG. 1 Periportal-type HCCs show the most favorable clinical features and the highest early (2-year) disease-free and overall survival rates after resection.
  • A Clinical features of HCC subclasses in a 247-patient dataset(34).
  • B Kaplan-Meier plots of subclass- specific overall and disease-free survival; *P ⁇ 0.05, **P ⁇ 0.01, ***P ⁇ 0.001.
  • C Subclass- specific clinical features, CTNNB1 and TP53 mutation rates (full genome sequencing) in an external validation 210-HCC RNAseq dataset (TGCA-LIHC-US).
  • D Subclass -specific mPvNA expression levels of Periportal HCC signature genes in 1133 HCCs.
  • E Kaplan- Meier plots of overall and disease-free survival in HCC patients with and without the Periportal HCC signature in two datasets.
  • AFP serum alpha-fetoprotein
  • NA serum alpha-fetoprotein
  • BCLC Barcelona Clinic Liver Cancer
  • CLIP Cancer of the Liver Italian Program.
  • Probes detected over background in at least one HCC were quantile normalized (R package preprocessCore) and log2 intensity expression values for each probe set were calculated by Robust Multi-array Average Cross-platform and batch-dependent variances were corrected with COMBAT(l l) (R package sva) in the 1133-HCC metadata set and with YuGene(12) (R package YuGene) in the datasets used for CTNNB 1 mutation prediction.
  • a robust 5- gene score predicts CTNNB 1 mutations in large transcriptomic datasets As described in the Patients and Methods section, nine public transcriptomic datasets were integrated into a metadata set of 1133 HCCs and 9542 genes (data not sown). The 1133- HCC transcriptomic dataset was not annotated for CTNNB 1 mutational status; thus, we set up a robust pipeline to predict CTNNB 1 activating mutations (data not shown). The model achieved a prediction accuracy of 87% in the training set and 93% in the independent validation sets (data not shown).
  • HAL Histidine Ammonia-Lyase
  • VNN1 Vanin 1
  • nuclear ⁇ -catenin immuno staining was positively correlated with CTNNBl mutations, GLUL, ODAM and LGR5 and negatively with VNNl and HAL and (data not shown).
  • Tissue microarray-based immunohistochemistry in 20 HCCs carrying mutant versus 20 HCCs carrying wild-type CTNNBl revealed a clear-cut difference in GLUL expression between HCCs showing mutant versus wild-type CTNNBl at low power microscopic examination, whereas HAL and VNNl were globally higher in wild-type samples (data not shown).
  • ODAM protein expression was low in all samples (not shown), but detected in HCCs carrying mutant CTNNBl and expressing high GLUL (data not shown).
  • HAL HCC cell lines carrying wild- type CTNNBl, i.e., Huh7 or HepaRG, than in those carrying activating CTNNBl mutations, i.e., B16, BC2, HepG2 and Huh-6.
  • VNNl was expressed at much higher levels in HepaRG cells than in the cell lines carrying mutant CTNNBl.
  • Huh7 expressed VNNl at low levels.
  • ODAM was clearly expressed at higher levels in cell lines carrying mutant than in those carrying wild-type CTNNB 1.
  • the GSK3P inhibitor e-bromoindirubin-S -oxime (BIO), which activates ⁇ -catenin signaling,(17) strongly upregulated ⁇ -catenin-dependent transcriptional activity (data not shown).
  • BIO upregulated GLUL, LGR5 and ODAM (data not shown) and attenuated the increase in HNF4A, ALDOB, HAL and VNN1 mRNA expression over the 30 days required for differentiation of HepaRG progenitors to hepatocyte-like cells (data not shown).
  • HepaRG cells transfected with ⁇ -catenin targeting siRNA downregulated AXIN2 and ODAM and upregulated HAL and VNN1 mRNA expression (data not shown).
  • Predicted CTNNB1 mutations cluster within a homogeneous tumor subclass after analysis of transcriptomic data from 1343 HCCs
  • CTNNB1 was predicted to be mutated in 89% of HCCs (data not shown).
  • the red subclass showed the highest levels of GLUL, LGR5 and ODAM and the lowest levels of VNNl and HAL (data not shown).
  • Well-differentiated HCCs display a preserved metabolic liver zonation program.
  • ECM cancer extracellular matrix
  • HCC integrin cell-surface interactions
  • KRAS integrin cell-surface interactions
  • TGFB TGFB
  • IL6 the MMP14 network typical of invasive tumors.
  • the last HCC subclass was associated with high grade metastasis signatures, tumor aggressiveness with decreased patient survival,(23) the cancer stem cell program predicting metastasis and death(25) and upregulation of p53 mutation markers (data not shown). It was also enriched in signatures of cell cycle progression (MYC, RAC, AURKA, RBI and PDGFRB pathways), HCCs displaying stem cell features(26) and extrahepatic undifferentiated cancers of various origins, as well as cancer cell resistance to doxorubicin and vincristine. Thus, we called this subclass "STEM-type HCCs".
  • ECM- and STEM-type HCCs shared signatures of high tumor cell proliferation ⁇ ) and were associated with the Wnt/TGF- ⁇ (SI) HCC subclass, (5) indicating bad prognosis. (27) Also, they were both associated with early recurrence(28). Functional genomics findings were confirmed by gene ontology analysis of gene clusters (data not shown).
  • TCF4, ⁇ -catenin and HNF4A(20) governs the differential distribution of metabolic liver functions along the porto-central axis of the liver, which is known as "liver zonation".
  • HNF4A HNF4A-KO mice
  • Hnf4a-WT Hnf4a-WT mice
  • a first cluster was strongly upregulated in Hnf4a-KO mice and clearly enriched in genes upregulated in ECM/STEM HCCs.
  • a second cluster was downregulated in Hnf4a-KO mice and enriched in genes upregulated in Periportal-type HCCs. The rest of the genes (20%) were poorly affected by HNF4A.
  • Periportal-type HCCs show the most favorable clinical features and the highest early (2- year) disease-free and overall survival rates after resection
  • the Periportal-type is a well-differentiated, favorable-outcome HCC subclass carrying wild-type CTNNB1, displaying a periportal liver metabolic program and expressing HNF4A target genes.
  • the Peri venous-type is a well-differentiated HCC subclass carrying mutant CTNNB1, displaying a perivenous liver metabolic program and expressing ⁇ -catenin target genes.
  • STEM-type HCCs The overall survival of Perivenous-type HCCs was significantly more favorable than that of STEM-type HCCs in both the 247-HCC transcriptomic (Fig. IB) and in the 210-HCC RNAseq (data not shown) datasets.
  • a Periportal-type HCC gene signature we searched for genes meeting the following criteria: >2 fold change between the Periportal and the other HCC subclasses; high connectivity within the periportal gene network in HCCs (>0.30 correlation coefficient with >50% of the genes) and association with survival (p ⁇ 0.05 in >7/8 tests.
  • the resulting 8-gene Periportal-type HCC signature (Fig. ID) was associated with favorable overall and disease-free outcome in the 247-HCC transcriptomic (34) (Fig. IE) and in the 210-HCC RNAseq (Fig. IF) datasets.
  • Periportal-type HCCs showed the lowest early (2-year) recurrence and the highest overall survival rates after resection among all other HCCs taken together. Univariate and multivariate survival analysis revealed that the Periportal-type HCC signature was independently associated with low early recurrence after HCC resection.
  • the Periportal-type HCC signature was predominantly expressed in normal liver, as shown by analysis of their mRNA expression levels in 84 tissues, (35, 36) from the GSE1133 microarray dataset (data not shown).
  • the expression levels of the eight genes constituting the signature were highly correlated (data not shown). These genes were expressed at higher levels in Periportal-type HCCs than in the other HCC subclasses (Fig. ID).
  • the expression levels of these genes in 70 Periportal HCCs were closer to those detected in 232 non-tumor livers than in 167 non-Periportal HCCs. Two of these genes (AGXT and OTC) were not significantly different in non-tumor livers from Periportal HCCs (data not shown).
  • Example 2 Exploration of the impact of phenotypic diversity in the outcome of Peri venous-type HCCs.
  • HepaRG cells expressing mutated CTNNBl confirmed the specificity of the mutation markers GLUL, LGR5, HAL, VNN1 and ODAM (data not shown).
  • HCCs with mutated CTNNBl Discriminant analyses revealed the phenotypic diversity of HCCs with mutated CTNNBl, which ranged from well-differentiated tumors with hepatocyte-like features to HCCs expressing a stem/progenitor-like cell program. Thus, HCCs with mutated CTNNBl could develop substantial cancer stem/progenitor cell subpopulations overtime. Conclusions: Albeit non-proliferative, HCCs with mutant CTNNBl may evolve toward an undifferentiated phenotype with bad outcome, which justifies early HCC detection.
  • Bonzo JA Ferry CH, Matsubara T, Kim JH, Gonzalez FJ. Suppression of hepatocyte proliferation by hepatocyte nuclear factor 4alpha in adult mice. The Journal of biological chemistry 2012;287:7345-7356.
  • Odontogenic ameloblast-associated protein inhibits growth and migration of human melanoma cells and elicits PTEN elevation and inactivation of PI3K/AKT signaling.
  • Minguez B Hoshida Y, Villanueva A, Toffanin S, Cabellos L, Thung S, Mandeli J, et al. Gene-expression signature of vascular invasion in hepatocellular carcinoma. Journal of hepatology 2011;55: 1325-1331.
  • Neoangiogenesis-related genes are hallmarks of fast-growing hepatocellular carcinomas and worst survival. Results from a prospective study. Gut 2016;65:861-869.

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Abstract

La présente invention concerne la prédiction du résultat de l'issue de la maladie d'un patient souffrant de HCC. Cette étude a été conduite pour déterminer si des HCC non prolifératifs portant le CTNNB1 de type sauvage sont pris en considération comme sous-classe de tumeur distincte, cliniquement pertinente. Les inventeurs ont construit un ensemble de métadonnées transcriptomiques 1133-HCC et ont identifié quatre sous-classes de HCC par l'intermédiaire d'analyses discriminantes et de regroupement hiérarchique. Ils ont mis au point un procédé de prédiction des mutations CTNNB1 dans un ensemble indépendant de 225 HCC à séquençage β-caténine et de classification validée de HCC, de prédiction de mutations CTNNB1 et d'analyses de survie dans un ensemble de données d'ARNseq séquencées de génome complet 210-HCC. L'ensemble, des analyses des données provenant de 1 568 patients HCC a permis d'identifier deux nouvelles sous-classes bien différenciées, à faible prolifération de HCC. Les deux sous-classes (type périportail et type périveineux) ont présenté des issues favorables de la maladie. Les HCC de type périportail ont présenté les taux de survie sans récurrence à 2 ans les plus élevés, suggérant que ces tumeurs présentent le potentiel le plus faible de récurrence précoce parmi tous les HCC. Ainsi, l'invention concerne un procédé de prédiction du temps de survie d'un patient souffrant de HCC comprenant la détermination du niveau d'expression des gènes sélectionnés dans le groupe constitué de AGXT, FETUB, GLS2, GNMT, SLC10A1 et SLC22A7.
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CN113416786A (zh) * 2021-08-09 2021-09-21 深圳市人民医院 一种用于肝细胞癌预后评估的生物标志物组合及其筛选方法和应用
CN114252612A (zh) * 2021-12-10 2022-03-29 四川大学华西医院 基于神经细胞粘附分子的肝癌转移预测系统及方法
CN114252612B (zh) * 2021-12-10 2023-11-14 四川大学华西医院 基于神经细胞粘附分子的肝癌转移预测系统及方法

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