WO2011039734A2 - Utilisation de gènes impliqués dans l'indépendance d'ancrage pour l'optimisation du diagnostic et du traitement du cancer humain - Google Patents

Utilisation de gènes impliqués dans l'indépendance d'ancrage pour l'optimisation du diagnostic et du traitement du cancer humain Download PDF

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WO2011039734A2
WO2011039734A2 PCT/IB2010/054470 IB2010054470W WO2011039734A2 WO 2011039734 A2 WO2011039734 A2 WO 2011039734A2 IB 2010054470 W IB2010054470 W IB 2010054470W WO 2011039734 A2 WO2011039734 A2 WO 2011039734A2
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gab2
cancer
signature
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expression
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Enzo Medico
Claudio Isella
Alessia Mira
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Enzo Medico
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    • 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
    • C—CHEMISTRY; METALLURGY
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    • 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
    • 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
    • G01N33/57415—Specifically defined cancers of breast
    • 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
    • G01N33/5743—Specifically defined cancers of skin, e.g. melanoma
    • 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
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • 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
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    • 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
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    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers
    • G—PHYSICS
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    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/60—Complex ways of combining multiple protein biomarkers for diagnosis

Definitions

  • the present invention is related to identification of GAB2-driven processes and anchorage independence associated with diagnosis, prognosis, metastasis, metastatic relapse, metastatic potential and prediction of response to treatment of cancers.
  • a GAB2-signature based on anchorage independence is identified which can serve to define processes relevant to progression and response to treatment of human cancers.
  • GFs growth factors
  • ECM extracellular matrix
  • MCF10A cells a spontaneously immortalized human breast line (Soule et al. 1990, Cancer Res, 50, 6075-6086) that relies on both GFs and anchorage to proliferate. When these cells are cultured in the absence of anchorage, for instance on polyhema-coated plates, they undergo growth arrest and detachment- induced apoptosis, also known as anoikis (Reginato et al. 2003).
  • MCF10A cells represent an ideal model to screen for genes conferring anchorage-independence.
  • Xenoarray analysis based on transduction of mammalian cells of a given species with an expression library from another species, followed by one-shot quantitative tracing with DNA microarrays of library-derived transcripts before and after a selective stress, to disclose genes conferring resistance to the selection (Martelli et al. 2008, BMC Genomics, 9, 254).
  • MCF10A cells were selected for growth in suspension and murine microarrays were used to compare signal intensities for the exogenous cDNAs before and after selection, to detect the enriched ones.
  • Independent infection-selection experiments highlighted significant and reproducible enrichment for murine Gab2-encoding transcripts, suggesting a role of this gene in anchorage-independent growth.
  • Gab2 promotes anchorage-independent growth of normal and neoplastic cells, and drives a transcriptional program linked to metastatic progression of breast cancer.
  • the invention provides identification of GAB2-driven processes and anchorage independence associated with diagnosis, prognosis, metastasis, metastatic relapse, metastatic potential and prediction of response to treatment of cancers. Furthermore, a GAB2-signature based on anchorage independence is identified which can serve to define processes relevant to progression and response to treatment of human cancers.
  • the invention provides a method for diagnosing or prognosing cancer in subjects comprising detecting expression of GAB2 and/or of its transcriptional target genes in the tumor tissue and/or in tumor cells isolated from the subject.
  • the method provides GAB 2- signature genes of the invention useful for diagnosis or prognosis of any human cancer, especially breast cancer and myeloma, comprising detecting in the tumor tissue and/or in tumor cells isolated from the subject expression of at least two of GAB2-signature genes listed in Table 1, 2, 3, 4 or 5.
  • the two genes can be selected from a single independent list (single table) or across the tables (more than one table).
  • the invention provides a method for predicting metastasis or metastatic relapse or metastatic potential or response to treatment in cancer patients comprising detecting the expression of GAB2 and or its transcriptional target genes in the tumor tissue and/or in tumor cells isolated from the subject.
  • the method provides GAB2- signature genes of the invention useful for diagnosis or prognosis of any human cancer, especially breast cancer and myeloma, comprising detecting in the tumor tissue and/or in tumor cells isolated from the subject expression of at least two of GAB2-signature genes listed in Table 1, 2, 3, 4 or 5.
  • the two genes can be selected from a single independent list (single table) or across the tables (more than one table).
  • the cancer treatment as provided herein encompasses all know cancer treatment including targeted drug therapy, chemotherapy, radiation therapy or a combination thereof.
  • the invention provides a method of treating a subject with cancer comprising the steps of:
  • the invention also provides a method of treating a subject suffering from cancer comprising the steps of:
  • the invention provides a method of using in vitro anchorage independence model for deriving gene signature, the said signature comprising a set of genes associated with diagnosis, prognosis, metastasis and predicting response to treatment in cancer.
  • the gene signature of the said method is GAB2-signature comprising at least two GAB2 and or its transcriptional target genes listed in Tables 1 , 2, 3, 4 or 5.
  • the two genes can be selected from a single independent list (single table) or across the tables (more than one table).
  • a method of predicting the grade of a tumor in a cancer patient comprising detecting the expression of GAB2 and/or its transcriptional target genes in the tumor tissue and/or in tumor cells isolated from the subject.
  • This method encompasses detecting the expression of at least two of GAB2-signature genes listed in Table 1, 2, 3, 4 or 5.
  • the two genes can be selected from a single independent list (single table) or across the tables (more than one table).
  • the invention also provides a GAB2-signature for diagnosing or prognosing human cancer, especially breast cancer or myeloma, in subjects comprising GAB2 and/or its transcriptional target genes in the tumor tissue and/or in tumor cells isolated from the subject as diagnostic or prognostic markers.
  • the diagnosis or prognosis comprises detecting in the tumor tissue and/or in tumor cells isolated from the subject expression of at least two of GAB 2- signature genes listed in Tables 1, 2, 3, 4 or 5.
  • the two genes can be selected from a single independent list (single table) or across the tables (more than one table).
  • the invention provides a GAB 2- signature for predicting
  • cancer patients including breast cancer and myeloma patients, comprising GAB2 and or its transcriptional target genes.
  • the prediction of metastasis, metastatic relapse, metastatic potential or response to treatment is detected in tumor tissue and/or in tumor cells isolated from the patient expression of at least two of GAB2-signature genes listed in Tables 1, 2, 3, 4 or 5.
  • the two genes can be selected from a single independent list (single table) or across the tables (more than one table).
  • the cancer treatment as provided herein encompasses all know cancer treatment including targeted drug therapy, chemotherapy, radiation therapy or a combination thereof.
  • the invention provides an array comprising polynucleotides capable of specifically hybridizing to at least two genes listed in Table 1, 2, 3, 4 or 5.
  • the invention also encompasses kit comprising the array for diagnosing or prognosing cancer or predicting metastasis or metastatic relapse or metastatic potential of cancer cells in a subject by determining the expression of at least 2 genes listed in Table 1, 2, 3, 4 or 5. Furthermore, a kit for diagnosing or prognosing cancer cells or predicting metastasis or metastatic relapse or metastatic potential of cancer cells in a biological sample comprising a primer pair for amplifying a nucleic acid sequence selected from a group consisting of GAB 2- signature genes listed in Table 1, 2, 3, 4 and 5 and containers for the primers is also provided.
  • kits for diagnosing or prognosing cancer cells or predicting metastasis or metastatic relapse or metastatic potential of cancer cells in a biological sample comprising an oligonucleotide probe that binds under high stringency conditions to an isolated nucleic acid sequence selected from a group consisting of GAB2-signature genes listed in Table 1, 2, 3, 4 and 5 and a container for the probe is also provided by the invention.
  • the invention provides a kit for diagnosing or prognosing cancer cells or predicting metastasis or metastatic relapse or metastatic potential of cancer cells in a biological sample comprising an antibody which binds immunologically to a protein having an amino acid sequence encoded by a polynucleotide selected from a group consisting of GAB2-signature genes listed in Table 1, 2, 3, 4 and 5 and a container for the probe.
  • Figure 1 Xenoarray analysis on MCF10A cells and acquisition of anchorage independence by library-transduced selected cells.
  • A MTT growth assay on polyhema-selected populations after 48h and 72h in adhesion or suspension, as indicated. Cell growth is expressed as a ratio between library-transduced and GFP-transduced cells, after normalization to the amount of viable plated cells at day 0. The data represent the mean and standard error of triplicate values (Adhesion 48h p ⁇ 0.05, Suspension 48h p ⁇ 0.01, Suspension 72h p ⁇ 0.05).
  • B Soft agar assay on GFP- and library-transduced cells, unselected or selected on polyhema, as indicated. Phase- contrast images were captured by a BD Pathway microscopic station (BD biosciences) after 3 weeks in agar.
  • C Dot plot of single colony sizes as calculated by the Attovision software (BD Biosciences, version 1.5) for the GFP-SEL and LIB-SEL populations grown in soft agar.
  • A Real-time PCR validation of enriched transcripts in both selections.
  • the y-axis represents the relative increase in abundance of the transcripts in selected cells compared to unselected cells.
  • B Western blot analysis on GFP- and library-transduced cells before and after selection to detect Gab2 protein enrichment.
  • A Mock and GAB2-overexpressing (GAB2) MCF10A cells were incubated in adhesion (ADH) or suspension (SUSP) in the presence or absence of MEK inhibitor (PD98059, 40 ⁇ ), PBK inhibitor (LY294002, 50 ⁇ ), Src inhibitor (PP2, ⁇ ), or JNK inhibitor (SP600125, ⁇ ).
  • MEK inhibitor PD98059, 40 ⁇
  • PBK inhibitor LY294002, 50 ⁇
  • Src inhibitor PP2, ⁇
  • JNK inhibitor SP600125, ⁇
  • Cell vitality was assessed with the MTT assay after 24h from the treatment and the drug effect was expressed as percent growth inhibition (with respect to untreated cells). The data represent the mean and standard error of triplicate values from two independent experiments.
  • B Boxplots of detailed analysis of the effects of Src inhibition by PP2 on cell growth in various conditions.
  • C Western blot analysis on Mock and Gab2-expressing cells in adhesion or after 24h and 48h in suspension. Antibodies directed against the activated form of Src (phosphorylated at tyrosine 416) and Stat3 (phosphorylated at tyrosine 705), or total Src or Stat3 were used.
  • FIG. 5 Knock-down of endogenous Gab2 impairs MCF10A growth and anchorage-independent growth of human neoplastic cells.
  • C Soft agar growth of cells expressing Gab2 shRNA or scramble vector (CTRL).
  • Phase-contrast images were captured by a BD Pathway microscopic station (BD biosciences) after 3 weeks in agar.
  • D Western blot analysis of Src and Stat3 activation in control and GAB2 shRNA- transduced cells, as indicated.
  • A Heatmap showing the expression of the two main gene functional modules in the NKI311 breast cancer dataset.
  • the samples (columns) are ordered by decreasing GAB 2- signature metastasis score (GAB2 MTS Score), which is graphically reported in the second row.
  • GAB 2- signature metastasis score GAB 2- signature metastasis score
  • the white vertical line crossing the heatmap indicates the 0 threshold value of metastasis score discriminating good and poor prognosis samples.
  • White and black dots on the right highlight the genes annotated to the two functional modules, respectively downregulated and upregulated in poor prognosis samples.
  • the GAB2-signature is independent from existing clinical and genomic breast cancer classifiers, and from estrogen receptor status.
  • GP good prognosis
  • PP prognosis
  • G-H Kaplan-Meier analysis on the 198-samples dataset subdivided in ER-negative (G) and ER-positive (H) samples, then further subdivided by the GAB2-signature in good prognosis (GP) or poor prognosis (PP) samples.
  • the GAB2-signature predicts prognosis in Estrogen Receptor-negative breast cancer.
  • GP prognosis
  • PP prognosis
  • Figure 9 The GAB2-signature predicts response of breast cancer to antineoplastic treatment.
  • A Receptor-Operated Channel (ROC) analysis of the performance of the GAB2- signature Metastasis Score as a predictor of response to neoadjuvant treatment in the Hess dataset. AUC indicates the area under the Curve.
  • B Dot plot analysis of the the GAB2- signature Metastasis score (x-axis) for the samples from patients showing pathological complete response (pCR) or residual disease (RD), as indicated.
  • Microarrays and realtime PCR generate highly correlated diagnostic scores. Dot plot showing the correlation between Metastasis Score calculated for 32 breast cancer samples from microarray data (x-axis) and from realtime PCR data (y-axis), using 15 genes of the GAB2 signature.
  • FIG. 11 The GAB2-signature is correlated to melanoma progression.
  • Heatmap showing Log2Ratio expression values for 83 Affymetrix probesets (rows) across tissue samples of different stages of melanoma progression (columns). The first row indicates the type of sample (from Normal Skin, black, to Metastatic Melanoma, white, as indicated). Samples have been subdivided, based on expression of the GAB2 genes, in four clusters of progressively increasing aggressiveness, from normal skin and benign nevi to metastatic melanoma.
  • GAB2 is a key promoter of anchorage independence of human neoplastic cells a. Gain-of-function screening for anchorage independence in MCFIOA cells
  • MCFIOA cells were transduced with a commercial mouse testis retroviral expression library (Stratagene) or with GFP as a control.
  • infections were performed in duplicate (A and B), using an estimated multiplicity of infection of 1 , to avoid multiple integrations in the same cell.
  • To detect and quantify library-derived transcripts we performed Xenoarray analysis (Martelli et al. 2008, BMC Genomics, 9, 254), by extracting total RNA from the four cell populations and hybridizing the resulting cRNAs on murine expression arrays, to allow specific detection of library-derived transcripts of murine origin.
  • Gab2 is a scaffolding/docking protein involved in multiple signaling pathways downstream from membrane receptors (Nishida et al. 1999, Blood, 93, 1809-1816).
  • MCFIOA cells To directly assess whether Gab2 may promote anchorage-independent growth, we transduced MCFIOA cells with the human Gab2 coding sequence, cloned in a retroviral vector (Brummer et al. 2006).
  • adherent GAB2-overexpressing cells showed a significant increase in proliferation, which was further enhanced in the absence of anchorage.
  • Gab2-driven growth advantage was almost totally lost when cells were kept in starving medium (no EGF, and serum lowered to 2%), indicating that Gab2 promotes proliferation independently from cell anchorage to the ECM, but dependently from the presence of GFs and/or serum. Accordingly, Gab2 overexpressing cells formed larger and more abundant colonies in soft agar, compared to wild-type cells ( Figure 3B).
  • To evaluate whether Gab2 promotes survival of detached cells we estimated the fraction of dead cells after 48h of suspension culture. Surprisingly, after 48h of polyhema plating, we detected a comparable extent of cell death between wild-type and Gab2-expressing cells (Figure 3C).
  • Gab2-driven anchorage independence requires Src, which typically is activated by integrins when cells are adherent and becomes inactivated upon detachment (Playford and Schaller 2004, Oncogene, 23, 7928- 7946). Consistently, western blot analysis on cell lysates from control and Gab2- expressing cells cultured in adhesion or suspension confirmed Gab2-driven activation of Src and of one of its downstream targets, Stat3 ( Figure 4C). In adhesion, Gab2-expressing cells displayed a stronger basal phosphorylation of Src. Active Src levels were reduced in cells kept in suspension, but while in control cells Src activation was completely abolished at 48h, Gab2expressing cells maintained some phosphorylation.
  • Metastatic potential as meant in the current specification relates to the ability of a cancer cell to invade and to spread of cancer cells to other parts of the body.
  • the same method that was used to derive the signatures in MCFIOA cells transduced with GAB-2 or under different experimental conditions as described above can be easily replicated for a variety of cancers, in particular breast cancer, to determine their metastatic potential, the response to treatments and prognosis of the disease.
  • a micro-array seeded with probes that represent the signature that was derived in the above experiment and use it against a fluorescent, chemiluminescent or similar detection-capable tagged probes derived from tumor biopsies to determine their metastatic potential as well as the responsiveness to antineoplastic treatments, together with the general prognosis of the disease.
  • Any alternative method for measuring expression of the signature genes, at the RNA or protein level such as for example quantitative PCR in an array format or individually or immunohistochemistry using antibodies targeted to the proteins encoded by few or all of the signature genes, can be easily employed for the same task.
  • the GAB2-signature is enriched in genes correlated to response to treatment and to metastatic propensity
  • Each line of the NCI-60 panel is annotated for sensitivity to a wide number of drugs.
  • Dasatinib is an oral small molecule inhibitor of Src-family kinases (Lombardo et al., 2004), currently employed for the treatment of leukemias. Recently, multiple clinical trials are assessing its efficacy on various solid tumors, including breast cancer and melanoma. These results confirm that the Src-STAT3 signaling axis plays a key role in GAB2-driven biological and transcriptional responses independently of tissue and cell type, and propose GAB2 and its transcriptional targets as predictors of sensitivity to targeted drugs blocking SRC and/or STAT3 activation. These studies also demonstrate the value of the assay in defining GAB2-driven signatures as predictor of many anti-cancer drugs whether singly or in combination and also response to other cytotoxic agents like radiation.
  • Such signatures could be a powerful tool for determining prior to treatment for breast cancer or other cancers, which drug or combination of drugs (or radiation) would be most effective against the tumor of a particular patient.
  • Such signature would also to a significant extent be able to identify the dose of the drug or combination of the drug would be most effective for treating the tumor of a particular patient. Practically, this would help the physician in avoiding using drugs or therapies that would not be expected to have any meaningful effect on the tumor of a particular patient and also identify the best drug or combination of drug and its dose that would be expected to have the most effect at the least doses.
  • the GAB2-signature could be associated to human breast cancer aggressiveness.
  • the signature was mapped on a 311-sample breast cancer dataset generated at the Netherland Cancer Institute on 2-color oligonucleotide microarrays (NKI dataset) and published in two works (van, V et al. 2002b; van, V et al. 2002a). After filtering for expression, the GAB2-signature was mapped to 150 probes.
  • the signature resulted to be strongly enriched in genes discriminating breast cancer patients with or without metastatic recurrence within five years from the initial
  • Determining the aggressiveness of cancer is a critical component of any treatment plan for cancer at present. This is typically done using histochemical assays of a section of the tumor tissue derived from a biopsy and visually observing the difference in tissue architecture between normal tissue and the tumor tissue (level of differentiation) using a microscope. Based on the experience of the pathologist, a grade is assigned to the tumor - - higher the grade, the more aggressive the tumor. The physician makes important decisions on the treatment design from this score as to how to treat including whether to treat the disease aggressively or not. The main pitfall of determining the grade by this method is that the grade value derived by two pathologists could vary as much as 50% leading to the physician making the wrong treatment design.
  • GAB2-associated gene expression signatures can be used to determine the grade of a tumor even though additional clinical studies would be required to assign accurate grade of a patient's tumor with a particular GAB2- driven signature.
  • a breast cancer classifier based on the GAB2-signature predicts metastatic relapse
  • ILMN_90844 Hs.430502 0 79239592 5.492 5.975 7.555 7.244 1.666
  • IGFBP5 46094066 7.516 7.814 5.907 5.536 -1.944
  • ILMNJ 23833 Hs.571652 0 13579761 4.104 4.711 6.471 7.080 2.368
  • ILMN_12288 NMJ20879.1 IAA1505 55741666 5.482 6.055 7.407 7.915 1.892
  • ILMNJ 1202 NM_000481.2 AMT 44662837 6.966 6.825 8.480 8.461 1.575
  • ILMNJ 7B82 NM_000201.1 ICAM1 4557877 5.194 5.426 6.784 6.966 1.565
  • ILMNJ 5059 NM_013269.2
  • CLEC2D 52426785 10.826 10.913 12.253 12.563 1.538
  • ILMNJ1 39 NM_002198.1 IRF1 4504720 9.600 9.730 11.063 11.357 1.545
  • ILMN_71591 Hs.19339 0 34191392 7.770 7.846 9.050 9.362 1.398
  • ILMNJ 608 NM_001070.3 TUBG1 34222287 9.796 9.729 8.397 8.332 -1.398
  • ILMNJ 29103 Hs.576922 0 27552801 7.093 7.597 5.463 5.687 -1.770
  • ILMN 28750 NM 000067.1 CA2 4557394 11.209 11.329 9.358 9.048 -2.066
  • ILMNJ0005 NM_031966.2 CCNB1 34304372 10.136 10.300 6.759 6.498 -3.590

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Abstract

La présente invention concerne l'identification de processus induits par GAB2 et de l'indépendance de l'ancrage associée aux diagnostic, pronostic, métastase, rechute métastasique, potentiel métastasique et prédiction de réponse au traitement de cancers. En particulier, une signature de GAB2 basée sur l'indépendance d'ancrage est identifiée, celle-ci pouvant servir à définir des processus associés à la progression et la réponse au traitement de cancers humains.
PCT/IB2010/054470 2009-10-02 2010-10-04 Utilisation de gènes impliqués dans l'indépendance d'ancrage pour l'optimisation du diagnostic et du traitement du cancer humain WO2011039734A2 (fr)

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WO2011039734A3 WO2011039734A3 (fr) 2012-02-23

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