EP2467496A1 - Procédé de détermination du risque de formation de métastases servant d'indicateur pour un diagnostic d'imagerie - Google Patents

Procédé de détermination du risque de formation de métastases servant d'indicateur pour un diagnostic d'imagerie

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Publication number
EP2467496A1
EP2467496A1 EP10732854A EP10732854A EP2467496A1 EP 2467496 A1 EP2467496 A1 EP 2467496A1 EP 10732854 A EP10732854 A EP 10732854A EP 10732854 A EP10732854 A EP 10732854A EP 2467496 A1 EP2467496 A1 EP 2467496A1
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European Patent Office
Prior art keywords
expression
risk
metastasis
increased
tumor
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EP10732854A
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German (de)
English (en)
Inventor
Michael Untch
Ralph Markus Wirtz
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Siemens Healthcare Diagnostics Inc
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Siemens Healthcare Diagnostics Inc
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Priority to EP10732854A priority Critical patent/EP2467496A1/fr
Publication of EP2467496A1 publication Critical patent/EP2467496A1/fr
Withdrawn legal-status Critical Current

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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 is in the field of in vitro diagnostics and relates to a method for determining the metastasis risk of a tumor, wherein a high risk of metastasis indicates that subsequent examinations are indicated to the patient by means of imaging methods are.
  • Cancers are the second leading cause of death in Europe. Currently, about 100 different cancers are known, which differ greatly in disease pattern, chance of survival and treatment options. In particular, the metastasis, d. H. The removal of tumor cells of the primary tumor into other, sometimes distant organs is of crucial importance for the survival of a patient.
  • tumor diagnostics in vitro methods for the determination of tumor markers are increasingly used, such.
  • tissue-based gene studies at the RNA or DNA level or blood tests. These markers allow disease prediction, efficient follow-up, and therapy assessment.
  • Further indications for tumor-diagnostic markers are the investigation of risk groups (eg in case of a positive family history, liver cirrhosis, undescended testicles, gynecological tumors), the differential diagnosis in case of unclear tumors, eg. For example, in an unfindable primary tumor and the prognosis of the course of the disease.
  • the goal of tumor diagnosis is the Increasing the survival time for the affected patient, improving his quality of life, but also reducing treatment and other follow-up costs.
  • Previous genetic examinations usually have the aim of enabling prognostic or predictive statements regarding a defined initial treatment of a tumor disease. The statements are not specified at a specific time or the location of metastases. The previous genetic studies also have no aim to predict the failure of a primary treatment for the purpose of performing an adapted aftercare and secondary treatment.
  • Tumor markers are substances that are produced by the cancer itself or by the organism in response to tumor growth. Tumor markers occur in elevated concentrations in the blood or other body fluids, e.g. As tear secretions, ascites, cerebrospinal fluid or urine. Determining the concentration of tumor markers allows conclusions to be drawn as to the presence, course and prognosis of tumor diseases.
  • the measurable concentration of tumor markers in body fluids depends, inter alia, on the total number of tumor cells (tumor mass), the reaction of the surrounding tumor stroma, the rate of synthesis of the tumor marker, the blood and lymph supply of the tumor and the marker-specific half-life.
  • tumor markers which have so far been used mostly in serum and plasma diagnostics, almost without exception are characterized by unsatisfactory sensitivity and specificity.
  • metastases of hormone receptor-negative high-risk tumors are not recognized by conventional markers such as CEA and CA15-3 [Sener Dede D, Aksoy S, Bulut N, Dizdar O, Arik Z, Gulu I 1 Ozisik Y, Altundag K (2009) Comparison of serum levels of CEA and CA 15-3 in triple-negative breast cancer at the time of metastases and serum levels at the time of first diagnosis.
  • metastasis screening designed purely for tumor marker diagnostics in blood samples can not exceed a sensitivity of 60-70%.
  • the primary diagnosis of a tumor disease is generally diagnosed by a clinical examination, by imaging and / or endoscopic procedures and / or a biopsy with subsequent pathological clarification. Subsequently the tumor-specific laboratory parameters are determined in vitro, since tumor follow-up must be planned at the time of the primary diagnosis.
  • Most cancers are treated as potentially systemic diseases because there is already a significant risk for the presence of unrecognizable micro- or macro-metastases in more distant body regions at an early stage.
  • systemic therapy eg, chemotherapy or endocrine therapy
  • chemotherapy e.g., chemotherapy or endocrine therapy
  • endocrine therapy e.g., chemotherapy or endocrine therapy
  • These minimal residual diseases are at the early time of primary treatment of the primary tumor using the standard in vivo imaging techniques, such as.
  • PET-CT, PET-MRI or MRI are not yet detectable.
  • the growth of non-detectable micrometastases to clinically manifest macrometastases takes different lengths, depending on the tumor biology of the primary tumor, overall constitution of the patient and more or less random implantation of tumor cells in distant organ systems.
  • the lymph node status of cancer patients is conventionally determined by surgical removal of the axillary lymph nodes and pathological assessment thereof.
  • this parameter alone is insufficiently sensitive and specific with respect to the presence of micrometastases and their development into lethal macrometastases and also says nothing about the time or place of metastasis.
  • biopsy is completely unsuitable for screening (screening) wide asymptomatic collectives.
  • Another form of tumor diagnostics is the use of so-called imaging techniques. These are understood as investigation methods by means of which structures and organs of the body can be made visible. Examples include X-ray examinations, computed tomography, magnetic resonance imaging, ultrasound diagnostics, scintigraphy, positron emission tomography. Endoscopy also falls under the imaging techniques, but in contrast to the above methods, a probe must be inserted into the body of the patient. Imaging methods have the disadvantage that they are associated with high costs and often go hand in hand with radiation exposure. Therefore, these methods are also not suitable for screening large asymptomatic collectives.
  • the object of the present invention is therefore to provide a noninvasive in vitro method with which the metastasis risk of a tumor can be predicted reliably, ie specifically and sensitively, or with which those cancer patients can be identified with high probability To develop metastases.
  • diagnostic is understood to mean the proportion of true-positive test results in the total number of all patients in percent.
  • diagnosis specificity is understood to mean the proportion of true-negative test results in the total number of non-sufferers in percent.
  • tissue-based gene measurement or also the combination of tissue-based gene measurement and blood-based tumor marker measurement can be used to predict metastasis screening with high sensitivity and meaningful specificity.
  • This makes it possible for the first time at the time of the first diagnosis or shortly before or after the first treatment, which generally usually surgery, radiation, chemo and possibly also includes endocrine therapies, to be able to carry out a further therapy planning, which includes an intensified aftercare program.
  • metastatic risks are predicted time-dependent, so that, in contrast to the usual predictors, risk collectives are defined that are time-dependent, for example within the first three years or in the years 3 to 5 or in the years 8 to 12 after initial diagnosis, for a defined metastatic event are enriched.
  • the object is achieved according to the invention in that at least the expression of MMP7 is quantitatively determined in a biological sample of a tumor patient, wherein a high (increased) MMP7 expression indicates an increased risk of metastasis and a lack or low MMP7 expression does not indicate an increased metastasis risk.
  • 604 patients with advanced breast tumors T1-3 N1 MO or T3N0M0
  • Formalin-fixed and paraffin-embedded samples from 315 treatment-na ⁇ ve patients were available for analysis.
  • RNA from a 10 ⁇ m tumor section was isolated by means of a semi-automated, bead-based technique (Bohmann K.
  • RNA Extraction from Archival FFPE Tissue A Comparison of Manual, Semi-Automated and Mobile Automated Purification Methods Clin Chemistry 2009, ePub JuIy 17, 2009).
  • the relative expression values of MMP7 were then used by quantitative PCR using TaqMan® probes for the respective target genes and housekeeping genes identical to the previously published data and methods [Pentheroudakis G. et al., Gene expression of estrogen receptor, progesterone receptor and microtubule -associated protein Tau in high-risk early breast cancer: a quest for molecular predictors of treatment benefit in the context of a Hellenic Cooperative Oncology Group trial. Breast Cancer Res Treat.
  • the number of reaction cycles is used as the measured value for this gene.
  • the height of this measurement correlates with the amount of mRNA of a target gene present in the tissue sample.
  • the threshold is exceeded depending on the initial amount of the target gene at a different early time of the reaction cycles performed. The more mRNA was present, the sooner the threshold is exceeded.
  • the reaction cycle, in which the threshold value of the respective gene is exceeded, is also referred to as the "CT” value ("cycle of threshold”).
  • a CT value which is higher by the value 1 corresponds to a doubling of the starting amount of the target gene RNA, which corresponds mathematically to a logarithmic representation of the relative gene expression.
  • the term "increased risk of metastasis” is understood to mean a risk of the occurrence of metastases, in contrast to the status-dependent basic risk of the occurrence of metastases for a particular type of tumor taking into account the influence of any treatment, tumor size, proliferation status of the tumor cells, age of the patient, etc It is known, for example, that in the case of nodal positive breast cancer despite chemotherapy and endocrine therapy there is a basic risk of approximately 15% to 20%, and adjuvant treatment within 5 years after the first diagnosis in neoadjuvant treated patients or after surgery In the example of the adjuvant HE10 / 97 study, the risk of having distant metastasis within the first three years was about 20% in the subgroup of 315 patients examined, ie within the first three patients of the patient group Years a symptomatic distant metastasis discovered (Figure 3).
  • the invention relates to a method for determining the risk of metastasis of a tumor, wherein in a biological sample of a tumor patient at least the expression of MMP7 is quantified, wherein a high (increased) MMP7 expression indicates an increased metastatic risk and a lack or low MMP7 expression does not indicate an increased metastatic risk.
  • the method according to the invention has the advantage that an increased risk of metastasis of a tumor can be reliably predicted and that a cancer patient can thus be assigned to a risk group for whom diagnostic follow-up examinations aimed at distant metastasis, preferably by means of imaging methods, are indicated. Furthermore, in the high-risk group for early metastasis, follow-up after more than three years can be saved.
  • "Remote metastasis-targeted diagnostic follow-up examinations” include, in particular, imaging techniques by means of which structures and organs of the living body can be visualized, for example x-ray examinations, computed tomography (CT), magnetic resonance imaging, ultrasound, scintigraphy, positron emission tomography (PET ), Magnetic resonance imaging (MRI).
  • the method according to the invention already enables a follow-up planning for the targeted further treatment of the patient at the time of the primary diagnosis of the primary tumor or shortly before or after the first treatment, which generally comprises surgery, radiation, chemotherapy and / or endocrine therapy.
  • the method according to the invention thus makes it possible to identify patients who, because of their increased risk of metastasis, will benefit from intensified follow-up, preferably by means of imaging techniques, in that metastases can be detected and treated as early as possible by means of a targeted, regular examination by means of imaging techniques improve the chances of survival.
  • the method according to the invention makes it possible to identify patients who would not benefit from intensified follow-up by means of imaging methods because of an undiminished risk of metastasis.
  • the expression of ESR1 in a biological sample of the tumor patient is determined quantitatively, wherein a missing or low ESR1 expression indicates an increased risk of metastasis and a high (increased) ESR1 expression does not indicate an increased risk of metastasis.
  • Estrogen receptor activity directly represses stem cell activities of transcription factors that mediate stem cell properties (eg, Slug, Snail, FOXC2, and Twist) and indirectly inhibits other stem cell properties by upregulating inhibitory members of stem cell activity signaling pathways (e.g., increased expression of E-cadherin , thereby reducing WNT stem cell activity due to the decreased amount of beta-catenin).
  • Genes of interest in this regard are ESR1, MLPH, AR, ALCAM as hormone receptor marker genes and MMP7, SFRP1, Snail, Slug, FOXC2, TWIST, KRT5, notch, TGFB, OPN as stem cell activity marker.
  • ESR1 and MMP7 are exemplified.
  • the difference between the two negatively regulated genes MMP7 and ESR1 was calculated by subtracting non-RPL37A normalized ESR 1 CT from the non-RPL37A normalized CT value of MMP7 (CT MMP7 - CT ESR1).
  • CT MMP7 - CT ESR1 CT MMP7 - CT ESR1
  • ESR1 - MMP7 both bills are equivalent.
  • this gene ratio for various reasons. On the one hand, because the ratio allows more breast cancer patients to be categorized as high-risk who metastasize within three years. This causes an increased sensitivity. With the MMP7 individual proof, 36 patients are assigned to the high-risk group and give an approx. 50% Remote metastasis risk (18 out of 36 MMP7 positive patients relapse).
  • Another advantage of this methodology is that the formation of the gene ratio by subtraction of the raw CT values eliminates the need to measure one or more housekeeping genes, which reduces the risk of biasing the data through systematic errors, if by definition "Neutral” and always uniformly produced housekeeping gene is not so evenly produced and in certain tumors, without being associated with the prognosis, the patient is produced stronger or weaker. This entails the risk that over or underestimation of the risk could result for individual tumors.
  • the inventive combination of two information-bearing genes that are counter-regulated, this risk is no longer. Furthermore, it saves on reagent costs, increases the throughput of patient samples and creates the possibility of a multiplex measurement of all necessary genes in only one reaction vessel (eg one well of a microtiter plate with 384 reaction chambers).
  • the expression of MAPT and the expression of RACGAP1 in a biological sample of the tumor patient is determined quantitatively, wherein a low MAPT expression combined with a high RACGAP1 expression indicates an increased risk of metastasis and a high MAPT Expression combined with low RACGAP1 expression indicates a low risk of metastasis (FIG. 6).
  • the ratio of the two processes can be determined in particular by the difference between the crude CT values or the values normalized to the housekeeping gene RPL37A.
  • the addition of MMP7 to the expression ratio RACGAP1 to MAPT makes sense.
  • the expression ratio of RACGAP1 to MAPT was linked to the RPL37A normalized MMP7 gene by decision tree with defined cut-off (DCT of 31.8 for MMP7 and 0.39 in the gene ratio of RACGAP1 MAPP) ( Figure 7). This detects a high-risk collective.
  • DCT decision tree with defined cut-off
  • splitting with MMP7 offers the possibility of predicting the site of metastasis, since the resulting MMP7 positive patient group preferentially metastasizes in the brain, lungs and liver, especially in the bones, especially if it is in addition to Her-2 / new positive tumors (DCT> 38 from Her-2 / neu).
  • the method according to the invention is suitable inter alia for determining the risk of metastasis of a tumor from the group of breast cancer, ovarian carcinoma, colorectal carcinoma, lung carcinoma, gastric carcinoma and head and neck carcinoma.
  • the quantitative determination of the expression of a gene can be carried out both at the nucleic acid level (eg RNA hybridization techniques, RT-PCR methods, array-based methods) and at the protein level (eg immunological detection methods such as ELISA or RIA).
  • the quantitative determination of the expression of a gene by detecting the mRNA by means of reverse transcription and polymerase chain reaction (RT-PCR).
  • the quantitative determination of the expression of a gene at the mRNA level can be carried out by any suitable method, e.g. With kinetic PCR or gene expression array techniques, including commercially available platforms such as TaqMan®, Lightcycler®, Affymterix, Illumina, Luminex, Planar Waveguide, microarray chips with optical, magnetic, electrochemical or gravimetric chips
  • the determination of the expression of a gene such as MMP7, RACGAP1, MAPT and / or ESR1, is carried out in a biological sample of a tumor patient, preferably in a sample of tumor tissue, the z. B. was obtained by biopsy.
  • the tumor tissue may be fresh or it may be fixed and / or embedded, for example with formalin and / or paraffin.
  • the biological sample must be pretreated to provide the analyte (s), i. H. the gene expression products of the genes, eg. As proteins or mRNAs, for a subsequent detection reaction to enrich or make available.
  • the invention has been tested as an embodiment on a breast cancer study cohort.
  • a prospective randomized clinical trial Hellenic Cooperative Oncology Group Trial HE 10/97
  • a total of 595 high-risk breast cancer patients (T1-3N1 M0 or T3N0M0) treated with chemotherapy were treated over a 3-year period (1997- 2000).
  • These patients had been biopsied for tumor tissue fixed with formalin and embedded in paraffin (FFPE sample material).
  • FFPE sample material formalin and embedded in paraffin
  • the mRNA was isolated from this FFPE sample material by mRNA extraction and purified by reverse transcription and associated kinetic PCR (kPCR). Based on TaqMan® (Applied Biosystems) the expression of the various marker genes was quantified.
  • FIG. 1 A first figure.
  • the relative expression level was determined according to the formula "40- (CT MMP7-CT RPL37A)", so that a comparatively high number corresponds to a high expression level of MMP7, while a low value corresponds to a low MMP7 level of expression.
  • the genes MMP7 and RPL37A were measured by reverse transcription and related kinetic PCR based on TaqMan®.
  • the fluorescence signals generated within the kinetic PCR reaction are proportional to the initial amount of the original gene particles (RNAs or mRNAs) and exceed a predefined threshold according to the
  • CT value The CT values thus obtained were then transformed into a relative and normalized by either the formula "40- (CT target gene - CT housekeeping gene)", ie "40- (CT MMP7-CT RPL37A)"
  • breast cancer subtypes are listed according to their specific metastasis time; For example, triple negative tumors (classically due to immunohistochemistry negativity for ER, PR, and Her-2 / redefined) metastasize earlier (up to three years), often show elevated MMP7 expression and concomitantly decreased ESR1 expression, and preferentially metastasize to lung (See also below.)
  • the reduction to two major biological motifs for breast cancer, ie stem cell activity and hormone receptor activity allows the prediction of metastatic events in both timing and localization
  • WNT stem cell activities as measured by MMP7 marker gene expression, prevent implantation of tumor cells migrating into the blood and / or lymph circulation into the bones, in particular due to the increased expression of SFRP1 (DCT> 35 according to the formula "40 - (CT SFRP1 - CT RPL37A) ", ie after Abgle me on the housekeeping gene RPL37A.
  • SFRP1 prevents the activation of Bone marrow stem cells and thus prevents the Einnistung of circulating tumor cells in the bone and their development into micrometastatic lesions.
  • Tumor cells with increased stem cell activity represented by increased expression of MMP7 (DCT> 33), SPP1 (DCT> 38), have the ability to metastasize into bone simultaneously with low expression of SFRP1 (DCT ⁇ 35). This is especially true for Her-2 / neu positive tumors that inhibit SFRP1 expression due to Her-2 / neu-related activity.
  • the degree of direct and indirect, negative interaction of stem cell activities is crucial for the metastasis behavior.
  • Estrogen receptor activity mediated largely by the isoforms of ESR1 when there is sufficient estrogen, directly represses transcription factors that mediate stem cell properties (eg, Slug, Snail, FOXC2, and Twist) and indirectly inhibits other stem cell properties by upregulating inhibitory members of stem cell activity.
  • Signaling pathways eg, increased expression of E-cadherin, thereby reducing WNT stem cell activity due to the decreased amount of beta-catenin).
  • ESR1 increased expression after alignment on RPL37A as of DCT 34
  • MLPH increased expression after alignment on RPL37A as of DCT 34
  • ALCAM increased expression after alignment on RPL37A as of DCT 34
  • Hormone receptor marker genes and MMP7 increased expression after alignment on RPL37A from DCT 32
  • SFRP1 increased expression after alignment on RPL37A from DCT 35
  • KRT5 increased expression after alignment on RPL37A from DCT 34
  • OPN increased expression after alignment on RPL37A DCT 34
  • ESR1 have an elevated and early metastasis rate in the time frame between one and three years ("1", lower red line)
  • Example characterized the tumors whose DCT ratios of MMP7 and ESR1, according to the formula "(40 - (CT MMP7 - CT RPL37A)) - (40 - (CT ESR1 - CT RPL37A))” or "CT MMP7 - CT ESR1" , above the value -2,7.
  • Patients with MMP7-negative tumors ("2", upper green line) show no increased and early metastasis rate in the 1 to 3 year window compared to the underlying risk within this cohort shown in FIG.
  • the genes RACGAP1 and MAPT were measured by reverse transcription and related kinetic PCR based on TaqMan®.
  • FIG. 1 shows by way of example a refined algorithm consisting of the gene ratio of RACGAP1 and MAPT in combination with MMP7 as a flowchart or decision tree.
  • Primary breast tumors from 315 patients were available for analysis. Based on the ratio of RACGAP1 to MAPT and the cut-off point of DCT 0.39, the patients were divided into two groups.
  • cytoskeleton of the cell is of crucial importance for cell division and migration.
  • the balance between migration and micrutulbar stabilization is of crucial importance for both the level of cell division activity (Y-axis), as well as the time of distant metastasis (X-axis) and the location of distant metastasis.
  • breast cancer subtypes are listed according to their specific metastasis time; For example, triple negative tumors (classically due to immunohistochemistry negativity for ER, PR and Her-2 / redefined) metastasize earlier (up to three years), often show elevated RACGAP 1 expression and simultaneously decreased MAPT expression, and preferentially metastasize in lung, brain and liver and more rarely in the bones (see also below) .
  • triple negative tumors classically due to immunohistochemistry negativity for ER, PR and Her-2 / redefined metastasize earlier (up to three years)
  • RACGAP 1 epidermatitis
  • MAPT preferentially metastasize in lung, brain and liver and more rarely in the bones
  • the reduction to two crucial biological motifs for breast cancer both on regulation of the microtubule cell skeleton, allows prediction of metastatic events.
  • the hormone receptors ESR1 and PGR influence the microtubulidynamics by increasing the MAPT expression in order to differentiate the cells.
  • the degree of positive versus negative regulation of microtubility is crucial for metastasis behavior and resistance to chemotherapeutic agents. This is particularly relevant for resistance to taxane-containing therapies (such as in the HE10 / 97 study) because they are said to "freeze” the microtubule system and cause suicide of the dividing or migrating cell
  • genes of interest in this regard are RACGAP1 (increased expression after alignment on RPL37A from DCT 34) and TOP2A (increased expression after alignment on RPL37A as of DCT 34), as cell division and migration motif and MAPT (increased expression after alignment on RPL37A as of DCT 34), ESR1 (ESR1) increased expression after alignment on RPL37A from DCT 34), PGR (increased expression after alignment on RPL37A from DCT 32), as a microtubule stabilization and differentiation motif
  • RACGAP1 and MAPT are exemplified (see target gene activity)
  • Tumors with elevated RACGAP1 to MAPT ratio (DCT> 0.39) using ALCAM identified those tumors that have a low risk of metastasis.
  • the decision point used is the cut-off of RPL37A normalized ALCAM values at a DCT value of 35.4.
  • Tumors with ALCAM expression above DCT 35.4 are at lower risk ("2" mean green line, 10% femtastasis rate at three years) than tumors with lower ALCAM expression ("3" lower blue line; 44% femtastastation rate after three years) years).
  • the low-cost protocol is characterized by a low ratio of RACGAP1 to MAPT (DCT ⁇ 0.39) and is identical to the low-cost protocol of Figures 8 and 6.
  • sequence accession numbers are from the following database: http://genome.ucsc.edu/ UCSC Genome Browser:

Abstract

L'invention se rapporte au domaine du diagnostic in vitro et concerne un procédé de détermination du risque de formation de métastases d'une tumeur, un risque élevé de formation de métastases signifiant que des essais subséquents au moyen de procédés d'imagerie sont indiqués pour les patients.
EP10732854A 2009-08-21 2010-06-29 Procédé de détermination du risque de formation de métastases servant d'indicateur pour un diagnostic d'imagerie Withdrawn EP2467496A1 (fr)

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EP10732854A EP2467496A1 (fr) 2009-08-21 2010-06-29 Procédé de détermination du risque de formation de métastases servant d'indicateur pour un diagnostic d'imagerie
PCT/EP2010/003938 WO2011020522A1 (fr) 2009-08-21 2010-06-29 Procédé de détermination du risque de formation de métastases servant d'indicateur pour un diagnostic d'imagerie

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WO2019154884A1 (fr) * 2018-02-07 2019-08-15 Ecole Polytechnique Federale De Lausanne (Epfl) Procédé de détermination de l'invasivité du cancer et du pronostic d'un patient
CN111681712A (zh) * 2020-05-29 2020-09-18 董晓荣 一种组合物在制备用于确定非小细胞肺癌患者脑转移风险状态的诊断试剂中的应用

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WO2007030611A2 (fr) * 2005-09-09 2007-03-15 The Board Of Regents Of The University Of Texas System Indice calcule d'expression genomique de recepteurs des oestrogenes (er) et genes associes aux er
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