WO2014190449A1 - Kit de test à réactif pour diagnostic assisté d'un patient atteint de carcinome pulmonaire non à petites cellules - Google Patents
Kit de test à réactif pour diagnostic assisté d'un patient atteint de carcinome pulmonaire non à petites cellules Download PDFInfo
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- WO2014190449A1 WO2014190449A1 PCT/CN2013/000629 CN2013000629W WO2014190449A1 WO 2014190449 A1 WO2014190449 A1 WO 2014190449A1 CN 2013000629 W CN2013000629 W CN 2013000629W WO 2014190449 A1 WO2014190449 A1 WO 2014190449A1
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Classifications
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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
- G01N33/57407—Specifically defined cancers
- G01N33/57423—Specifically defined cancers of lung
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
- G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
- G01N2333/4701—Details
- G01N2333/4742—Keratin; Cytokeratin
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/90—Enzymes; Proenzymes
- G01N2333/902—Oxidoreductases (1.)
- G01N2333/904—Oxidoreductases (1.) acting on CHOH groups as donors, e.g. glucose oxidase, lactate dehydrogenase (1.1)
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- G—PHYSICS
- G01—MEASURING; TESTING
- 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 relates to a kit for assisting diagnosis of a patient with non-small cell lung cancer.
- Lung cancer is a major disease that seriously threatens human life and health.
- WHO World Health Organization
- IAHO International Agency for Research on Cancer
- lung cancer is the leading malignant tumor with the highest morbidity and mortality.
- the number of new cases worldwide is 1,600,000, and the number of deaths is 1,377,000, accounting for 12.7% and 18.2% of all malignant tumors.
- WHO World Health Organization
- IAHO International Agency for Research on Cancer
- lung cancer is the leading cause of death in malignant tumors in the sample area, and the crude death rate is 30.83/100,000, of which 41.34/100,000 are male. Women 19.84/100,000; the first cause of cancer death among men and women. With the acceleration of global aging and the increase of environmental pollution, the incidence of lung cancer will continue to rise. Therefore, the demand for the development of diagnosis and treatment of lung cancer must be more and more intense.
- lung cancer can be divided into non-small cell lung cancer (NSCLC, about 85%) and small cell lung cancer (SCLC, about 15%).
- NSCLC non-small cell lung cancer
- SCLC small cell lung cancer
- lung cancer screening and diagnosis methods are mainly imaging techniques such as chest X-ray examination and CT scanning. Although these imaging data play an important role in diagnosis, there are also many limitations, such as high false positive rate, inability to detect recessive lesions, subclinical lesions, and micrometastatic lesions.
- diagnosis of lung cancer also includes invasive procedures such as bronchoscopy and perforating biopsy. These methods take a long time and increase patient suffering. Therefore, the search for non-invasive, non-radiative, low-cost, rapid diagnosis, sensitive and specific screening and diagnosis methods is an urgent need for early diagnosis of cancer.
- Tumor marker refers to a biologically active substance produced by tumor cells or tissues due to abnormal expression of oncogenes or other tumor-related genes and their products, or is itself detached from cancerous tissues, and has a certain degree of expression or yield in normal tissues or benign diseases. Very little. It reflects the development of cancer The process can be detected in tumor tissues, body fluids and excretions, and is widely used in the diagnosis of tumors, monitoring recurrence, metastasis, prognosis, and predictive efficacy.
- Several major markers that are widely recognized in clinical practice are: Tumor antigen 125 ( CA125 ) for ovarian cancer, antigen 19-9 (CA19-9) for pancreatic cancer, for colorectal cancer.
- CA125 Tumor antigen 125
- CA19-9 antigen 19-9
- PSA prostate specific antigen
- Other cancers, such as breast and lung cancer still lack credible tumor markers for screening.
- the markers that have been used in the clinical diagnosis of lung cancer are only protein markers, which are the following:
- CEA Gold and Freeman first discovered CEA in colorectal cancer in 1965. It is a glycoprotein with a molecular weight of 180KD and a half-life of 3-4 days. It is an antigen produced during embryonic development and drops significantly after birth. Its specificity is not strong, but it can be used for monitoring tumor development, efficacy judgment and prognosis estimation. It is not sensitive to early diagnosis. Although lung cancer patients have elevated, there are high false negatives and false positives, which are not suitable for lung cancer screening. Used alone in the diagnosis;
- CA125 Bast first discovered CA125, a macromolecular glycoprotein with a half-life of about 4. 8 days, mainly used in ovarian cancer, and also in lung cancer.
- CYFRA211 is a water-soluble fragment of cytokeratin 19 with a half-life of about 4 days;
- IDH1 is a NADP + -dependent isocitrate dehydrogenase located in the cytoplasm and peroxisomes that catalyzes the oxidative decarboxylation of isocitrate to a-ketoglutarate.
- the inventors of the present invention have found in previous studies that the levels of IDH1 in patients with lung squamous cell carcinoma and lung adenocarcinoma are significantly higher than those in the normal population and benign lung tumors, and can be used as a new diagnostic marker for lung cancer.
- kits for assisting diagnosis of a patient with non-small cell lung cancer comprising a product for detecting protein marker IDH1, a product for detecting protein marker CA125, a product for detecting protein marker CYFRA21-1, and having recorded
- the following functional formula: P -
- the protein marker IDH1 may specifically be a protein represented by GENBANK ACCESSION NO. CAG46496. 1 (sequence 1 of the sequence listing; GENBANK ACCESSION NO. CAG46496. 1; 01: 49456351; linear PRI 16-OCT-2008).
- the protein marker CA125 may specifically be a protein represented by GENBANK ACCESSION NO. AAL65133. 2 (GENBANK ACCESSION NO.
- the protein marker CYFRA21-1 may specifically be a protein represented by GENBANK ACCESSION NO. NP-002267. 2 (Sequence Listing 2; 01: 24234699; linear PRI 06- MAY-2012).
- the unit of the concentration of the protein marker IDH1 is specifically U/L
- the unit of the concentration of the protein marker CA125 is specifically U/mL
- the unit of the concentration of the protein marker CYFRA21-1 is specifically ng/mL.
- the following diagnostic criteria can also be recorded on the carrier: When P 0. 846, the patient to be tested is a candidate for non-small cell lung cancer, when? ⁇ 0. At 846, the patient to be tested was a candidate for non-small cell lung cancer.
- the present invention also protects a product for detecting the protein marker IDH1, a product for detecting the protein marker CA125, a product for detecting the protein marker CYFRA21-1, and a carrier having a functional formula and a diagnostic standard for preparing a non-diagnostic diagnosis.
- a product for detecting the protein marker IDH1 a product for detecting the protein marker CA125
- a product for detecting the protein marker CYFRA21-1 a carrier having a functional formula and a diagnostic standard for preparing a non-diagnostic diagnosis.
- Xl represents the concentration of the protein marker IDH1, the unit is U/L, x2 represents the concentration of the protein marker CA125, the unit is U/mL, and x3 represents the concentration of the protein marker CYFRA21-1, and the unit is ng/mL;
- the patient to be tested is a candidate for non-small cell lung cancer, when? ⁇ 0.
- the patient to be tested was a candidate for non-small cell lung cancer.
- the protein marker IDH1 may specifically be a protein represented by GENBANK ACCESSION NO. CAG46496. 1 (sequence 1 of the sequence listing; GENBANK ACCESSION NO. CAG46496. 1; 01 : 49456351; Linear PRI 16- OCT- 2008).
- the protein marker CA125 may specifically be a protein represented by GENBANK ACCESSION NO. AAL65133. 2 (GENBANK ACCESSION NO.
- the protein marker CYFRA21-1 may specifically be a protein represented by GENBANK ACCESSION NO. NP-002267. 2 (Sequence Listing 2; 01: 24234699; linear PRI 06- MAY-2012).
- the product for detecting the protein marker IDH1 may specifically be an IDH1 enzyme-linked immunosorbent assay kit (ELISA Kit; including IDH1 standard) purchased from Wuhan Yousheng Technology Co., Ltd.
- IDH1 enzyme-linked immunosorbent assay kit ELISA Kit; including IDH1 standard
- the product for detecting the protein marker CYFRA21-1 as described above may specifically be a CYFRA21-1 quantitative assay kit purchased from Roche Diagnostics (Shanghai) Co., Ltd.
- the product for detecting the protein marker CA125 may specifically be a CA125 quantitative assay kit of Roche Diagnostics (Shanghai) Co., Ltd.
- the invention also protects a method for assisting diagnosis of a patient with non-small cell lung cancer, comprising the steps of:
- Xl represents the concentration of the protein marker IDH1, the unit is U/L, x2 represents the concentration of the protein marker CA125, the unit is U/mL, x3 represents the concentration of the protein marker CYFRA21-1, and the unit is ng/mL;
- the patient to be tested at 846 is a candidate for non-small cell lung cancer, when? ⁇ 0. At 846, the patient to be tested was a candidate for non-small cell lung cancer.
- the protein marker IDH1 may specifically be a protein represented by GENBANK ACCESSION NO. CAG46496. 1 (sequence 1 of the sequence listing; GENBANK ACCESSION NO. CAG46496. 1; 01: 49456351; linear PRI 16-OCT-2008).
- the protein marker CA125 may specifically be a protein represented by GENBANK ACCESSION NO. AAL65133. 2 (GENBANK ACCESSION NO.
- the protein marker CYFRA21-1 may specifically be a protein represented by GENBANK ACCESSION NO. NP-002267. 2 (Sequence Listing 2; 01: 24234699; linear PRI 06- MAY-2012).
- the product for detecting the concentration of the protein marker IDH1 may specifically be an IDH1 enzyme-linked immunosorbent assay kit (ELISA Kit; purchased from Wuhan Youersheng Technology Co., Ltd.; IDH1 standard).
- IDH1 enzyme-linked immunosorbent assay kit ELISA Kit; purchased from Wuhan Youersheng Technology Co., Ltd.; IDH1 standard.
- the product for detecting the concentration of the protein marker CYFRA21-1 may specifically be a CYFRA21-1 quantitative assay kit purchased from Roche Diagnostics (Shanghai) Co., Ltd.
- the product for detecting the concentration of the protein marker CA125 may specifically be a CA125 quantitative assay kit of Roche Diagnostics (Shanghai) Co., Ltd.
- Figure 1 shows the R0C curve of the NSCLC diagnostic model.
- the ordinate is sensitivity and the abscissa is specific.
- Plasma samples There were 943 plasma samples from NSCLC patients, and healthy people (normal control). A total of 479 plasma samples were taken from patients with lung cancer who were diagnosed by pathology in the Department of Thoracic Surgery, Cancer Hospital of Chinese Academy of Medical Sciences and the normal population who participated in the cancer screening. The experiment was approved by the ethics committee, and the subjects were informed of the informed consent to sign the informed consent form. Plasma samples were obtained before surgery, and patients had not received chemotherapy, radiotherapy, intervention, etc. before.
- R0C curve (receiver operat ing characteri ic curve) with sensitivity as the ordinate (Y-axis) and specificity as the abscissa (X-axis).
- the corresponding coordinate points can be generated, and the curve generated by the line is generated. That is the ROC curve.
- the ROC curve can compare the diagnostic efficiency of different tumor markers, and the larger the area under the curve (AUC), the higher the diagnostic efficiency.
- the data was analyzed by Logistic binomial regression of SPSS software, and the model was tested using SAS, and a model was finally determined for the diagnosis of NSCLC.
- the calculated results of the model were plotted on the R0C curve (see Figure 1).
- the area under the curve was 0.896 (95% confidence interval: 0.871-0.918, p ⁇ 0.0001), and the marker with the highest diagnostic efficiency for NSCLC - IDH1 (AUC Compared with 0.817), there is a significant difference (/ 0.0001).
- step 1 by performing a large amount of data simulation and model establishment on a large number of clinical samples for detection of various protein markers, the functional formula for assisting diagnosis of non-small cell lung cancer is as follows:
- Xl represents the concentration of the protein marker IDH1 (unit: U/L)
- ⁇ 2 represents the concentration of the protein marker CA125 (unit: U/mL)
- x3 represents the concentration of the protein marker CYFRA21-1 (unit: ng/mL).
- the protein marker IDH1 concentration, the protein marker CA125 concentration, and the protein marker CYFRA211 concentration in the obtained sample are calculated, and then the p value is calculated by the above functional formula, and the patient to be tested is candidate when P 0.846 Non-small cell lung cancer patients, when? ⁇ 0.846 hours
- the patient to be tested was a candidate for non-small cell lung cancer.
- Example 2 verification of the method of the invention
- the patients used in this example were 150 patients with clinically diagnosed non-small cell lung cancer (peripheral venous blood was obtained before surgery, patients had not received chemotherapy, radiotherapy, intervention, etc.) and 50 healthy people (not non-small) Patients with cell lung cancer) are volunteers with informed consent.
- step 2 Dissolve the sample from step 1 for 3 h at room temperature, then centrifuge at 3000 r/min for 5 min.
- the protein marker IDH1 may specifically be a protein represented by GENBANK ACCESSION NO. CAG46496. 1 (sequence 1 of the sequence listing; GENBANK ACCESSION NO. CAG46496. 1; 01: 49456351; linear PRI 16-OCT-2008).
- the protein marker CA125 may specifically be a protein represented by GENBANK ACCESSION NO. AAL65133. 2 (GENBANK ACCESSION NO.
- the protein marker CYFRA21-1 may specifically be a protein represented by GENBANK ACCESSION NO. NP-002267. 2 (sequence 2 of the list; 01: 24234699; linear PRI 06- MAY-2012).
- the protein marker CEA can specifically be a protein represented by GENBANK ACCESSION NO. CAE75559. 1 (sequence 3 of the sequence listing; GENBANK ACCESSION NO. CAE75559. 1; 01 : 38522495; linear PAT 25-NOV- 2003).
- the IDH1 enzyme-linked immunosorbent assay kit (ELISA Kit; including IDH1 standard; catalog number E97839Hu 96T) purchased from Wuhan Youersheng Technology Co., Ltd. was used and the concentration of the protein marker IDH1 was determined according to the instructions of the kit.
- the CYFRA21-1 Quantitative Assay Kit (catalog number 11820966122) purchased from Roche Diagnostics (Shanghai) Co., Ltd. was used and the concentration of the protein marker CYFRA21-1 was measured according to the kit instructions.
- the concentration of the protein marker CEA was determined using the CEA Quantitative Assay Kit from Roche Diagnostics (Shanghai) Co., Ltd. and following the instructions in the kit (Cat. No. 11731629322).
- the CA125 Quantitative Assay Kit (Cat. No. 11776223822) from Roche Diagnostics (Shanghai) Co., Ltd. was used and the concentration of the protein marker CA125 was measured according to the kit instructions.
- the results of steps 3 and 4 are shown in Tables 1 and 2 (in gender, 1 represents male and 2 represents female).
- Tables 1 and 2 the diagnosis results of the respective individual protein markers were used as a control for the results of the diagnosis using the functional formula of Example 1.
- the protein marker IDH1 was used alone, according to the conventional threshold, when the concentration was 2.19, the patient to be tested was a candidate non-small cell lung cancer patient, and when the concentration was ⁇ 2.19, the patient to be tested was a candidate for non-small cell lung cancer.
- Protein marker alone when the concentration is 35, the patient to be tested is a candidate non-small cell lung cancer patient, and when the concentration is ⁇ 35, the patient to be tested is a candidate for non-small cell lung cancer.
- the protein marker CYFRA21-1 when used alone, according to the conventional threshold, when the concentration was 3.3, the patient to be tested was a candidate non-small cell lung cancer patient, and when the concentration was ⁇ 3.3, the patient to be tested was a candidate for non-small cell lung cancer.
- the protein marker CEA when used alone, according to the conventional threshold, when the concentration is 5, the patient to be tested is a candidate non-small cell lung cancer patient, and when the concentration is ⁇ 5, the patient to be tested is a candidate for non-small cell lung cancer.
- the protein marker IDH1 and its threshold were used alone for the determination.
- the sensitivity was 43.33% and the specificity was 92%.
- the protein marker CA125 and its threshold were used alone to determine the sensitivity, with a sensitivity of 13.33% and a specificity of 98%.
- the protein marker CYFRA21-1 and its threshold were used alone to determine the sensitivity, with a sensitivity of 55.33% and a specificity of 82%.
- the protein marker CEA and its threshold were used alone to determine the sensitivity, with a sensitivity of 25.33% and a specificity of 72%. Taking into account the sensitivity and specificity, the functional formula and diagnostic method of Example 1 is significantly superior to the use of several separate protein markers for diagnosis.
- Lung cancer ranks first in the world for cancer deaths and is the number one cancer killer that harms the health of our people. Therefore, looking for early diagnosis of lung cancer, individual treatment, prognosis and monitoring of recurrence Tumor markers have become a hot spot in recent years.
- the kit provided by the present invention and assisting diagnosis of non-small cell lung cancer patients according to the corresponding diagnostic criteria, the sensitivity and the specificity are strong, and the reliability of the diagnosis is much higher than that of using each individual protein marker for diagnosis. It has great value and application prospects for the diagnosis and treatment of lung cancer.
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Abstract
L'invention concerne un kit de test à réactif pour le diagnostic assisté d'un patient atteint de carcinome pulmonaire non à petites cellules. Le kit de test à réactif selon la présente invention comprend un produit utilisé pour détecter le marqueur de protéine IDH1, un produit utilisé pour détecter le marqueur de protéine CA125, un produit utilisé pour détecter le marqueur de protéine CYFRA21-1 et un porteur décrivant la fonction suivante : formule I, où x1 représente la concentration d'IDH1, x2 représente la concentration de CA125 et x3 représente la concentration de CYFRA21-1. Le diagnostic assisté du patient atteint de carcinome pulmonaire non à petites cellules en employant le kit de test à réactif selon la présente invention et en suivant un critère de diagnostic correspondant se caractérise par une sensibilité élevée et une forte spécificité, permet à la fiabilité du résultat d'un diagnostic d'être nettement supérieure à celle obtenue en utilisant chacun des marqueurs de protéine individuels pour le diagnostic, et présente d'importantes perspectives de valeur et d'application dans le diagnostic et le traitement du carcinome pulmonaire non à petites cellules.
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PCT/CN2013/000629 WO2014190449A1 (fr) | 2013-05-28 | 2013-05-28 | Kit de test à réactif pour diagnostic assisté d'un patient atteint de carcinome pulmonaire non à petites cellules |
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CN102827073A (zh) * | 2011-06-17 | 2012-12-19 | 安吉奥斯医药品有限公司 | 治疗活性组合物和它们的使用方法 |
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CN102827073A (zh) * | 2011-06-17 | 2012-12-19 | 安吉奥斯医药品有限公司 | 治疗活性组合物和它们的使用方法 |
CN102321760A (zh) * | 2011-08-26 | 2012-01-18 | 泸州医学院附属医院 | 一种非小细胞肺癌标志物及应用 |
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