CN102735840B - Reagent for diagnosis or screening of ovarian cancer - Google Patents
Reagent for diagnosis or screening of ovarian cancer Download PDFInfo
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- CN102735840B CN102735840B CN201110092429.4A CN201110092429A CN102735840B CN 102735840 B CN102735840 B CN 102735840B CN 201110092429 A CN201110092429 A CN 201110092429A CN 102735840 B CN102735840 B CN 102735840B
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Abstract
The invention discloses a reagent for diagnosis or screening of ovarian cancer. The reagent comprises concentration substances of three proteins including a tumor detection antigen 125, a nidogen 1 and a matrix metalloproteinase inhibitor 2. The product of the invention has accuracy, sensitivity and specificity respectively at 98.3%, 96.6% and 100% in diagnosis of ovarian cancer. In addition, detectable rate of early ovarian cancer patients is 86.7%.
Description
Technical field
The present invention relates to for diagnosing or the reagent of examination oophoroma.
Background technology
Worldwide, approximately there are every year 200000 women to suffer from oophoroma.In China, the incidence of disease of oophoroma presented rising trend in 2000～2005 years, reached 38/100,000.For example the incidence of disease of Shanghai City oophoroma is number two in gynecological tumor.Although the incidence of disease of oophoroma is relatively low, its death-incidence of disease is only second to lung cancer in the common ten kinds of tumours of American Women's.The five year survival rate of the ovarian cancer patients that (comprises I phase and II phase) is in early days 80～95%, and late period (comprising III phase and IV phase) ovarian cancer patients five year survival rate only have 10～30%.Oophoroma is in the time of commitment, and patient still lacks specific symptom, exceedes 2/3rds oophoroma case and proceeded to late period in the time of diagnosis, it serves to show the importance of early diagnosis.The detection of blood serum tumor markers has been applied to oophoroma early diagnosis clinically, U.S. food (the Food and Drug Administration of Drug Administration at present, FDA) the clinical oophoroma blood serum designated object that can be used for of approval comprises tumour antigen 125 (Cancer antigen 125, and people's epididymal proteins 4 (Human epididymis protein 4, HE4) CA125).Both have very high value in ovarian cancer patients postoperative curative effect context of detection, but lack enough susceptibility and specificity for the early diagnosis of oophoroma.In addition, U.S. FDA has also been ratified one for preoperative plasma proteins mark spectrum (called after OVA1 test) of pelvic swelling thing being carried out to ovarian cancer risk assessment, comprise five albumen, they are respectively transthyretin (gene title: TTR), apoplipoprotein A-1 (gene title: APOA1), beta2-microglobulin (gene title: B2M), serotransferrin (gene title: TF) and cancer antigen 125 (gene title: MUC16 or CA125).But OVA1 test is not also suitable for the examination of oophoroma.
Summary of the invention
The object of this invention is to provide diagnosis or the product of auxiliary diagnosis oophoroma and the product of examination or auxiliary examination oophoroma.
The product of diagnosis provided by the present invention or auxiliary diagnosis oophoroma, the product of examination or auxiliary examination oophoroma, by the material composition that detects tumour antigen 125, nestin 1 and these three kinds of protein concentrations of Tissue inhibitor of metalloproteinase 2.
Wherein, tumour antigen 125 (gene title: MUC16 or CA125), nestin 1 (gene title: NID1) and Tissue inhibitor of metalloproteinase 2 (gene title: TIMP2) three's amino acid sequence refers to UniprotKB/Swiss-Prot database (http://expasy.org/sprot/), respectively according to " Q8WXI7 " (CA125), " P14543 " (NID1), " P16035 " (TIMP2) retrieve.
The material that can detect these three protein concentrations all can be used as the component in the product of this diagnosis or auxiliary diagnosis oophoroma and the product of examination or auxiliary examination oophoroma, as the monoclonal antibody for these three albumen or polyclonal antibody.
The material that detects CA125, NID1 and these three kinds of protein concentrations of TIMP2 can be instrument, also can be reagent.As the protein concentration that detects CA125 can be used Modular E170 instrument (Roche, Mannheim, Germany); The R & D systems that the concentration that detects NID1 can be DY2570 with article No., USA; The R & D systems that the concentration that detects TIMP2 can be DY971 with article No., USA.
Said monoclonal antibody or polyclonal antibody can oneself be prepared, and also can obtain from commercial channels.
Utilize the said goods can be according to the Model Diagnosis in embodiment or examination oophoroma.Utilize the said goods diagnosis or examination oophoroma, tool has the following advantages:
(1) detect the protein concentration in blood plasma, there is higher repeatability and operability;
(2) deciphering of result is objective, and is easily understood.
Utilize product diagnosis of ovarian cancer of the present invention, its accuracy rate, susceptibility and specificity are respectively 98.3%, 96.6% and 100.0%.In addition, reach 86.7% for early ovarian cancer patient's recall rate.
Accompanying drawing explanation
Fig. 1 is experimenter's operating characteristic (Receiver Operating Characteristic, ROC) curve of joint-detection model and unique identification thing
Embodiment
A kind of novel method (patent No.: ZL 200310112981.0) that obtains solid tumor related free protein in blood of utilizing laboratory invention in early stage, has obtained a large amount of oophoroma candidate albumen marks.The present invention filters out three albumen from candidate's oophoroma mark of having verified, and has set up the joint-detection model for ovarian cancer diagnosis.
Model is the protein concentration in 59 routine ovarian cancer patients and 58 routine healthy person blood plasma based on three albumen.Wherein adopt the Modular E170 instrument (Roche of Beijing Union Medical College/Cancer Hospital of Chinese Academy of Medical Sciences clinical laboratory, Mannheim, Germany) protein concentration of CA125 in mensuration blood plasma, the protein concentration of NID1 and TIMP2 in employing DASELISA immuning adsorpting analysis (enzyme-linked immunosorbent assay, ELISA) mensuration blood plasma.Adopt the two sorted logic Returns Law (Binary logistic regression), build the mathematical function (seeing formula (I)) take these three protein concentrations as variable, functional value (being P value) represents the value-at-risk that experimenter has ovarian cancer, P > 0.5 represents excessive risk (oophoroma), and P≤0.5 represents low-risk (health).
P＞0.5，H(High-risk)
P≤0.5，L(Low-risk)
Formula (I)
CA125, NID1 and TIMP2 in this mathematical function represent respectively protein concentration separately.First the protein concentration that detects CA125, NID1 and TIMP2 in every experimenter's blood plasma, then obtains P value by the relevant position of these three value substitution functions.As P > 0.5, be judged to be excessive risk individuality, i.e. ovarian cancer patients; When P≤0.5, be judged to be low-risk individuality, i.e. healthy person.
From detecting usefulness (in table 1 and Fig. 1), joint-detection model is better than any single protein marker in the time distinguishing ovarian cancer patients and healthy person, and its accuracy rate, susceptibility and specificity are respectively 98.3%, 96.6% and 100.0%.In addition, joint-detection model reaches 86.7% for early ovarian cancer patient's recall rate.Below all illustrate that this model is applied to the advantage on ovarian cancer diagnosis.
The detection usefulness of table 1. joint-detection model and unique identification thing
A: in the time distinguishing ovarian cancer patients and healthy person, the cutoff value of TIMP2, NID1 and CA125 protein concentration is respectively: 121.57ng/mL, 185.02ng/mL and 35U/mL;
B: the computing formula of accuracy rate:
C: the computing formula of susceptibility:
D: specific computing formula:
PPV: positive predictive value (positive prediction value), computing formula is
NPV: negative predictive value (negative prediction value), computing formula is
In above-mentioned formula, true positives number of cases is that clinical diagnosis is the number of cases of oophoroma; True negative number of cases is that clinical diagnosis is healthy number of cases; The number of cases of oophoroma group is that clinical diagnosis is the number of cases of oophoroma; The number of cases of healthy group is that clinical diagnosis is healthy number of cases; Positive number of cases in oophoroma group is that product of the present invention detects the number of cases for P > 0.5; Negative number of cases in healthy group is that product of the present invention detects the number of cases for P≤0.5; False positive number of cases is that product of the present invention detects as P > 0.5 but clinical diagnosis is healthy number of cases; False negative number of cases is that product of the present invention detects as P≤0.5 but the number of cases that clinical diagnosis is oophoroma.Wherein, the clinical diagnosis of oophoroma is as the criterion with pathological diagnosis report.In Fig. 1, (area under the ROC curve, AUC) is larger for area under curve, and the diagnostic accuracy of mark is higher.The AUC of each mark is respectively: TIMP2_0.65 (0.55,0.75), NID1_0.91 (0.86,0.96), CA125_0.98 (0.97,1.00), 3-albumen joint-detection _ 0.99 (0.98,1.00).
Following examples are convenient to understand better the present invention, but are not limited to the present invention.Experimental technique in following embodiment, if no special instructions, is conventional method.Experiment material used in following embodiment, if no special instructions, all can buy and obtain from routine biochemistry reagent company.
The composition of the product of embodiment 1, diagnosis of ovarian cancer
This product is made up of two kinds of double-antibody sandwich elisa Kit and a kind of clinical laboratory conventional sense reagent forms, and wherein two kinds of ELISA Kit all buy and obtain from biological reagent company, specifically in table 2:
Table 2.NID1, TIMP2 and CA125 Protein Detection system
Embodiment 2, utilize the product diagnosis of ovarian cancer of embodiment 1
1, detect the foundation of protein concentration method
Adopt the ELISA Kit of the NID1 shown in table 2 to detect NID1 protein concentration in experimenter's blood plasma, concrete operation step is as follows: coated 96 orifice plates (Costar, USA) of capture antibody (dilution in 1: 500) are in 4 ℃ of overnight incubation; Seal 96 orifice plates, room temperature 4h with 2%BSA solution; 1 × PBST washing lotion is washed plate 3 times; Add blood plasma to be measured (dilution in 1: 10), room temperature 1h with 50 μ l/well; 1 × PBST washing lotion is washed plate 7 times; Detect antibody (dilution in 1: 180) incubated at room 1h; 1 × PBST washing lotion is washed plate 3 times; Add Streptavidin-HRP (dilution in 1: 4000), room temperature 30min; 1 × PBST washing lotion is washed plate 3 times; Add nitrite ion (GBI, China), lucifuge reaction 30min finally reads optical density value (optical density, OD) by microplate reader (Bio-Rad Laboratory, USA) under 450nm/570nm dual wavelength is set.According to the concentration of NID1 standard protein (42.500ng/ml, 21.250ng/ml, 10.625ng/ml, 5.313ng/ml, 2.656ng/ml, 1.328ng/ml) and the corresponding OD value of each concentration drawing standard curve, and then extrapolate blood plasma NID1 concentration to be measured.
Adopt the ELISA Kit of the TIMP2 shown in table 2 to detect TIMP2 protein concentration in experimenter's blood plasma, concrete operation step is as follows: coated 96 orifice plates of capture antibody (dilution in 1: 180) are in 4 ℃ of overnight incubation; Seal 96 orifice plates, room temperature 4h with 2%BSA solution; 1 × PBST washing lotion is washed plate 3 times; Add blood plasma to be measured (dilution in 1: 200), room temperature 1h with 50 μ l/well; 1 × PBST washing lotion is washed plate 7 times; Detect antibody (dilution in 1: 180) incubated at room 1h; 1 × PBST washing lotion is washed plate 3 times; Add Streptavidin-HRP (dilution in 1: 200), room temperature 20min; 1 × PBST washing lotion is washed plate 3 times; Add nitrite ion, lucifuge reaction 30min finally reads optical density value (optical density, OD) by microplate reader (Bio-Rad Laboratory, USA) under 450nm/570nm dual wavelength is set.According to the concentration of TIMP2 standard protein (2.000ng/ml, 1.000ng/ml, 0.500ng/ml, 0.250ng/ml, 0.125ng/ml, 0.063ng/ml, 0.0313ng/ml) and the corresponding OD value of each concentration drawing standard curve, and then extrapolate blood plasma TIMP2 concentration to be measured.
Adopt Modular E170 instrument (Roche, the Germany) robotization of Beijing Union Medical College/Cancer Hospital of Chinese Academy of Medical Sciences clinical laboratory to detect the protein concentration of CA125 in blood plasma.
2, utilize the model of formula (I) to diagnose
Experimenter comprises 59 routine ovarian cancer patients and 58 routine healthy persons.Use said method to detect NID1, TIMP2 and CA125 protein concentration in every experimenter's blood plasma.On this basis, further integrate these three protein concentrations, adopt the two sorted logic Returns Law (Binary logistic regression) to build the mathematical function (seeing formula (I)) take these three protein concentrations as variable, functional value (being P value) represents the value-at-risk that experimenter has ovarian cancer, P > 0.5 represents excessive risk (oophoroma), and P≤0.5 represents low-risk (health).This model is in the time distinguishing ovarian cancer patients and healthy person, and its accuracy rate, susceptibility and specificity are respectively 98.3%, 96.6% and 100.0%.And early ovarian cancer patient's recall rate is reached to 86.7% (table 1).
The clinical diagnosis of oophoroma is judged according to pathological diagnosis result.First, according to (the International Federation of Gynecology and Obstetrics of FIGO, FIGO) standard is carried out stages of ovarian carcinoma, (pathology involves one or bilateral ovaries to be divided into I phase (pathology is confined to ovary), II phase, companion's pelvic cavity shifts), the III phase, (pathology involved one or bilateral ovaries, beyond companion's pelvic cavity, plantation or retroperitoneal lymph node or inguinal lymph nodes shift, the shallow table of liver shifts and also belongs to the III phase) and (DISTANT METASTASES IN, need find malignant cell when hydrothorax exists the IV phase; Hepatic metastases need be involved liver parenchyma), wherein I phase and II phase belong in early days, and III phase and IV phase belong to late period.Secondly, slurry type oophoroma is the main Types of oophoroma, its clinical criteria be its cancer cell often to form blister cavities and nipple as feature, but more or less retain original tissue morphology.Oophoroma type beyond slurry type is referred to as non-slurry type oophoroma.Healthy clinical criteria is not carry pelvic swelling thing (comprising ovarian neoplasm and other pelvic swelling thing).
The concrete diagnostic result of the routine ovarian cancer patients of table 3.59 and 58 routine healthy persons
Claims (1)
1. the product of diagnosis or auxiliary diagnosis oophoroma, is made up of the material that detects tumour antigen 125, nestin 1 and these three kinds of protein concentrations of Tissue inhibitor of metalloproteinase 2.
2, the application in the product that is integrated into preparation diagnosis or auxiliary diagnosis oophoroma being formed by the material that detects tumour antigen 125, nestin 1 and these three kinds of protein concentrations of Tissue inhibitor of metalloproteinase 2.
3, the product of examination or auxiliary examination oophoroma, is made up of the material that detects tumour antigen 125, nestin 1 and these three kinds of protein concentrations of Tissue inhibitor of metalloproteinase 2.
4, the application in the product that is integrated into preparation examination or auxiliary examination oophoroma being formed by the material that detects tumour antigen 125, nestin 1 and these three kinds of protein concentrations of Tissue inhibitor of metalloproteinase 2.
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| CN105717146B (en) * | 2016-03-29 | 2018-11-09 | 复旦大学附属中山医院 | A kind of cancer risk assessment kit being directed to Chinese city population people at highest risk based on CT images and biomarker spectrum |
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