CN103645319B - The application of GDF-15 in diagnosis of colorectal carcinoma - Google Patents

The application of GDF-15 in diagnosis of colorectal carcinoma Download PDF

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CN103645319B
CN103645319B CN201310705853.0A CN201310705853A CN103645319B CN 103645319 B CN103645319 B CN 103645319B CN 201310705853 A CN201310705853 A CN 201310705853A CN 103645319 B CN103645319 B CN 103645319B
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张伟
王小兵
田海梅
李艳芬
李茉
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Abstract

The present invention relates to the application of GDF-15 in diagnosis of colorectal carcinoma. Particularly, the present invention relates to the purposes in reagent or the kit of tumor markers colorectal cancer in preparation diagnosis and/or monitoring experimenter, wherein said tumor markers comprise macrophage inhibition factor 1 and TPS the two. The reagent or the kit that the invention still further relates to colorectal cancer in diagnosis and/or monitoring experimenter, it comprises the reagent of detection tumor markers of the present invention. Tumor markers combination of the present invention has good complementarity, can significantly improve the detector efficiency of colorectal cancer, has a good application prospect.

Description

The application of GDF-15 in diagnosis of colorectal carcinoma
Technical field
The present invention relates to diagnosis of colorectal carcinoma monitoring field. Particularly, the present invention relates to macrophage inhibition factor 1 greatlyApplication in intestinal cancer diagnosis and monitoring, relate in particular to macrophage inhibition factor 1 other tumor markers of associating as MIC-1,CEA, TPS are in the particularly application in early stage diagnosis of colorectal carcinoma of colorectal cancer.
Background technology
Colorectal cancer comprises colon cancer and the carcinoma of the rectum, and the death rate occupies the 4th in China city, occupies the 5th in rural area. EarlyIn phase PATIENTS WITH LARGE BOWEL, mostly there is no obvious clinical symptoms and sign, once find be middle and advanced stage, in China, colorectal cancer send outSick rate has obvious ascendant trend, is that of human health threatens greatly. The early detection of colorectal cancer can effectively reduce intestinal cancerThe death rate, thereby the early diagnosis of colorectal cancer research becomes the focus in intestinal cancer research.
There is no at present the tumor markers of desirable diagnosis colorectal cancer, Clinical detection is anti-with carcinomebryonic antigen (CEA) and sugar chainFormer (CA) is main. CEA is the colorectal cancer blood serum tumor markers of finding the earliest, and molecular weight is about the glycoprotein of 180kD, coding baseBecause being positioned at chromosome No. 19, CEA all has rising in various degree in most of malignant tumour serum, is often used as and disappears clinicallyChange the auxiliary diagnostic index of road malignant tumour, but the sensitiveness of its detection and specificity all can not meet the demand of Clinical detection,The positive rate of preoperative CEA is greatly between 30%-40%. On the cell membrane of the main expression of CA series and canceration, also can be discharged into thinIn matrix matter, thereby can be used for diagnosis and the treatment monitoring of tumour, be usually used at present diagnosis of colorectal carcinoma have CA199,CA125, CA242 and CA724, size, Bormann somatotype, lymphatic infiltration and the pathology of CA series antigen and tumour is found in researchThere is correlation in type, has important value, but have too sensitiveness and special in the diagnosis of colorectal cancer and treatmentThe problem that property is poor, the diagnostic sensitivity less than 30% of single CA mark. A large sample clinical research result shows, intestinal cancerBefore operation in patients, CEA positive rate is that 32.6%, CA199 positive rate is 25.0%. The positive rate of CEA and CA199 joint-detection is44.2%, though illustrate that the positive rate of joint-detection is high compared with individual event mensuration, little to the diagnostic value of the carcinoma of the rectum.
Value of tissue polypeptide specific antigen (TissuePolypeptideSpecificantigen, TPS) is tumour cellA kind of polypeptide antigen of secretion is to report in recent years a more tumor markers for malignant tumor of digestive tract diagnosis.TPS concentration increases relevant with tumour epithelial cell proliferation activity of conversion, is the special of reflection tumour cell division and proliferation activityIndex, belongs to tumor promotion dependent form label. There are some researches show, TPS can be effective in FOL-FIRI Regimen Chemotherapy colorectal cancerMonitoring curative effect, treatment responder TPS level significantly declines, disease progression person significantly raise, and its susceptibility is high, variationTime early, can be reacted change of illness state quickly than CEA, CA. For advanced colorectal cancer, to diagnose clearly, it is right that it is more conducive toThe monitoring for the treatment of, the variation of dynamically observing serum T PS level can be used as an index evaluating treatment of colorectal cancer effect.
Even if large quantity research shows associating CEA, TPA and CA series, the still less than 60% of sensitivity of its diagnosis colorectal cancer, facesBed meaning is limited, and particularly not enough, three combines the sensitivity less than 30% of early stage (I+II phase) colorectal cancer of diagnosis. Improve intestinesCancer patient's early detection and treatment are the effective ways that reduces the intestinal cancer death rate, and for this reason, exploration discovery can be used in early daysThe tumor markers of diagnosis intestinal cancer becomes an important task.
Summary of the invention
Digital proof MIC-1 serum reagent box of the present invention has shown before good application in diagnosis of colorectal carcinoma researchScape. Digital proof MIC-1 of the present invention is better than CEA in intestinal cancer diagnosis in early days, at patients with bowel cancer group and Normal group serumMIC-1 level has significant difference (P < 0.001). In early days in patients with bowel cancer, the diagnostic sensitivity of MIC-1 (the I phase:22.7%; The II phase: 34.7%) all higher than the sensitiveness of CEA, CA199, the each tumor markers of TPS.
The diagnosis of combining of tumor markers at present is also more and more widely used in clinical. But, for cost-saving, shortenDetection time, reduce many-sided considerations such as experimental error, combine in diagnosis and especially need to consider that the minimum mark of associating obtainsObtain sufficiently high sensitiveness and specificity. Due to the compatibility between various tumor markerses, the simple combination of existing markBe difficult to obtain gratifying effect, and how from known numerous tumor markers, to obtain can significantly improve sensitiveness andSpecific 2-3 kind mark is realized efficient diagnosis and is very difficult to expection, has become the problem that this area is furtherd investigate.Inventor finds that MIC-1 and CEA, TPS have good incompatibility surprisingly, and in the middle of patient, MIC-1 and TPS are simultaneouslyPresent positive result and only have a very little part, the positive rate of MIC-1+TPS can reach 57.8%, and MIC-1+CEA+TPSThe positive rate being combined in colorectal cancer detection can bring up to 72.5% especially. More it is shocking, in early days (I phase+IIPhase) MIC-1, CEA, TPS three combine diagnosis in intestinal cancer sensitiveness can reach 61.3%, and adds after CA199 fourThe sensitiveness of closing diagnosis is equally matched, in the patients with bowel cancer serum of III phase+IV phase, also has similar result. In addition inventor,Find to use other marks (CA125, CA242, CA724) of CA series to replace CA199, result is similar, all fails to improve and examinesDisconnected sensitivity. Therefore, result of the present invention shows only to combine MIC-1+TPS the two can significantly improve the positive of diagnosisRate, associating MIC-1, CEA, TPS three can obtain gratifying effect, and further combine CA199 or other CA markThing can not significantly improve positive rate.
Therefore, one aspect of the present invention relates to the examination of tumor markers colorectal cancer in preparation diagnosis and/or monitoring experimenterPurposes in agent or kit, wherein said tumor markers comprise macrophage inhibition factor 1 and TPS the two.
In one embodiment of the invention, described tumor markers do not comprise CA mark as CA199, CA125,CA242 and CA724.
In one embodiment of the invention, described tumor markers comprise macrophage inhibition factor 1, TPS andCEA。
In one embodiment of the invention, described tumor markers is made up of macrophage inhibition factor 1 and TPS.Prove that MIC-1 and TPS present positive result simultaneously and only have a very little part, used the sun of the two associating of MIC-1+TPSProperty rate can be up to 57.8%, and known combination as the Positive rate of CEA and CA199 be only 44.2%.
In another embodiment of the invention, described tumor markers is by macrophage inhibition factor 1, TPS and CEAComposition. Proved that MIC-1 and CEA, TPS have good incompatibility, MIC-1+CEA+TPS is combined in colorectal cancer detectionPositive rate is up to 72.5%. Inventor finds that MIC-1+CEA+TPS three is especially suitable for combining diagnosis early surprisinglyPhase (I+II phase) colorectal cancer, sensitiveness can reach 61.3%, and the sensitivity deficiency of the mark joint-detection of existing report30%. More it is shocking, inventor finds, except MIC-1+CEA+TPS combination, further to use the mark of CA seriesWill thing is as CA199, CA125, and CA242, CA724 fails to significantly improve the sensitivity of diagnosis. Therefore, only combine MIC-1, CEA,TPS three can obtain gratifying effect, and when diagnosing early stage colorectal cancer, this is very amazing. Therefore, in a preferred embodiment of the invention, the tumor markers using do not comprise CA mark as CA199,CA125, CA242 and CA724 etc.
In one embodiment of the invention, described colorectal cancer is early stage colorectal cancer.
In one embodiment of the invention, described colorectal cancer is I phase and/or II phase colorectal cancer.
In one embodiment of the invention, described reagent or kit for T by stages and/or M by stages.
In one embodiment of the invention, reagent of the present invention or kit can be used for tissue in situ detect and/orMonitor the expression (for example mRNA level) of described tumor markers, or for detection of and/or monitor described tumor markersSerum levels.
The opposing party of the present invention aspect relates to reagent or the kit of colorectal cancer in diagnosis and/or monitoring experimenter, wherein bagDraw together above-described reagent or kit. Find that in the present invention the combination of tumor markers can be used for detection or the monitoring of colorectal cancerAfter, such reagent and/or kit can easily be prepared by this area routine techniques. For example described reagent and/or reagentBox can comprise the antibody that detects described tumor markers, preferably monoclonal antibody, or for detection of described tumor markersPrimer and/or the probe etc. of expressing. Described reagent or kit can also comprise the conventional buffer solution that carries out PCR reaction, poly-Synthase, dNTPs mixture etc. Kit of the present invention can also comprise operation instructions etc.
Brief description of the drawings
Fig. 1: detect MIC-1, CA199, CEA and the TPS level of collected serum sample, and with this sample and normally rightThe ROC curve of drawing according to the concentration of the MIC-1, the CA199 that organize and CEA is (because not obtaining and contrasting corresponding TPS numerical value, so ROCCurve does not comprise TPS).
Detailed description of the invention
1 materials and methods
1.1 medical history information
All cases are all from October, 2009 to 2011 year Cancer Hospital of Chinese Academy of Medical Sciences outpatient service in January and the trouble of being in hospitalPerson's (in table 1) case group 429 examples, 58.6 years old mean age, the median age 59.0 years old, normal control 129 examples, mean age 43.3Year, the male sex's 75 examples, women's 54 examples, age 20-80 year, 43.3 years old mean age, the median age 44.0 years old, normal control fromAcademy of Medical Sciences tumour hospital of state people taking physical examination, all, without digestive system illness, hepatic and renal function is normal.
Table 1: patient clinical pathological characters
1.2 detection method
1.2.1 the collection of blood serum sample adopts and extracts respectively with the import vacuum test tube (reddish tone pipe) of inertia separation gelPatient's limosis vein blood 4ml; Nature aggegation 30min, 8 DEG C, the centrifugal 15min separation of serum of 4000rpm; Also-80 DEG C of low temperature of packingRefrigerator store is to be measured. MIC-1, CA199, CEA, TPS critical reference value be respectively 1000pg/ml, 37U/ml, 5ng/ml and110U/L, in the time of its critical reference value, specificity is all in 97% left and right. Combining employing series connection associating diagnosis in diagnosis, allIn tumor markers, there is a positive just to judge that assay is positive, improve the sensitiveness of diagnosis.
1.2.2MIC-1 it is that Cancer Hospital of Chinese Academy of Medical Sciences grinds that detection method MIC-1 detects kit usedSend out, adopt the ELISA double-antibody sandwich two-step method of biotin-avidin amplification system, with Bole imark ELIASA, 450nm,655nm dual wavelength detects each hole OD value, and operation is carried out in strict accordance with instrument and reagent operation instructions.
1.2.3CA199, the detection method of CEA, TPS all adopts RocheCobas601 electrochemical luminescence immunity analysis instrumentAnd matched reagent box (Roche) detects, operation is carried out in strict accordance with instrument and reagent operation instructions, high and low quality-control productValue is all in claimed range.
1.3 statistical procedures
In serum, MIC-1 concentration represents with means standard deviation and median. Application SPSS18.0 software carries out statisticalAnalyse, Mann-WhitneyUtest analyzes each group of MIC-1 level, ROC tracing analysis MIC-1 detects usefulness and determines that it is criticalValue, Chi-SquareTest detect MIC-1 in the difference detection sensitivity in colorectal cancer by stages. Statistical test is bilateralInspection, P < 0.05 has statistical significance for difference.
2. result
2.1ROC curve
Detect MIC-1, CA199, CEA and the TPS level of collected serum sample, and with this sample and Normal groupMIC-1, CA199 and the concentration of CEA draw ROC curve and (see Fig. 1, because not obtaining and contrasting corresponding TPS numerical value, so ROCCurve does not comprise TPS). Result shows that the AUC of MIC-1 is 0.803, higher than CA199 (0.762) and CEA (0.697). Comprehensively examineConsidered 2 times of standard deviations of MIC-1 mean value ± and ROC curve in normal population, the critical value of establishing MIC-1 is 1000pg/ml. When specialProperty is 96.9 o'clock, and the sensitiveness of MIC-1 is 35.2%.
MIC-1 level in 2.2 patients with bowel cancers and normal control serum
Detect respectively the MIC-1 level in patients with bowel cancer and normal control serum, found that in patients with bowel cancer serumMIC-1 concentration is significantly higher than Normal group (P < 0.001) (table 2)
Table 2: patients with bowel cancer and the horizontal table of comparisons of normal control serum MIC-1
The AUC of MIC-1, CA199, CEA and diagnostic value in 2.3 intestinal cancer
Known according to testing result and ROC curve, the AUC value of MIC-1 is 0.803, higher than now for Clinical detectionCEA (0.697) and CA199 (0.762), when specificity is 97% left and right, the detection sensitivity of MIC-1 be 35.2% with CEA phaseWhen, and be significantly higher than CA199 (Fig. 1, table 3)
Table 3: AUC value and the diagnostic value of MIC-1, CA199, CEA and TPS in patients with bowel cancer
2.4MIC-1 and TNM relation by stages
According to Analysis of test results MIC-1 level respectively with T by stages, N by stages, M relation by stages, result show MIC-1Concentration in serum raises (P < 0.05) with T stage development and detection sensitivity raises with T stage development, statistics knotFruit has statistical significance (P=0.016); The concentration of MIC-1 in serum is at N0 and N1 is interim a significant difference (P=0.033), at N1 and N2, N2 and N3 is interim there is no significant difference (P > 0.05), and detection sensitivity in different N by stagesNo difference of science of statistics in intestinal cancer (P=0.146); The level of MIC-1 in serum has extremely remarkable in M0 and M1 phase colorectal cancerDifference (P < 0.001), and its detection sensitivity also has significant difference in the statistics of different M phase intestinal cancer, andWith development by stages raise (P=0.002) (table 4)
Table 4:MIC-I and T by stages, N by stages, M relation by stages
Remarks: P1For MIC-1 is at the difference result that the concentration level U in Serum In Patients With Colorectal Carcinoma detects, P by stages2For MIC-The Chi-Square assay a of 1 detection sensitivity is PearsonChi-Square; B is Fisher ' sExactTest; cFor ContinuityCorrection (a)
The relation of 2.5MIC-1 and differentiation
This experimental analysis the MIC-1 level in the intestinal cancer patients serum of different differentiation degrees, at high, medium and low differentiation intestinesIn cancer, the sensitiveness of MIC-1 does not have significant difference (P=0.404), but the blood of the PATIENTS WITH LARGE BOWEL of different differentiation degreesClear water is flat is different, differentiated large with middle differentiation Serum In Patients With Colorectal Carcinoma in, MIC-1 level does not have significant difference (P=0.319), still, in middle differentiation and low differentiation Serum In Patients With Colorectal Carcinoma, MIC-1 concentration level has significant difference (P=0.044)
The relation of table 5:MIC-1 detection sensitivity and different differentiation degree intestinal cancer
Remarks: P1For the result that the concentration level U of MIC-1 in different differentiation degree Serum In Patients With Colorectal Carcinomas detects, P2ForThe Chi-Square assay a of MIC-1 detection sensitivity is PearsonChi-Square
2.6MIC-1, CA199, CEA, TPS are in the difference sensitiveness in intestinal cancer by stages
MIC-1 in early days the sensitiveness in intestinal cancer (I phase+II phase) higher than in CA199, CEA, TPS:I phase patients with bowel cancer fourThe sensitiveness of planting mark is respectively 22.7%, 6.8%, 13.6% and 13.6%: these four kinds of tumours in II phase patients with bowel cancerThe sensitiveness of mark is respectively 34.7%, 11.3%, 29.8% and 29.0. MIC-1 in the interim sensitiveness of I～IV in table 6.
Table 6:MIC-1, CA199, CEA, TPS are in the difference sensitiveness in intestinal cancer by stages
2.7MIC-1, CA199, CEA, TPS combine diagnosis
The sensitiveness of combining diagnosis and can significantly improve diagnosis of tumor markers, this experiment has been chosen MIC-1 with conventionalIntestinal cancer detects mark CA199, CEA and TPS combines diagnosis (table 7), and result shows MIC-1 and CEA, tri-kinds of tumor-markers of TPSThing is combined diagnosis can obtain good sensitiveness, and in intestinal cancer, the diagnostic sensitivity of MIC-1+CEA+TPS can reach especially in early daysTo 61.3%. Analyzing and testing found that, MIC-1 and CEA, TPS have good incompatibility, in the middle of patient, MIC-1 withCEA or MIC-1 and TPS present positive result simultaneously and only have a very little part, thus combine this detection index can be significantlyImprove the detector efficiency of colorectal cancer. The positive rate that the positive rate of MIC-1+CEA can reach 62.7%, MIC-1+TPS can reachTo 57.8%, and the positive rate that MIC-1+CEA+TPS is combined in colorectal cancer detection can bring up to 72.5% especially. EspeciallyMIC-1+TPS, MIC-1+CEA+TPS combination, there is no at present the report that this combination detects for colorectal cancer, and this research is also anticipatedOuter discovery MIC-1, CEA, TPS three have good complementarity in colorectal cancer serum detects, and have good application prospect.
Table 7: tumor markers is combined the positive rate (%) of diagnosis
3. discuss
Colorectal cancer is one of malignant tumour of serious threat human health, and China's colorectal cancer death rate occupies in city in recent yearsThe 4th, occupy the 5th in rural area, and M & M journey ascendant trend year by year. Research shows early stage colorectal cancer postoperative 5Year survival rate can reach 97%, and 5 years survival rates of advanced colorectal cancer only 40% one 50%, thereby improve the early stage of patients with bowel cancer and send outBe now the effective way that reduces the intestinal cancer death rate with treatment, the tumor markers that exploration discovery can be used in early diagnosis becomesAn important task.
GDF-15 (MIC-1) [1,2] is the tumor markers of a wide spectrum in recent years finding, asThe member of TGF-'beta ' family, the biological processes such as wide participation Apoptosis, metastasis. Maturation in normal human serumMIC-1 albumen is low-level stably express, under pathological state as its expression of tumour, acute injury and inflammation can be a mistakeProperty significantly raise [3,4]. Multinomial research shows in polytype Serum of Cancer Patients, all have MIC-1 in various degree to expressLevel raises, and especially in some infantile tumour patients serums, MIC-1 level can be used as a good mark promptingThe generation of tumour.
Foreign study is found the pernicious transformation that body serum MIC-1 level and body shift to far-end from normal, adenoma, cancerProcess is proportionate, and is progressively ascendant trend and difference and has statistical significance (P < 0.05) [5]. High serum MIC-1 oftenIndicating possibility increase and the shortening [5,7] of life cycle of DISTANT METASTASES IN and recurrence.
This laboratory also double-antibody sandwich elisa serum MIC-1 detection kit based on independent research has been done in a large number and has been groundStudy carefully work, research finds that in early days in Pancreas cancer patients, diagnostic sensitivity can reach 77.9%[8], cancer of the stomach and lung cancer in early daysIn diagnosis, also demonstrate good prospect, be better than other tumor markers [9,10] for cancer of the stomach and pulmonary cancer diagnosis at present. ThisIn research, find, although total sensitiveness and the CEA of MIC-1 are similar, MIC-1 is better than CEA in intestinal cancer diagnosis in early days, in intestinal cancerPatient group and Normal group serum MIC-1 level have significant difference (P < 0.001), and in patients with bowel cancer with TNM by stagesDevelopment and progressively raise, the also (T:P=0.016 that is proportionate of development by stages with M by stages with T of its detection sensitivity; M:P=0.002) no difference of science of statistics (P=0.146) and in different N patient by stages.
This research is also analyzed the intestinal cancer serum MIC-1 of different differentiation degrees, finds the intestinal cancer of different differentiation degreesThe sensitiveness that in serum, MIC-1 detects does not have significant difference (P=0.404), points out us MIC-1 gene and breaks up in differenceIn the intestinal cancer of degree, all there is expression activation in various degree. In early days in patients with bowel cancer, the diagnostic sensitivity of MIC-1 (the I phase:22.7%; The II phase: 34.7%) all higher than CEA, CA199, the each tumor markers of the TPS sensitiveness of diagnosis separately, this result withThe discovery of this laboratory in early-stage Study is consistent.
Because single markers in diagnosis is often difficult to meet the needs of Clinical detection, the associating of tumor markers at presentDiagnosis is also more and more widely used in clinical, tumor markers combine the Developing Tendency that diagnosis is also early diagnosis of cancerGesture. Not yet find that there is at present MIC-1+TPS, MIC-1+CEA+TPS applied in any combination in the report of colorectal cancer detection, in this researchFind MIC-1, CEA, TPS in intestinal cancer detects, be can be complementary tumor markers, this combination can significantly improve colorectal cancerDetect the sensitiveness that especially early stage colorectal cancer detects. The sensitiveness of MIC-1, CEA, TPS in (I phase+II phase) intestinal cancer in early daysBe respectively 31.5%, 25.6% and 25.0%, can reach 61.3% but three combines the sensitiveness of diagnosis, and addAfter CA199, four to combine diagnosis 62.5% sensitiveness equally matched, and be significantly higher than each mark sensitiveness of diagnosis separately.In the patients with bowel cancer serum of III phase+IV phase, also there is similar result (79.7%vs80.8%). This result of study is for entering oneThe liquid phase suspending chip multi-tumor marker detection kit of step exploitation based on xMAP technology provides theoretical foundation, this technology energyThe enough sensitiveness that further improves Clinical detection, use manpower and material resources sparingly.
In sum, MIC-1, as a sensibility tumor mark of intestinal cancer early diagnosis, has very important facingBed using value. Can significantly improve the diagnosis of early stage intestinal cancer and MIC-1 and CEA, TPS three combine diagnosis, also tool hasVery important clinical value.
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2.Unsicker，K.，B.SpittauandK.Krieglstein，ThemultiplefacetsoftheTGF-betafamilycytokinegrowth/differentiationfactor-15/macrophageinhibitorycytokine-1.CytokineGrowthFactorRev，2013.
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10. pair super, etal., GDF-15 Probe of level in Serum of Patients with Lung Cancer. cancer progression,2011.9(4)：p.384-388。

Claims (5)

1. tumor markers is diagnosed and/or supervises by detecting and/or monitor the serum levels of described tumor markers in preparationPurposes in survey experimenter in reagent or the kit of colorectal cancer, wherein said tumor markers is by macrophage inhibition factor 1With TPS composition, or wherein said tumor markers is made up of macrophage inhibition factor 1, TPS and CEA.
2. purposes claimed in claim 1, wherein said colorectal cancer is early stage colorectal cancer.
3. purposes claimed in claim 1, wherein said colorectal cancer is I phase and/or II phase colorectal cancer.
4. purposes claimed in claim 1, wherein said reagent or kit for T by stages and/or M by stages.
5. reagent or the kit of colorectal cancer in diagnosis and/or monitoring experimenter, wherein said reagent or kit are that right is wantedAsk the detection defining in any one in 1-4 and/or reagent or the kit of monitoring the serum levels of tumor markers, wherein saidTumor markers is made up of macrophage inhibition factor 1, TPS and CEA.
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