CN105067822A - Marker for diagnosing esophagus cancer - Google Patents
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- CN105067822A CN105067822A CN201510493944.1A CN201510493944A CN105067822A CN 105067822 A CN105067822 A CN 105067822A CN 201510493944 A CN201510493944 A CN 201510493944A CN 105067822 A CN105067822 A CN 105067822A
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Abstract
The invention discloses a marker for diagnosing esophagus cancer. The marker comprises MMP13, CHI3L1 and SPP1. Based on the three indexes, namely, the CHI3L1, the MMP13 and the SPP1, a mathematical model for diagnosing esophagus cancer is established as follows: Logit (p=ESCC)=-5.278+0.025*CHI3L1+0.028*SPP1+0.747*MMP13, and the AUC (area under the curve) of the prediction probability of the mathematical model is 0.942 when the mathematical model is used for diagnosing esophagus cancer. According to the marker, when the sensitivity is set at 90%, the cut-off is 0.4, the specificity reaches 76.04%, the positive predictive value is 85.44%, and the negative predictive value is 82.95%; when the marker is used for early diagnosis of esophagus cancer, the sensitivity is 90.14%, the specificity is 76.04%, the AUC is 0.933, the positive predictive value is 73.56%, and the negative predictive value is 91.25%; the prediction probability is much higher than the separate prediction probability of the MMP13, the CHI3L1 and the SPP1.
Description
Technical field
The present invention relates to a kind of mark for esophagus cancer diagnosis.
Background technology
The cancer of the esophagus is common tumor in digestive tract, and the whole world about has 300,000 people to die from the cancer of the esophagus every year.Its M & M various countries are widely different.China is one of Esophageal Cancer area in the world, and every annual is died of illness about 150,000 people.Man is more than female, and age of onset is many more than 40 years old.The typical symptom of the cancer of the esophagus is Progressive symmetric erythrokeratodermia dyscatabrosis, before this food of difficult dry throat, is semiliquid diet then, and last water and saliva can not be swallowed.The detection of the cancer of the esophagus is the basis of effectively treating the cancer of the esophagus.
The cancer of the esophagus blood serum designated object of current clinical practice mainly contains squamous cell carcinoma antigen (SquamousCellCarcinomaAntigen, SCCA), carcinomebryonic antigen (carcino-embryonicantigen, CEA), cytokeratin 19 fragment (CYFRA21-1).But all there is sensitivity and the not high shortcoming of specificity in existing serologic marker thing, especially more outstanding in cancer of the esophagus early diagnosis.External report, change of serum C EA diagnoses the sensitivity of early stage esophageal squamous cell carcinoma to be only about 17%
[1], serum SCCA diagnoses sensitivity that is early stage and advanced esophageal cancer to be respectively 22% and 37%
[2].CYFRA21-1 diagnosis sensitivity that is early stage and advanced esophageal cancer is respectively 22.2% and 77.8%.Domestic report, CEA, Cyfra21-1 and SCCA diagnose the positive rate of esophageal squamous cell carcinoma to be respectively 10.3%, 25.6% and 42.3%
[3].These researchs all illustrate that the sensitivity of traditional blood serum tumor markers diagnosis esophageal squamous cell carcinoma is all lower.Therefore, find new blood serum designated object, the sensitivity of raising oesophagus squama cancer diagnosis is a study hotspot in recent years.
The new cancer of the esophagus serodiagnosis mark of current screening mainly adopts following 3 strategies:
(1) strategy of epigenetics screening serum cancer of the esophagus specific methylation DNA mark is adopted: Kuroki etc.
[4]research finds that the tumor-related genes such as FHIT, CDKN2A, MGMT, RASSF1 exist abnormal methylation in human esophageal carcinoma, and the dissociative DNA of these abnormal methylation can be detected in blood, the sensitivity of diagnosis of esophageal cancer is 45%, specificity 78%.Lima etc.
[5]utilize the IlluminaGoldenGate chip that methylates to compare the abnormal methylation state of 10 pairs of cancer of the esophagus and cancer beside organism, filter out TFF1 as potential early diagnosis of tumor index, sensitivity reaches 61%.Domestic Li Bo etc.
[6]from human esophageal carcinoma, filter out 5 abnormal methylation p16 gene, CDH1, RASSF1A, DAPK and RAR-β, wherein CDH1, DAPK and RASSF1A are present in peripheral blood, and the sensitivity of diagnosis of esophageal cancer is 84.4%, and specificity is 86.7%.Li Xufeng etc.
[7]filter out 3 abnormal methylation gene EPB41L3 be present in blood, GPX3 and COL14A1, the sensitivity 64.3% of joint-detection diagnosis of esophageal cancer, specificity reaches 100%.In blood, the sensitivity of abnormal methylation DNA diagnosis of esophageal cancer and specificity are apparently higher than traditional blood serum tumor markers.But its weak point is that the abnormal methylation DNA that each research group filters out is different, and its diagnostic need further checking.Its sensitivity diagnosing the early stage cancer of the esophagus is not reported in most research in addition, still needs research further, and methylate DNA detection technique is complicated, is not easy to clinically generally to carry out.
(2) protein science finds new cancer of the esophagus blood serum designated object strategy: adopt proteomic techniques in recent years, compare the differential expression of patient with esophageal carcinoma and normal human serum protein groups, finds esophagus cancer diagnosis blood serum designated object.Fan Naijun etc.
[8]in esophagus cancer patient blood serum, search out 3 up-regulated expression albumen by protein groups technology, diagnosis of esophageal cancer sensitivity is 60%-70%.Liu Lihua etc.
[9]filter out different protein combination, the sensitivity of its diagnosis of esophageal cancer is close to 90%.Owing to there is high-abundance proteins in serum as albumin and IgG, inevitably disturb the detection of low-abundance protein, protein groups technology all can not reach the requirement of analysis to the sensitivity of low-abundance protein and precision.Adopt this strategy to find new cancer of the esophagus serodiagnosis mark, the target protein having diagnostic value that some are potential may be missed.
(3) the serum cancer of the esophagus mark strategy that microRNA cDNA microarray is new: Zhang Chenyu etc.
[10]adopt microRNA cDNA microarray to go out 7 kinds of miRNA:miR-10a, miR-22, miR-100, miR-148b, miR-223, miR-133a and miR-127-3p the cancer of the esophagus being had to higher diagnostic value, diagnostic sensitivity is about 81.2%, and specificity is about 83.0%.YamamotoS etc.
[11]also find miR-507 ,-634 ,-450a ,-129-5p and the cancer of the esophagus occur to develop closely related, diagnosis of esophageal cancer sensitivity about 60%.Although the serum miRNA marker diagnostic sensitivity of this Policy Filtering is higher, specificity is also better, but the miRNA of different seminar's screenings is different, its diagnostic value is also still to be tested, and the detection technique of serum miRNA requires high, complicated operation, mensuration in enormous quantities comparatively bothers, and is not suitable for clinically generally applying.
Adopt above strategy from serum, screen new cancer of the esophagus mark and respectively have its relative merits, the requirement of cancer of the esophagus early diagnosis clinically can't be met.Therefore, explore new strategy to be still necessary to screen better cancer of the esophagus serodiagnosis mark.
As everyone knows, the normal structure differential gene expression chip technology of human esophageal carcinoma and its pairing is one of cancer of the esophagus blood serum designated object screening strategy.This strategy finds by chip technology the gene that High Defferential expresses, if there is secretory protein, selects one of them or the wherein the most significant albumen of several differences, then carries out Virus monitory, verify that can it as esophagus cancer diagnosis mark.Japan ZenK etc.
[12]go out PARD3 by expression chip technology screening, the recall rate in cancer of esophagi human serum is 15%.TakumiYamabuki etc.
[4]also filter out DKK1 by constructed, its recall rate in esophagus cancer patient blood serum is 63.0%.The mark of differential gene expression chip technology screening can improve cancer of the esophagus detection sensitivity really, but because this technology is only for known, detect more difficult to low-abundance mRNA, inevitably cause the omission of object target, the target that simultaneously also there is the screening of different seminar is different.
In recent years, the high flux rna transcription group sequencing technologies of high speed development can make up the above-mentioned defect of gene expression chip.High flux rna transcription group sequencing technologies refers to and utilizes second generation high throughput sequencing technologies to carry out cDNA order-checking, obtains a certain species certain organs or the nearly all transcript under being organized in a certain state rapidly comprehensively.The advantage of this technology to obtain the high-precision transcript information of high coverage, and it can provide more system and more fully mrna expression digitized signal than expressing gene chip technology, low-abundance mrna expression level detected more delicately.Because mRNA level in-site is significantly higher than the protein level of its correspondence, especially the low-abundance protein do not measured is examined for protein science, RNA sequencing technologies can identify the gene of one or two order of magnitude higher than protein groups, substantially increase the sensitivity of detection, these characteristics become the good technical method of Screening Diagnosis tumor markers.
But, in prior art, still lack highly sensitive, the esophagus cancer diagnosis mark that specificity is good, which has limited the application of diagnostic markers.
Summary of the invention
The object of the present invention is to provide a kind of composite marker thing for esophagus cancer diagnosis, this composite marker thing has highly sensitive, the advantage that specificity is good.
The technical solution used in the present invention is:
One group, for the mark of esophagus cancer diagnosis, is made up of MMP13, CHI3L1, SPP1.
Preferably, the diagnostic formulation based on above-mentioned mark is
Logit(p＝ESCC)＝-5.278+0.025×CHI3L1+0.028×SPP1+0.747×MMP13，
In formula, the unit of MMP13, CHI3L1, SPP1 expression is that ng/ml, P value is defined as excessive risk when being greater than 0.43, otherwise is then low-risk.
For a kit for esophagus cancer diagnosis, the reagent containing quantitative MMP13, CHI3L1, SPP1 expression in this kit.
Above-mentioned in the kit of esophagus cancer diagnosis, value-at-risk is according to formula:
Logit (p=ESCC)=-5.278+0.025 × CHI3L1+0.028 × SPP1+0.747 × MMP13 calculates, in formula, the unit of MMP13, CHI3L1, SPP1 expression is that ng/ml, P value is defined as excessive risk when being greater than 0.43, otherwise is then low-risk.
A method of early diagnosis for the cancer of the esophagus, comprises the steps:
1) expression of MMP13, CHI3L1 and SPP1 in quantitative tissue to be measured;
2) according to the expression of MMP13, CHI3L1 and SPP1, the situation of the cancer of the esophagus is determined.
Especially, in above-mentioned diagnostic method, diagnostic formulation is:
Logit(p＝ESCC)＝-5.278+0.025×CHI3L1+0.028×SPP1+0.747×MMP13，
In formula, the unit of MMP13, CHI3L1, SPP1 expression is that ng/ml, P value is defined as excessive risk when being greater than 0.43, otherwise is then low-risk.
The invention has the beneficial effects as follows:
The present invention is based on CHI3L1, MMP13 and SPP1 these 3 Index Establishments mathematical model of diagnosis of esophageal cancer:
Logit (p=ESCC)=-5.278+0.025 × CHI3L1+0.028 × SPP1+0.747 × MMP13, the AUC of this mathematical model prediction probabilistic diagnosis cancer of the esophagus is 0.942.When sensitivity is decided to be 90%, cut-off is 0.4, and specificity can reach 76.04%, positive predictive value 85.44%, negative predictive value 82.95%.During early diagnosis for the cancer of the esophagus, sensitivity 90.14%, specificity 76.04%, AUC0.933, positive predictive value 73.56%, negative predictive value 91.25%, is significantly higher than CHI3L1 (sensitivity: 90.14%; Specificity: 22.92%; AUC:0.731), MMP13 (sensitivity: 90.14%; Specificity 48.96%:AUC:0.837), SPP1 (sensitivity: 90.14%; Specificity: 14.58%; AUC:0.7) diagnostic that any one index is independent.In checking group, Mathematical Diagnosis model prediction cancer of the esophagus AUC is 0.930, and when sensitivity is decided to be 90%, specificity can reach 78.75%, positive predictive value 90.0%, negative predictive value 79.75%.And it predicts that early stage cancer of the esophagus AUC is 0.943, when sensitivity is decided to be 90.53%, specificity can reach 88.75%, positive predictive value 89.41%, negative predictive value 89.87%.
Accompanying drawing explanation
Fig. 1 is 40 routine patient with esophageal carcinoma and 40 routine normal human serum ADAM12, CA9, CHI3L1, CST1, MMP13, POSTN, SFRP4, SPP1, LAMC2, SERPINE1 concentration comparable situation;
Fig. 2 is serum ADAM12, CHI3L1, MMP-13, SPP1 concentration comparable situation in test group (150 routine patient with esophageal carcinoma and 96 routine normal persons);
Fig. 3 is the ROC of the cancer of the esophagus in serum ADAM12, CHI3L1, MMP-13, SPP1 and Mathematical Diagnosis Model Diagnosis test group;
Fig. 4 is that in test group, the early stage patient with esophageal carcinoma of 71 example compares with 96 routine normal human serum CHI3L1, MMP-13, SPP1 concentration;
Fig. 5 is the ROC of the early stage cancer of the esophagus in change of serum C HI3L1, MMP-13, SPP1 and Mathematical Diagnosis Model Diagnosis test group;
Fig. 6 is change of serum C HI3L1 in checking group (169 routine patient with esophageal carcinoma and 80 routine normal persons), MMP-13, SPP1 concentration compares;
Fig. 7 is the ROC of the cancer of the esophagus in change of serum C HI3L1, MMP-13, SPP1 and Mathematical Diagnosis Model Diagnosis checking group;
Fig. 8 is that in checking group, the early stage patient with esophageal carcinoma of 84 example compares with 80 routine normal human serum CHI3L1, MMP-13, SPP1 concentration;
Fig. 9 is the ROC of the early stage cancer of the esophagus in change of serum C HI3L1, MMP-13, SPP1 and Mathematical Diagnosis Model Diagnosis checking group.
Embodiment
One group, for the mark of esophagus cancer diagnosis, is made up of MMP13, CHI3L1, SPP1.
Know MMP13, CHI3L1 and SPP1 combinationally use can obtain more high sensitivity and specificity time, existing case can be analyzed by detecting, in conjunction with the known technology of this area, determining rational diagnostic formulation and risk judgment standard.
Preferably, the diagnostic formulation based on above-mentioned mark is
Logit(p＝ESCC)＝-5.278+0.025×CHI3L1+0.028×SPP1+0.747×MMP13，
In formula, the unit of MMP13, CHI3L1, SPP1 expression is that ng/ml, P value is defined as excessive risk when being greater than 0.43, otherwise is then low-risk.
For a kit for esophagus cancer diagnosis, the reagent containing quantitative MMP13, CHI3L1, SPP1 expression in this kit.
Above-mentioned in the kit of esophagus cancer diagnosis, value-at-risk is according to formula:
Logit(p＝ESCC)＝-5.278+0.025×CHI3L1+0.028×SPP1+0.747×MMP13
Calculate, in formula, the unit of MMP13, CHI3L1, SPP1 expression is that ng/ml, P value is defined as excessive risk when being greater than 0.43, otherwise is then low-risk.
A method of early diagnosis for the cancer of the esophagus, comprises the steps:
3) expression of MMP13, CHI3L1 and SPP1 in quantitative tissue to be measured;
4) according to the expression of MMP13, CHI3L1 and SPP1, the situation of the cancer of the esophagus is determined.
Especially, in above-mentioned diagnostic method, diagnostic formulation is:
Logit(p＝ESCC)＝-5.278+0.025×CHI3L1+0.028×SPP1+0.747×MMP13，
In formula, the unit of MMP13, CHI3L1, SPP1 expression is that ng/ml, P value is defined as excessive risk when being greater than 0.43, otherwise is then low-risk.
Below in conjunction with concrete experimental technique, further illustrate technical scheme of the present invention.
The screening of new diagnostic markers
1) 6 pairs of ESCC tissues check order with the rna transcription group of pairing normal structure: extract 6 couples of ESCC and organize the RNA with pairing normal structure, carry out the order-checking of rna transcription group, bioinformatic analysis difference expression gene in Hua Da genome company;
2) for ensureing that the mark screened is applied to the sensitivity (>=80%) after esophageal squamous cell carcinoma Serologic detection and reliability, the present invention is centering to rare 5 with 6, and to organizing, there were significant differences expresses (sensitivity >=80%), adopt excel table, pick out 175 differential genes;
3) for searching out in serum the tumor markers being easy to detect, and the definition of tumor markers refers to that characteristic is present in malignant cell, or by the abnormal material produced of malignant cell, or the material that host produces the irritant reaction of tumour.The mark of up-regulated expression directly can react the existence of tumour, raising fold difference points out mark to be easy to detect in serum by straightforward procedure greatly to a certain extent, the present invention is centering to rare 4, and to raising multiple in cancerous tissue, more than 5 times, (log2 (T/N) >=2.3) is decided to be candidate rule by 6, from 175 genes of previous step screening, filter out 39 differential genes;
4) secretory protein bioinformatic analysis software SingnalP4.1 and Secretome2.0 is utilized, 32 secretory proteins except COL5A2, FAM176A, IGF2BP2, KIF26B, KRT14, KRT16P5, PPAPDC1A are filtered out, as candidate's secretory protein of next step screening from the gene of 39 candidate's differential expressions;
5) in GeneExpressionOmnibus (GEO), search, to 3 esophageal squamous cell carcinoma gene expression chip databases, verifies the expression of 32 genes in these chip databases screened.Because chip coverage is little compared with the order-checking of rna transcription group, three chips are not all covered to AMTN mark, and GSE20347 does not cover CPXM1 and CTHRC1 two marks.Unlapped mark continues to include next step screening in by the present invention.Due to ADAMTS12 and IGHG4 down-regulated expression in GSE20347, SDS is down-regulated expression in GSE33810, therefore remove this three marks, obtain 29 candidate's secretory proteins that also significant difference is expressed in other ESCC gene expression chip databases and carry out next step checking;
6) on GeneCards, inquiry obtains 29 marks, for same family mark, in only selecting this experiment rna transcription group to check order, the maximum mark of fold differences representatively, except COL10A1, COL3A1, COL5A1, MMP1, MMP10, MMP11, MMP12, CST2, remaining shown 21 marks of table 1.At the KEGGpathway that GeneCards includes, the signal path analyzing web sites such as GeneGlobePathway, SinoBiologicalPathway, ISS are to the signal path analysis of 21 candidate markers.Except AMTN, CPXM1, PDPN tri-does not search the support to tumour related pathways in Genecards and document, the signal path that remaining 18 candidate albumens (table 2) participate in all develops relevant with the generation of tumour;
7) on Genecards, the GeneOntology (GO) that includes then is inquired about to the functional annotation of the biological process that 18 candidate albumens participate in, candidate markers take part in the closely-related biological process with tumor development, comprise cell adherence, the biological processes as shown in table 2 such as anti-apoptotic, Angiogensis, short cell proliferation;
8) evidence of 18 albumen up-regulated expression in the cancer of the esophagus or other Serum of Cancer Patients is found in the literature, finishing screen selects 10 albumen having had report to support its high expressed in Serum of Cancer Patients: ADAM12, CA9, CHI3L1, CST1, LAMC2, POSTN, SFRP4 and SPP1, MMP13, WISP1, SERPINE1, as table 3 shows.
The foundation of Mathematical Diagnosis model and checking
1) preliminary screening to 4 candidate markers significantly expressed in patients with esophageal squamous cell carcinoma serum from 10 candidate albumens: MMP13, ADAM12, CHI3L1, SPP1: this research and utilization commercial ELISA kit, all adopts double-antibody method to detect 10 candidate albumen serum-concentrations in the normal human serum (deriving from test group) of 40 routine patients with esophageal squamous cell carcinomas and 40 example pairings.Normal group and esophageal squamous cell carcinoma group CST1 are compared in the rank test adopting two independent samples to compare, the difference of MMP13, ADAM12, SFRP4, POSTN, CA9, CHI3L1, SPP1, LAMC2, SERPINE1 serum-concentration finds: patients with esophageal squamous cell carcinoma change of serum C ST-1,6 marker concentration such as POSTN, CA9, SFRP4, LAMC2, SERPINE1 and normal human serum concentration do not have significant difference.And 4 marks: the serum-concentration difference between MMP13, ADAM12, CHI3L1, SPP1 esophageal squamous cell carcinoma group and normal group has statistical significance (P<0.05), and in patients with esophageal squamous cell carcinoma serum, 4 indexs significantly raise (Fig. 1);
2) MMP13, ADAM12, CHI3L1, SPP1 mark serum-concentration test group checking, esophagus cancer patient blood serum MMP13, ADAM12, CHI3L1, SPP1 concentration significantly raise.Because preliminary experiment prompting MMP13, ADAM12, CHI3L1, SPP1 can significantly distinguish patient with esophageal carcinoma and normal person, so inventor uses test group (150 routine patient with esophageal carcinoma and 96 routine normal human serums, two groups of crowd's sexes, age differences not statistically significants) to verify the result of preliminary experiment further.Result shows, esophagus cancer patient blood serum MMP13 (5.08ng/mlvs0.47ng/ml, P<0.001), ADAM12 (0.45ng/mlvs0.15ng/ml, P<0.001), CHI3L1 (85.00ng/mlvs45.64ng/ml, P<0.001), SPP1 (80.81ng/mlvs43.06ng/ml, P<0.001) concentration, apparently higher than normal human serum concentration, significantly can distinguish patient with esophageal carcinoma and normal person (Fig. 2);
3) performance of serum MMP13, ADAM12, CHI3L1, SPP1 mark Combining diagnosis cancer of the esophagus and the foundation of cancer of the esophagus Mathematical Diagnosis model: the serum-concentration detecting serum MMP13, ADAM12, CHI3L1, SPP1 mark in test group, utilizes the performance of its single Indexs measure of ROC tracing analysis and four index joint-detection diagnosis of esophageal cancers.Fig. 3 is presented in test group, and the AUC of the independent diagnosis of esophageal cancer of ADAM12, CHI3L1, MMP13, SPP1 is respectively 0.739,0.765,0.854 and 0.725; When sensitivity is due to 90% time, the specificity of the independent diagnosis of esophageal cancer of ADAM12, CHI3L1, MMP13, SPP1 respectively only 35.42%, 30.21%, 48.96% and 17.71%;
4) best of breed diagnosis of esophageal cancer in BinaryLogistic regretional analysis four indexs is made by ForwardCondition method, the standard sieve being less than 0.05 by P value selects three index: CHI3L1, MMP13 and SPP1, reject ADAM12 index (P>0.05), and setting up diagnosis of esophageal cancer mathematical model: Logit (p=ESCC)=-5.278+0.025 × CHI3L1+0.028 × SPP1+0.747 × MMP13 is used for cancer of the esophagus prediction probability and calculates, and carries out ROC curve esophagus cancer diagnosis performance evaluation (Fig. 3).In formula, the unit of MMP13, CHI3L1, SPP1 expression is ng/ml.The AUC of this mathematical model prediction probabilistic diagnosis cancer of the esophagus is 0.942.When sensitivity is decided to be 90%, specificity can reach 76.04%, positive predictive value 85.44%, negative predictive value 82.95%;
5) diagnosis performance of Mathematical Diagnosis model in the early stage cancer of the esophagus of test group: Fig. 4 shows early stage patient with esophageal carcinoma (comprising the 20 routine I phase cancer of the esophagus and the 51 routine II phase patient with esophageal carcinoma) serum MMP13 (5.17vs0.47 of 71 example in test group, P<0.001), CHI3L1 (80.48vs45.64, P<0.001), SPP1 (85.73vs43.06, P<0.001) concentration is significantly higher than normal person, significantly can distinguish early stage cancer of the esophagus crowd and normal population equally.As shown in Figure 5, on diagnosis performance in early days in the cancer of the esophagus, the early stage esophagus cancer diagnosis usefulness of Mathematical Diagnosis model is sensitivity 90.14%, specificity 76.04%, AUC0.933, positive predictive value 73.56%, negative predictive value 91.25%, is significantly higher than CHI3L1 (sensitivity: 90.14%; Specificity: 22.92%; AUC:0.731), MMP13 (sensitivity: 90.14%; Specificity 48.96%:AUC:0.837), SPP1 (sensitivity: 90.14%; Specificity: 14.58%; AUC:0.7) diagnostic that any one index is independent;
6) in checking group, Mathematical Diagnosis Model Diagnosis cancer of the esophagus performance is verified: the checking group serum specimen of 169 routine patient with esophageal carcinoma and 80 routine normal person's compositions, for verifying the usefulness of the diagnosis of esophageal cancer of this Mathematical Diagnosis model.Include the patient age of checking group in, sex ratio, by stages ratio are similar to test group.Result shows, and CHI3L1, MMP13, SPP1 in esophagus cancer patient blood serum are all higher than normal population (meta concentrations versus: CHI3L1,78.18vs34.64ng/ml; MMP13,3.951vs0.3836ng/ml; SPP1:79.84vs28.40ng/ml), difference all has statistical significance (P<0.001, Fig. 6).The prediction probability of each crowd of group is verified by Combining diagnosis calculated with mathematical model.At the diagnostic of cancer of the esophagus vs normal person, area under curve (AUC) is comprised, sensitivity, specificity with Mathematical Diagnosis model in ROC curve evaluation checking group.Result is presented in checking group, and the AUC of the independent diagnosis of esophageal cancer of CHI3L1, MMP13, SPP1 is respectively 0.822,0.835 and 0.750, and when sensitivity schedules 90.53%, its specificity is respectively 48.75%, 53.75% and 15.00%.And Mathematical Diagnosis model prediction cancer of the esophagus AUC is 0.930, when sensitivity is decided to be 90%, specificity can reach 78.75%, positive predictive value 90.0%, negative predictive value 79.75% (Fig. 7);
7) checking of Mathematical Diagnosis model in the early stage esophagus cancer diagnosis of checking group: Fig. 8 is presented at CHI3L1 in checking group, MMP13, the result of the early stage cancer of the esophagus of SPP1 diagnosis 84 example, CHI3L1, MMP13, SPP1 index all significantly can distinguish early stage cancer of the esophagus crowd and normal population (P<0.001).ROC curve (Fig. 9) evaluates display, and CHI3L1, MMP13, SPP1 diagnose separately the AUC of the early stage cancer of the esophagus to be respectively 0.828,0.852 and 0.731, when sensitivity is due to 90.48% time, and its specificity respectively only 42.50%, 51.25% and 5.00%.And the early stage cancer of the esophagus AUC of Mathematical Diagnosis model prediction is 0.943, when sensitivity is decided to be 90.53%, specificity can reach 88.75%, positive predictive value 89.41%, negative predictive value 89.87%.Demonstrate the usefulness of the cancer of the esophagus mathematical model early diagnosis cancer of the esophagus that inventor sets up equally.
Inventor finds and improves diagnosis of esophageal cancer sensitivity and specific serum standard from the secretory protein of the normal structure rna transcription group order-checking storehouse differential expression that human esophageal carcinoma and its match: MMP13, CHI3L1, SPP1.The Mathematical Diagnosis model set up can be used for the examination of the normal population cancer of the esophagus and the detection of the early stage cancer of the esophagus, and minimizing is failed to pinpoint a disease in diagnosis, for early screening and diagnosis of esophageal cancer provide a new way.
The signal path analysis of table 1:21 candidate markers
1same family mark with the maximum mark of rna transcription group order-checking fold differences for representative;
* Genecards does not include, and looks into from document; The mark for including next step screening in of overstriking;
-representative do not find to associated signal paths.
The Gobiologicalprocess annotation of table 2:18 candidate albumen
1same family mark with the maximum mark of rna transcription group order-checking fold differences for representative;
* Genecards does not include, and looks into from document; GOBP represents GObiologicalprocess.
Show 3:10 candidate albumen and express documentary evidence at Serum of Cancer Patients
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Claims (6)
1. one group is used for the mark of esophagus cancer diagnosis, is made up of MMP13, CHI3L1, SPP1.
2. mark according to claim 1, is characterized in that: diagnostic formulation is
logit (p=ESCC)=-5.278+0.025 × CHI3L1+0.028 × SPP1+0.747 × MMP13, in formula, the unit of MMP13, CHI3L1, SPP1 expression is that ng/ml, P value is defined as excessive risk when being greater than 0.43, otherwise is then low-risk.
3. for a kit for esophagus cancer diagnosis, it is characterized in that: the reagent containing quantitative MMP13, CHI3L1, SPP1 expression in this kit.
4. kit according to claim 3, is characterized in that: value-at-risk is according to formula
logit (p=ESCC)=-5.278+0.025 × CHI3L1+0.028 × SPP1+0.747 × MMP13calculate, in formula, the unit of MMP13, CHI3L1, SPP1 expression is that ng/ml, P value is defined as excessive risk when being greater than 0.43, otherwise is then low-risk.
5. a method of early diagnosis for the cancer of the esophagus, comprises the steps:
The expression of MMP13, CHI3L1 and SPP1 in quantitative tissue to be measured;
According to the expression of MMP13, CHI3L1 and SPP1, determine the situation of the cancer of the esophagus.
6. method of early diagnosis according to claim 5, is characterized in that: diagnostic formulation is
logit (p=ESCC)=-5.278+0.025 × CHI3L1+0.028 × SPP1+0.747 × MMP13, in formula, the unit of MMP13, CHI3L1, SPP1 expression is that ng/ml, P value is defined as excessive risk when being greater than 0.43, otherwise is then low-risk.
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