CN105067822B - Marker for diagnosing esophagus cancer - Google Patents
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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 there are about 300,000 people and dies from the cancer of the esophagus every year.Its incidence of disease and dead
Wang Shuai various countries are widely different.China is one of Esophageal Cancer area in the world, and die of illness about 150,000 people per annual.Man is more than
Female, age of onset is more more than 40 years old.The typical symptom of the cancer of the esophagus is progressive dyscatabrosis, before this food of difficult dry throat, after
But semiliquid diet, last water and saliva can not be swallowed.The detection of the cancer of the esophagus is the basis for effectively treating the cancer of the esophagus.
The cancer of the esophagus blood serum designated object of current clinical practice mainly has squamous cell carcinoma antigen (Squamous Cell
Carcinoma Antigen, SCCA), carcinomebryonic antigen (carcino-embryonic antigen, CEA), Cyfra21-1
Fragment (CYFRA21-1).But existing serologic marker thing all haves the shortcomings that sensitivity and specificity are not high, especially in oesophagus
Cancer early diagnosis aspect is more prominent.Foreign countries' report, the sensitivity of change of serum C EA diagnosis early stage esophageal squamous cell carcinomas is only about 17%[1], blood
The sensitivity of clear SCCA diagnosis early stage and advanced esophageal cancer is respectively 22% and 37%[2].CYFRA21-1 diagnosis early stage and
The sensitivity of advanced esophageal cancer is respectively 22.2% and 77.8%.Country's report, CEA, Cyfra21-1 and SCCA diagnosis food
The positive rate of pipe squamous carcinoma is respectively 10.3%, 25.6% and 42.3%[3].These researchs illustrate traditional blood serum tumor mark
The sensitivity of thing diagnosis esophageal squamous cell carcinoma is relatively low.Therefore, new blood serum designated object is found, improving oesophagus squama cancer diagnosis sensitivity is
A study hotspot in recent years.
New cancer of the esophagus serodiagnosis mark is screened at present mainly uses following 3 strategies：
(1) strategy of serum cancer of the esophagus specific methylation DNA marks is screened using epigenetics：Kuroki etc.[4]
Research finds that the tumor-related genes such as FHIT, CDKN2A, MGMT, RASSF1 have abnormal methylation in human esophageal carcinoma, can
The dissociative DNA of these abnormal methylations is detected in blood, and the sensitivity of diagnosis of esophageal cancer is 45%, specificity 78%.
Lima etc.[5]Compare the abnormal methylation of 10 pairs of cancer of the esophagus and cancer beside organism using the Illumina GoldenGate chips that methylate
State, filters out TFF1 as potential early diagnosis of tumor index, and sensitivity is up to 61%.Domestic Li Bo etc.[6]From cancer of the esophagus group
Filter out 5 abnormal methylation p16 genes in knitting, CDH1, RASSF1A, DAPK and RAR- β, wherein CDH1, DAPK and
RASSF1A is 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, GPX3 and the COL14A1 being present in blood, joint-detection diagnosis of esophageal cancer
Sensitivity 64.3%, specificity is up to 100%.The sensitivity and specificity of abnormal methylation DNA diagnosis of esophageal cancer are bright in blood
Aobvious is higher than traditional blood serum tumor markers.But it is disadvantageous in that the abnormal methylation DNA that each research group filters out is each not
Identical, its diagnostic need further checking.The sensitivity of its diagnosis early stage cancer of the esophagus is not reported in most researchs in addition, still
Need further research, and methylate DNA detection technique is complicated, is not easy to clinic and generally carries out.
(2) protein science finds new cancer of the esophagus blood serum designated object strategy：Proteomic techniques are used in recent years, compare food
Pipe cancer patient and the differential expression of normal human serum protein groups, find esophagus cancer diagnosis blood serum designated object.Fan Naijun etc.[8]Pass through
Protein groups technology searches out 3 up-regulated expression albumen in esophagus cancer patient blood serum, and diagnosis of esophageal cancer sensitivity is 60%-
70%.Liu Lihua etc.[9]Filter out different protein combinations, the sensitivity of its diagnosis of esophageal cancer is close to 90%.Due to being deposited in serum
In high-abundance proteins such as albumin and IgG, the detection of low-abundance protein is inevitably disturbed, protein groups technology is to low abundance egg
White sensitivity and precision can not reach the requirement of analysis.New cancer of the esophagus serodiagnosis mark is found using this strategy
Thing, may miss some potentially has the target protein of diagnostic value.
(3) the new serum oesophagus carcinoma marker strategy of microRNA cDNA microarrays：Zhang Chenyu etc.[10]Using microRNA cores
Piece filters out 7 kinds of miRNA for having diagnostic value higher to the cancer of the esophagus：miR-10a,miR-22,miR-100,miR-148b,miR-
223, miR-133a and miR-127-3p, diagnostic sensitivity is about 81.2%, specificity about 83.0%.Yamamoto S
Deng[11]It has also been found that miR-507, -634, -450a, -129-5p are closely related with the development of oesophagus carcinogenesis, and diagnosis of esophageal cancer is sensitive
Degree about 60%.Although the serum miRNA marker diagnostic sensitivity of this Policy Filtering is higher, specificity is also preferable, different
The miRNA of seminar's screening is different, and its diagnostic value is also still to be tested, and the detection technique requirement of serum miRNA is high, operation
Complexity, in high volume determines cumbersome, is not suitable for clinical commonly used.
Strategy screens new oesophagus carcinoma marker from serum more than respectively its advantage and disadvantage, is not met by clinically
The requirement of cancer of the esophagus early diagnosis.Therefore, explore new strategy screen that more preferable cancer of the esophagus serodiagnosis mark still has must
Will.
It is well known that human esophageal carcinoma and the normal structure differential gene expression chip technology of its pairing are oesophagus cancer-serums
One of mark screening strategy.This strategy finds the gene that High Defferential is expressed by chip technology, if there is secretory protein, choosing
One of them or the most significant albumen of wherein several differences are selected, Virus monitory is then carried out, verifies that can it used as the cancer of the esophagus
Diagnosis marker.Japanese Zen K etc.[12]PARD3 is gone out by expression chip technology screening, the detection in cancer of esophagi human serum
Rate is 15%.Takumi Yamabuki etc.[4]DKK1 is filtered out also by constructed, its inspection in esophagus cancer patient blood serum
Extracting rate is 63.0%.The mark of differential gene expression chip technology screening can actually improve cancer of the esophagus detection sensitivity, so
And because this technology is only for known, more difficult is detected to low-abundance mRNA, inevitably result in purpose target
Omit, while the target that there is also different seminar's screenings is different.
In recent years, the high flux rna transcription group sequencing technologies of high speed development can make up gene expression chip drawbacks described above.It is high
Flux rna transcription group sequencing technologies refer to carry out cDNA sequencings using second generation high throughput sequencing technologies, are rapidly obtained comprehensively
A certain species certain organs or the nearly all transcript being organized under a certain state.The advantage of the technology is to obtain covering high
High-precision transcript information is spent, it can provide more system and more fully mRNA expression numerals than expressing gene chip technology
Change signal, more delicately detect low-abundance mRNA expressions.Because mRNA level in-site is significantly higher than its corresponding albumen water
Flat, especially for the low-abundance protein that protein science inspection is not measured, RNA sequencing technologies can recognize one or two number higher than protein groups
The gene of magnitude, substantially increases the sensitivity of detection, and these characteristics become the good of Screening Diagnosis tumor markers
Technical method.
However, in the prior art, it is high still to lack sensitivity, the good esophagus cancer diagnosis mark of specificity, which has limited examining
The application of disconnected mark.
The content of the invention
It is an object of the invention to provide a kind of composite marker thing for esophagus cancer diagnosis, the composite marker thing has spirit
Sensitivity is high, the good advantage of specificity.
The technical solution used in the present invention is：
One group of mark for being used for 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 quantity is ng/ml, and P values are defined as excessive risk when being more than 0.43,
Otherwise it is then low-risk.
A kind of kit for esophagus cancer diagnosis, contains quantitative MMP13, CHI3L1, SPP1 expression quantity in the kit
Reagent.
In the above-mentioned kit for esophagus cancer diagnosis, value-at-risk is according to formula：
Logit (p=ESCC)=- 5.278+0.025 × CHI3L1+0.028 × SPP1+0.747 × MMP13 is calculated, formula
In, the unit of MMP13, CHI3L1, SPP1 expression quantity is ng/ml, and P values are defined as excessive risk when being more than 0.43, otherwise is then low
Risk.
A kind of method of early diagnosis of the cancer of the esophagus, comprises the following steps：
1) expression quantity of MMP13, CHI3L1 and SPP1 in test serum is quantified；
2) according to the expression quantity of MMP13, CHI3L1 and SPP1, the situation of the cancer of the esophagus is determined.
Particularly, 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 quantity is ng/ml, and P values are defined as excessive risk when being more than 0.43,
Otherwise it is then low-risk.
The beneficial effects of the invention are as follows：
Present invention Mathematical Modeling of diagnosis of esophageal cancer based on CHI3L1, MMP13 and SPP1 this 3 Index Establishments：
Logit (p=ESCC)=- 5.278+0.025 × CHI3L1+0.028 × SPP1+0.747 × MMP13, this mathematics
The AUC of the model prediction probabilistic diagnosis cancer of the esophagus is 0.942.When sensitivity is set to 90%, cut-off is 0.4, and specificity is reachable
76.04%, positive predictive value 85.44%, negative predictive value 82.95%.For the cancer of the esophagus early diagnosis when, sensitivity
90.14%, specificity 76.04%, AUC 0.933, 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) any one index list
Only diagnostic.In validation group, Mathematical Diagnosis model prediction cancer of the esophagus AUC is 0.930, when sensitivity is set to 90%,
Specificity is up to 78.75%, positive predictive value 90.0%, negative predictive value 79.75%.And its prediction early stage cancer of the esophagus AUC is
0.943, when sensitivity is set to 90.53%, specificity is up to 88.75%, positive predictive value 89.41%, negative predictive value
89.87%.
Brief description of the drawings
Fig. 1 be 40 patient with esophageal carcinoma and 40 normal human serums ADAM12, CA9, CHI3L1, CST1, MMP13,
POSTN, SFRP4, SPP1, LAMC2, SERPINE1 concentration comparable situation；
Fig. 2 be serum ADAM12 in test group (150 patient with esophageal carcinoma and 96 normal persons), CHI3L1, MMP-13,
SPP1 concentration comparable situations；
Fig. 3 is the cancer of the esophagus in serum ADAM12, CHI3L1, MMP-13, SPP1 and Mathematical Diagnosis Model Diagnosis test group
ROC；
Fig. 4 is 71 early stage patient with esophageal carcinoma and 96 normal human serum CHI3L1, MMP-13, SPP1 concentration in test group
Compare；
Fig. 5 be change of serum C HI3L1, MMP-13, SPP1 and in Mathematical Diagnosis Model Diagnosis test group the early stage cancer of the esophagus ROC；
Fig. 6 is change of serum C HI3L1, MMP-13, SPP1 concentration in validation group (169 patient with esophageal carcinoma and 80 normal persons)
Compare；
Fig. 7 be change of serum C HI3L1, MMP-13, SPP1 and in Mathematical Diagnosis Model Diagnosis validation group the cancer of the esophagus ROC；
Fig. 8 is 84 early stage patient with esophageal carcinoma and 80 normal human serum CHI3L1, MMP-13, SPP1 concentration in validation group
Compare；
Fig. 9 be change of serum C HI3L1, MMP-13, SPP1 and in Mathematical Diagnosis Model Diagnosis validation group the early stage cancer of the esophagus ROC.
Specific embodiment
One group of mark for being used for esophagus cancer diagnosis, is made up of MMP13, CHI3L1, SPP1.
Understand MMP13, CHI3L1 and SPP1 be applied in combination can obtain more high sensitivity and specificity when, can pass through
The existing case of detection and analysis, with reference to techniques known, it is determined that 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 quantity is ng/ml, and P values are defined as excessive risk when being more than 0.43,
Otherwise it is then low-risk.
A kind of kit for esophagus cancer diagnosis, contains quantitative MMP13, CHI3L1, SPP1 expression quantity in the kit
Reagent.
In the above-mentioned kit for 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 quantity is ng/ml, and P values are defined as height when being more than 0.43
Risk, on the contrary it is then low-risk.
A kind of method of early diagnosis of the cancer of the esophagus, comprises the following steps：
3) expression quantity of MMP13, CHI3L1 and SPP1 in test serum is quantified；
4) according to the expression quantity of MMP13, CHI3L1 and SPP1, the situation of the cancer of the esophagus is determined.
Particularly, 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 quantity is ng/ml, and P values are defined as excessive risk when being more than 0.43,
Otherwise it is then low-risk.
With reference to specific experimental technique, technical scheme is further illustrated.
The screening of new diagnostic markers
1) 6 pairs of ESCC tissues are sequenced with the rna transcription group with normal tissue：Extract 6 pairs of ESCC tissues normal with pairing
The RNA of tissue, rna transcription group sequencing, bioinformatic analysis difference expression gene are carried out in Huada gene company；
2) be ensure the mark that screens be applied to the sensitivity (>=80%) after esophageal squamous cell carcinoma Serologic detection and
Reliability, the present invention, using excel tables, is chosen with there were significant differences the expression (sensitivity >=80%) of the tissue of 6 centerings at least 5 pairs
Select 175 differential genes；
3) be to search out the tumor markers for being easy to detection in serum, and the definition of tumor markers to refer to characteristic be present
In malignant cell, or the IR of tumour is produced by the material of malignant cell generation extremely, or host
Material.The presence of the mark energy direct reaction tumour of up-regulated expression, prompting indicates to a certain extent greatly to raise fold difference
Thing is easy to be detected in serum with straightforward procedure, and 6 centerings are raised multiple more than 5 times at least 4 pairs by the present invention in cancerous tissue
(log2 (T/N) >=2.3) is set to candidate rule, and 39 differential genes are filtered out from 175 genes of previous step screening；
4) secretory protein bioinformatic analysis software SingnalP4.1 and Secretome2.0 are utilized, from 39 candidates
Filtered out except COL5A2, FAM176A, IGF2BP2, KIF26B, KRT14, KRT16P5, PPAPDC1A in the gene of differential expression
32 outer secretory proteins, as candidate's secretory protein that next step is screened；
5) searched for 3 esophageal squamous cell carcinoma gene expression chip data in Gene Expression Omnibus (GEO)
Storehouse, expression of 32 genes that checking is screened in these chip databases.Because chip coverage turns compared with RNA
The sequencing of record group is small, and three chips are not covered to AMTN marks, and GSE20347 does not cover two marks of CPXM1 and CTHRC1
Thing.The present invention continues unlapped mark to include next step screening.Due to ADAMTS12 and IGHG4 in GSE20347 table
Up to downward, SDS expresses downward in GSE33810, therefore removes these three marks, obtains 29 in other ESCC gene expressions
Also candidate's secretory protein of significant difference expression carries out next step checking in chip database；
6) inquiry obtains 29 marks on GeneCards, for same family's mark, only selects this experiment RNA
The maximum mark of fold differences is used as representative in transcript profile sequencing, except COL10A1, COL3A1, COL5A1, MMP1, MMP10,
MMP11, MMP12, CST2, remain 21 marks shown in table 1 below.In the KEGG pathway that GeneCards is included,
The signal path analyzing web sites such as GeneGlobe Pathway, Sino Biological Pathway, ISS are to 21 candidate markers
The signal path analysis of thing.Except AMTN, CPXM1, PDPN tri- does not search related logical to tumour in Genecards and document
The support on road, is left generation development of 18 signal paths of candidate albumens (table 2) participation all with tumour relevant；
7) life that the Gene Ontology (GO) for including are participated in 18 candidate albumens is then inquired about on Genecards
The functional annotation of thing process, candidate markers take part in the biological process closely related with tumor development, including thin
Born of the same parents adhere to, the biological process as shown in table 2 such as anti-apoptotic, Angiogensis, rush cell propagation；
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, finally
Filter out 10 and have been reported that the albumen for supporting its expression high in Serum of Cancer Patients:ADAM12,CA9,CHI3L1,
CST1, LAMC2, POSTN, SFRP4 and SPP1, such as MMP13, WISP1, SERPINE1, table 3 show.
The foundation of Mathematical Diagnosis model and checking
1) from 10 candidate albumens preliminary screening to 4 in patients with esophageal squamous cell carcinoma serum significantly expression candidate markers
Thing：MMP13、ADAM12、CHI3L1、SPP1：This research and utilization commercial ELISA kit, is detected using double-antibody method
10 candidate albumen serum-concentrations in 40 patients with esophageal squamous cell carcinoma and 40 normal human serums of pairing (deriving from test group).Adopt
The rank test compared with two independent samples compare Normal group and esophageal squamous cell carcinoma group CST1, MMP13, ADAM12, SFRP4,
The difference of POSTN, CA9, CHI3L1, SPP1, LAMC2, SERPINE1 serum-concentration finds：Patients with esophageal squamous cell carcinoma change of serum C ST-1,
6 marker concentrations such as POSTN, CA9, SFRP4, LAMC2, SERPINE1 and normal human serum concentration do not have significant difference.
And 4 marks：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 are significantly raised (Fig. 1)；
2) checking of MMP13, ADAM12, CHI3L1, SPP1 mark serum-concentration test group, esophagus cancer patient blood serum
MMP13, ADAM12, CHI3L1, SPP1 concentration are significantly raised.Because MMP13, ADAM12, CHI3L1, SPP1 are pointed out in preliminary experiment
Patient with esophageal carcinoma and normal person can be significantly distinguished, so inventor is further with test group, and (150 patient with esophageal carcinoma and 96 are just
Ordinary person's serum, two groups of crowd's sexes, age differenceses are not statistically significant) verify the result of preliminary experiment.Result shows, oesophagus
Cancer patients serum MMP13 (5.08ng/ml vs 0.47ng/ml, P<0.001)、ADAM12(0.45ng/ml vs 0.15ng/
Ml, P<0.001), CHI3L1 (85.00ng/ml vs 45.64ng/ml, P<0.001)、SPP1(80.81ng/ml vs
43.06ng/ml, P<0.001) concentration can significantly distinguish patient with esophageal carcinoma and normal person apparently higher than normal human serum concentration
(Fig. 2)；
3) performance and cancer of the esophagus mathematics of serum MMP13, ADAM12, CHI3L1, SPP1 marks Combining diagnosis cancer of the esophagus
The foundation of diagnostic model：The serum-concentration of serum MMP13, ADAM12, CHI3L1, SPP1 mark, utilizes in detection test group
ROC curve analyzes the performance of its single Indexs measure and four index joint-detection diagnosis of esophageal cancer.Fig. 3 is displayed in test group
In, 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 schedules 90%, the specificity difference of the independent diagnosis of esophageal cancer of ADAM12, CHI3L1, MMP13, SPP1 is only
35.42%, 30.21%, 48.96% and 17.71%；
4) best of breed in four indexs of Binary Logistic regression analyses is made with Forward Condition methods
Diagnosis of esophageal cancer, the standard screen by P values less than 0.05 selects three indexs：CHI3L1, MMP13 and SPP1, reject ADAM12 and refer to
Mark (P>0.05), and diagnosis of esophageal cancer Mathematical Modeling is set up：Logit (p=ESCC)=- 5.278+0.025 × CHI3L1+
0.028 × SPP1+0.747 × MMP13 is calculated for cancer of the esophagus prediction probability, and carries out ROC curve esophagus cancer diagnosis performance point
Analysis (Fig. 3).In formula, the unit of MMP13, CHI3L1, SPP1 expression quantity is ng/ml.This mathematical model prediction probabilistic diagnosis oesophagus
The AUC of cancer is 0.942.When sensitivity is set to 90%, specificity is up to 76.04%, and positive predictive value 85.44% is negative pre-
Measured value 82.95%；
5) diagnosis performance of the Mathematical Diagnosis model in the test group early stage cancer of the esophagus：71 early stages in Fig. 4 display test groups
Patient with esophageal carcinoma (including 20 I phases cancer of the esophagus and 51 II phases patient with esophageal carcinoma) serum MMP13 (5.17vs 0.47, P<
0.001), CHI3L1 (80.48vs 45.64, P<0.001), SPP1 (85.73vs 43.06, P<0.001) concentration is significantly higher than
Normal person, equally can significantly distinguish early stage cancer of the esophagus crowd and normal population.As shown in figure 5, the diagnosis in the early stage cancer of the esophagus
In performance, the early stage esophagus cancer diagnosis efficiency of Mathematical Diagnosis model is sensitivity 90.14%, 76.04%, AUC of specificity
0.933, positive predictive value 73.56%, negative predictive value 91.25% is significantly higher than CHI3L1 (sensitivity：90.14%；Specifically
Property：22.92%；AUC：0.731), MMP13 (sensitivity：90.14%；Specificity 48.96%：AUC：0.837), SPP1 is (sensitive
Degree：90.14%；Specificity：14.58%；AUC：0.7) the single diagnostic of any one index；
6) Mathematical Diagnosis Model Diagnosis cancer of the esophagus performance is verified in validation group：169 patient with esophageal carcinoma and 80 are normal
The validation group serum specimen of people's composition, the efficiency of the diagnosis of esophageal cancer for verifying the Mathematical Diagnosis model.Include validation group
Patient age, sex ratio, by stages ratio it is similar to test group.Result shows, CHI3L1 in esophagus cancer patient blood serum,
MMP13, SPP1 are above normal population (middle position concentrations versus：CHI3L1,78.18vs 34.64ng/ml；MMP13,3.951vs
0.3836ng/ml；SPP1：79.84vs 28.40ng/ml), the statistically significant (P of difference<0.001, Fig. 6).Examined with combining
Disconnected Mathematical Modeling is calculated the prediction probability of each crowd of validation group.With Mathematical Diagnosis model in ROC curve evaluation validation group
In the diagnostic of cancer of the esophagus vs normal person, including TG-AUC (AUC), sensitivity, specificity.Result is displayed in validation group
In, the AUC of the independent diagnosis of esophageal cancer of CHI3L1, MMP13, SPP1 is respectively 0.822,0.835 and 0.750, when sensitivity is scheduled
When 90.53%, its specificity is respectively 48.75%, 53.75% and 15.00%.And Mathematical Diagnosis model prediction cancer of the esophagus AUC
It is 0.930, when sensitivity is set to 90%, specificity is up to 78.75%, positive predictive value 90.0%, negative predictive value
79.75% (Fig. 7)；
7) checking of the Mathematical Diagnosis model in validation group early stage esophagus cancer diagnosis：Fig. 8 is displayed in CHI3L1 in validation group,
MMP13, SPP1 diagnose 84 results of the early stage cancer of the esophagus, and CHI3L1, MMP13, SPP1 index can significantly distinguish early stage oesophagus
Cancer crowd and normal population (P<0.001).ROC curve (Fig. 9) evaluates display, and CHI3L1, MMP13, SPP1 individually diagnose early stage
The AUC of the cancer of the esophagus is respectively 0.828,0.852 and 0.731, and when sensitivity schedules 90.48%, its specificity difference is only
42.50%, 51.25% and 5.00%.And Mathematical Diagnosis model prediction early stage cancer of the esophagus AUC is 0.943, when sensitivity is set to
When 90.53%, specificity is up to 88.75%, positive predictive value 89.41%, negative predictive value 89.87%.Equally demonstrate hair
The cancer of the esophagus Mathematical Modeling that a person of good sense sets up early diagnoses the efficiency of the cancer of the esophagus.
The secretory protein of the normal structure rna transcription group sequencing storehouse differential expression that inventor matches from human esophageal carcinoma with it
In find raising diagnosis of esophageal cancer sensitivity and specific serum standard：MMP13、CHI3L1、SPP1.The mathematics of foundation is examined
Disconnected model 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 reduction is failed to pinpoint a disease in diagnosis, and is early screening and diagnosis
The cancer of the esophagus provides a new way.
Table 1：21 signal path analyses of candidate markers
1Same family's mark is with the maximum mark of rna transcription group sequencing fold differences as representative；
* Genecards is not included, and is looked into from document；The mark to include next step screening of overstriking；
- represent do not find to associated signal paths.
Table 2：18 Go biological process annotations of candidate albumen
1Same family's mark is with the maximum mark of rna transcription group sequencing fold differences as representative；
* Genecards is not included, and is looked into from document；GO BP represent GO biological process.
Table 3：10 candidate albumens express documentary evidence in Serum of Cancer Patients
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Claims (4)
1. one group of mark for being used for esophagus cancer diagnosis, is made up of MMP13, CHI3L1, SPP1.
2. mark according to claim 1, it is characterised 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 quantity is
Ng/ml, P value are defined as excessive risk when being more than 0.43, otherwise are then low-risk.
3. application of the kit in esophagus cancer diagnosis kit is prepared, it is characterised in that：Containing quantitative in the kit
The reagent of MMP13, CHI3L1 and SPP1 expression quantity.
4. application according to claim 3, it is characterised in that：Value-at-risk is according to formula Logit (p=ESCC)=- 5.278+
0.025 × CHI3L1+0.028 × SPP1+0.747 × MMP13 is calculated, in formula, the unit of MMP13, CHI3L1, SPP1 expression quantity
It is ng/ml, P values are defined as excessive risk when being more than 0.43, otherwise is then low-risk.
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