CN115927608A - Biomarkers, methods and diagnostic devices for predicting risk of pancreatic cancer - Google Patents
Biomarkers, methods and diagnostic devices for predicting risk of pancreatic cancer Download PDFInfo
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Abstract
The present invention provides biomarkers, methods and diagnostic devices for predicting the risk of pancreatic cancer. Specifically, the invention provides application of genes, mRNA, cDNA, proteins or detection reagents thereof of markers of pancreatic cancer occurrence risk in preparation/establishment of diagnostic reagents or kits/models for judging the occurrence risk. Research shows that the pancreatic cancer risk marker can be used as a marker for judging pancreatic cancer occurrence, and has high sensitivity and specificity.
Description
Technical Field
The present invention relates to the field of clinical medicine, in particular to biomarkers, methods and diagnostic devices for predicting the risk of pancreatic cancer occurrence.
Background
Pancreatic cancer, known as the king of cancers, is one of the most fatal cancers. Most pancreatic cancer patients do not have any specific clinical symptoms in the early stage, and thus most pancreatic cancer patients miss the optimal treatment period. Over the past few decades, no method has been found to significantly improve patient survival, with pancreatic cancer patients having 5-15% of their 5-year survival, an overall survival of approximately 6%, and only 20% of patients undergoing surgical treatment at the time of discovery. Therefore, timely and effective diagnosis plays an important role in the pancreatic cancer prevention and treatment process.
Currently, the main diagnostic methods for pancreatic cancer mainly include imaging techniques including ultrasound examination, computed Tomography (CT), and nuclear magnetic resonance, but these imaging techniques cannot meet the requirement of early screening for pancreatic cancer. The blood tumor marker detection only needs a small amount of blood samples, has the advantages of minimal invasion and safety, and is an ideal mode for tumor screening and diagnosis. Some tumor antigens are used as relevant indexes for pancreatic cancer diagnosis, and Carbohydrate antigen 199 (Carbohydrate antigen 199, CA199) is the most widely used, but the sensitivity and specificity of the markers are low, so that the application of the markers in pancreatic cancer screening diagnosis is limited. There are currently no effective and accurate biomarkers for pancreatic cancer screening and diagnosis.
In conclusion, it is urgent to find new pancreatic cancer markers with diagnostic or combined diagnostic value and to develop targeted drugs in a targeted manner. Therefore, there is an urgent need in the art to develop pancreatic cancer specific markers with high sensitivity and specificity for early diagnosis or effective treatment of pancreatic cancer, or to evaluate the prognostic effect of the disease.
Disclosure of Invention
The invention aims to provide a pancreatic cancer marker with high sensitivity and high specificity and application thereof in clinical diagnosis and treatment.
In a first aspect of the present invention, there is provided a use of a gene, mRNA, cDNA, protein, or a detection reagent thereof of a pancreatic cancer risk marker for preparing a diagnostic reagent or kit for determining a risk of pancreatic cancer;
wherein the pancreatic cancer risk marker is selected from the group consisting of:
(A) Any one marker selected from A1 to A7, or a combination thereof: (A1) ZHX2; (A2) CYYR1; (A3) GJA4; (A4) GSDME; (A5) LYNX1; (A6) RARP10; (A7) ZNF250.
In another preferred embodiment, the pancreatic cancer risk marker further comprises any one or a combination of markers selected from the group B: (B1) COL10A1; (B2) COL17A1; (B3) CDH3; (B4) CUZD1; (B5) GPT; (B6) SLC45A4; (B7) SQLE.
In another preferred embodiment, the pancreatic cancer risk marker is mRNA or cDNA.
In another preferred example, the pancreatic cancer risk marker further comprises at least 2 selected from A1 to A7.
In another preferred embodiment, the pancreatic cancer risk marker is selected from the group consisting of one or more markers from A1 to A7 in combination with one or more markers from B1 to B7.
In another preferred embodiment, the markers A1-A7 are selected from table a:
TABLE A
In another preferred embodiment, the markers B1-B7 are selected from table B:
TABLE B
In another preferred embodiment, the pancreatic cancer risk marker combination is: (A1) ZHX2; (A2) CYYR1; (B1) COL10A1; (B2) COL17A1.
In another preferred embodiment, the pancreatic cancer risk marker combination is: (A2) CYYR1; (B1) COL10A1; (B2) COL17A1.
In another preferred embodiment, the pancreatic cancer risk marker combination is: (A1) ZHX2; (B1) COL10A1.
In a second aspect of the present invention, there is provided a kit comprising a detection reagent for detecting a gene, mRNA, cDNA, protein, or a combination thereof, of a pancreatic cancer risk marker,
wherein the pancreatic cancer risk markers are selected from the group consisting of:
(A) A combination of two or more markers selected from A1 to A7;
(B) Selected from the group consisting of one or more markers from A1 to A7 and one or more markers from B1 to B7.
In another preferred example, the detection reagent comprises:
(a) A specific antibody, a specific binding molecule directed against said pancreatic cancer risk marker; and/or
(b) A primer or primer pair, a probe or a chip (such as a nucleic acid chip or a protein chip) for specifically amplifying mRNA or cDNA of the pancreatic cancer risk marker.
In another preferred example, the pancreatic cancer risk marker is any one of the markers set forth in table a and/or table B, wherein the gene, mRNA, cDNA, or protein is derived from human.
In another preferred example, the subject is a human.
In another preferred embodiment, the subject is a non-tumor patient or a tumor patient.
In another preferred embodiment, the tumor patient comprises pancreatic cancer.
In another preferred example, the gene, mRNA, cDNA, or protein of the pancreatic cancer risk marker is derived from human.
In another preferred example, the test is a test for an ex vivo sample.
In another preferred embodiment, the ex vivo sample comprises: tissue samples, cell samples, blood samples, serum samples.
In another preferred embodiment, the detection reagent is coupled to or carries a detectable label.
In another preferred embodiment, the detectable label is selected from the group consisting of: chromophores, chemiluminescent groups, fluorophores, isotopes or enzymes.
In another preferred embodiment, the antibody is a monoclonal antibody or a polyclonal antibody.
In another preferred embodiment, the diagnostic reagent comprises an antibody, a primer, a probe, a sequencing library, a nucleic acid chip (e.g., a DNA chip), or a protein chip.
In another preferred embodiment, the nucleic acid chip comprises a substrate and specific oligonucleotide probes spotted on the substrate, wherein the specific oligonucleotide probes comprise probes specifically binding to the polynucleotide (mRNA or cDNA) of any one of the pancreatic cancer risk markers.
In another preferred embodiment, the protein chip comprises a substrate and specific antibodies spotted on the substrate, wherein the specific antibodies comprise specific antibodies against the pancreatic cancer risk marker.
In another preferred embodiment, the antibody is a monoclonal antibody or a polyclonal antibody.
In another preferred embodiment, the kit contains genes, mRNA, cDNA and/or proteins of pancreatic cancer risk markers as control substances or quality control substances.
In another preferred embodiment, the kit further comprises a label or instructions for use in (a) assessing the risk of developing pancreatic cancer, and/or (b) assessing the efficacy of a pancreatic cancer treatment.
In another preferred embodiment, the reagents comprise primers, probes, grnas or combinations thereof, more preferably primer pairs or probes for PCR, qPCR, RT-PCR.
In another preferred example, the detection of the pancreatic cancer risk marker can be performed by the following method: sequencing, PCR, or a combination thereof.
In another preferred embodiment, the detection of the pancreatic cancer risk marker is a quantitative detection.
In a third aspect of the present invention, there is provided a detection method comprising the steps of:
(a) Providing a test sample selected from a blood sample;
(b) Detecting the expression quantity of the pancreatic cancer risk marker gene in the detection sample, and recording as C1; and
(c) Comparing the pancreatic cancer risk marker concentration C1 to a control reference value C0;
wherein the pancreatic cancer risk markers are selected from the group consisting of:
(A) Any one marker selected from A1 to A7, or a combination thereof: (A1) ZHX2; (A2) CYYR1; (A3) GJA4; (A4) GSDME; (A5) LYNX1; (A6) RARP10; (A7) ZNF250;
indicating that the subject is at high risk of pancreatic cancer if the detection result of the risk of pancreatic cancer in the subject satisfies the following conditions:
(1) When a marker is an up-regulated marker in table a in a subject and the expression level of the marker is higher than a reference value or standard value C0, the subject is at high risk of developing pancreatic cancer;
(2) When a marker is a marker down-regulated in table a in a subject and the expression level of the marker is lower than the reference or standard value C0, the subject is at high risk of developing pancreatic cancer.
In a fourth aspect of the present invention, there is provided a pancreatic cancer diagnosis apparatus including:
(a) An input module for inputting pancreatic cancer risk marker data for a blood sample of a subject;
wherein said risk marker gene comprises a gene selected from the group consisting of:
(A) Any one marker selected from A1 to A7, or a combination thereof: (A1) ZHX2; (A2) CYYR1; (A3) GJA4; (A4) GSDME; (A5) LYNX1; (A6) RARP10; (A7) ZNF250;
(b) The processing module is used for calculating the input marker genes according to a preset scoring formula to obtain risk degree scores; and comparing the score to a Cut-off value (Cut-off) to obtain a discrimination result, wherein when the risk score is higher than the Cut-off value (Cut-off), the subject is suggested as a pancreatic cancer patient; when the risk score is below the Cut-off value (Cut-off), then the subject is suggested as a non-pancreatic cancer patient; and
(c) And the output module is used for outputting the diagnosis result.
In another preferred example, the scoring formula is as follows:
wherein, the Wi is the weight value of each gene; pi is the expression level of each gene.
In another preferred example, the scoring formula may be calculated manually.
In another preferred embodiment, the scoring formula can be automatically calculated by designing a computer-aided program.
In a fifth aspect of the present invention, there is provided a method for detecting the expression level of a combination of pancreatic cancer risk markers, comprising the steps of:
(a) Providing a serum sample;
(b) Extracting total RNA of the serum sample;
(c) Reverse transcription of the product RNA obtained in step (b);
(d) Performing fluorescent quantitative PCR on the reverse transcription product obtained in the step (c) so as to obtain the gene expression level of the risk marker;
wherein the risk marker is selected from the group consisting of:
(A) Any one marker selected from A1 to A7, or a combination thereof: (A1) ZHX2; (A2) CYYR1; (A3) GJA4; (A4) GSDME; (A5) LYNX1; (A6) RARP10; (A7) ZNF250.
In another preferred embodiment, the method is a non-diagnostic, non-therapeutic method;
in another preferred embodiment, the method is an in vitro method. In another preferred embodiment, in the quantitative PCR in step (d), the upstream and downstream specific primer sequences corresponding to each gene are: 1-28 of SEQ ID NO.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Drawings
FIG. 1 shows ROC plots for the diagnostic effect of regimen 1 (COL 10A1, COL17A1, CYYR1, ZHX2 as combination markers)
FIG. 2 shows the ROC plot of the diagnostic effect of protocol 2 (COL 10A1, COL17A1, CYYR1 as combined markers)
FIG. 3 shows ROC plots for the diagnostic effect of protocol 3 (COL 10A1, ZHX2 as a combination marker)
Detailed Description
The present inventors have conducted extensive and intensive studies and have developed for the first time a marker combination for pancreatic cancer diagnosis with high sensitivity and high specificity. Specifically, through database studies, the mRNA expression profile levels of pancreatic cancer and normal pancreatic tissue samples were analyzed, and 37 specific mRNA markers were first screened out by statistical methods. Serum level tests prove that 14 specific mRNA markers selected from the mRNA markers can effectively distinguish pancreatic cancer patients from healthy people so as to carry out corresponding auxiliary treatment or intervention treatment on the pancreatic cancer patients with high risk as early as possible. The present invention has been completed based on this finding.
Term(s) for
The term "sample" or "specimen" as used herein refers to a material that is specifically associated with a subject from which specific information about the subject can be determined, calculated, or inferred. The sample may be composed in whole or in part of biological material from the subject.
As used herein, the term "expression" includes the production of mRNA from a gene or portion of a gene, and includes the production of protein encoded by an RNA or gene or portion of a gene, as well as the presence of a test substance associated with expression. For example, cDNA, binding of a binding partner (e.g., an antibody) to a gene or other oligonucleotide, protein or protein fragment, and chromogenic moieties of the binding partner are included within the scope of the term "expression". Thus, an increase in the density of half-dots on immunoblots such as Western blots is also within the scope of the term "expression" based on biological molecules.
As used herein, the term "reference value" or "control reference value" refers to a value that is statistically correlated with a particular result when compared to the results of an analysis. In a preferred embodiment, the reference value is determined from comparing the mRNA expression and/or protein expression of markers at risk of pancreatic cancer and performing a statistical analysis. Some of these studies are shown in the examples section herein. However, studies from the literature and user experience with the methods disclosed herein can also be used to produce or adjust the reference values. Reference values can also be determined by considering conditions and outcomes particularly relevant to the patient's ethnic group, medical history, genetics, age, and other factors.
Pancreatic cancer risk markers
As used herein, the term "pancreatic cancer risk marker of the invention" refers to one or more markers shown in table a and/or table B.
In the present invention, the terms "pancreatic cancer risk marker protein of the present invention", "polypeptide of the present invention", or "marker shown in table a and/or table B" are used interchangeably and all refer to a marker having any one or more of the pancreatic cancer risk markers of the present invention.
In the present invention, the terms "pancreatic cancer risk marker gene", "polynucleotide of a pancreatic cancer risk marker" are used interchangeably and all refer to the nucleotide sequence of any one of the pancreatic cancer risk markers shown in table a and/or table B.
It is understood that nucleotide substitutions in codons are acceptable when encoding the same amino acid. It is also understood that nucleotide changes may be acceptable when conservative amino acid substitutions are made by nucleotide substitutions.
When information on a marker of pancreatic cancer risk is obtained, a nucleic acid sequence encoding it can be constructed therefrom, and a specific probe can be designed based on the nucleotide sequence. The full-length nucleotide sequence or a fragment thereof can be obtained by PCR amplification, recombination, or artificial synthesis. For the PCR amplification method, primers can be designed based on the nucleotide sequences, particularly the open reading frame sequences, of the pancreatic cancer risk markers disclosed in the present invention, and the relevant sequences can be amplified using a commercially available cDNA library or a cDNA library prepared by a conventional method known to those skilled in the art as a template. When the sequence is long, two or more PCR amplifications are often required, and then the amplified fragments are spliced together in the correct order.
Once the sequence of interest has been obtained, it can be obtained in large quantities by recombinant methods. This is usually done by cloning it into a vector, transferring it into a cell, and isolating the relevant sequence from the propagated host cell by conventional methods.
In addition, the sequence of interest can be synthesized by artificial synthesis, especially when the fragment length is short. Generally, fragments with long sequences are obtained by first synthesizing a plurality of small fragments and then ligating them.
At present, the DNA sequence encoding the protein of the present invention (or its fragments, derivatives) can be obtained completely by chemical synthesis. The DNA sequence may then be introduced into various existing DNA molecules (e.g., vectors) and cells known in the art.
The polynucleotide sequences of the present invention may be used to express or produce recombinant markers of pancreatic cancer risk by conventional recombinant DNA techniques.
Specific antibodies
In the present invention, the terms "antibody of the present invention" and "antibody specific to a pancreatic cancer risk marker" are used interchangeably to refer to an antibody that can be used to specifically bind to and detect a pancreatic cancer risk marker of the present invention.
The antibodies of the present invention directed to markers of pancreatic cancer risk (table a and/or table B) include specific polyclonal and monoclonal antibodies, particularly monoclonal antibodies.
The invention encompasses not only intact monoclonal or polyclonal antibodies, but also immunologically active antibody fragments, such as Fab' or (Fab) 2 A fragment; an antibody heavy chain; an antibody light chain; genetically engineered single chain Fv molecules (Ladner et al, U.S. Pat. No.4,946,778); or chimeric antibodies, such as antibodies that have murine antibody binding specificity but retain portions of the antibody from a human.
The antibodies of the invention can be prepared by a variety of techniques known to those skilled in the art. For example, a purified gene product of a human pancreatic cancer risk marker, or an antigenic fragment thereof, can be administered to an animal to induce the production of polyclonal antibodies. Similarly, cells expressing human pancreatic cancer risk marker proteins or antigenic fragments thereof can be used to immunize animals to produce antibodies. The antibody of the present invention may also be a monoclonal antibody. Such monoclonal antibodies can be prepared using hybridoma technology.
Antibodies against human pancreatic cancer risk marker proteins can be used in immunohistochemical techniques to detect human pancreatic cancer risk marker proteins in a sample, particularly a tissue sample or a blood sample. Since the pancreatic cancer risk marker protein is present in a blood sample or a tissue sample, the expression level thereof can be a subject to be detected.
Detection method
Based on the differential expression of the pancreatic cancer risk markers in the tissue sample or the blood sample, the invention also provides a corresponding method for judging the pancreatic cancer risk.
The present invention relates to diagnostic assays for the quantitative and localized detection of protein or mRNA levels of markers of pancreatic cancer risk. These assays are well known in the art. The levels of human pancreatic cancer risk marker proteins or mRNA levels detected in the assay can be used to determine (including aiding in the determination) whether there is a risk of pancreatic cancer.
A preferred method is to perform PCR/qPCR/RT-PCR on mRNA or cDNA for quantitative detection.
A preferred method is to sequence mRNA or cDNA for quantitative detection.
Polynucleotides of markers of pancreatic cancer risk are useful in the diagnosis of pancreatic cancer risk. A part or all of the polynucleotides of the present invention can be immobilized as a probe on a microarray or a DNA chip for differential expression analysis of genes in analysis and gene diagnosis.
In addition, the present invention can also be tested at the protein level. For example, antibodies against pancreatic cancer risk markers can be immobilized on a protein chip for detecting pancreatic cancer risk proteins in a sample.
Detection kit
Based on the correlation between the pancreatic cancer risk marker and the pancreatic cancer risk, the pancreatic cancer risk marker can be used as a judgment marker of pancreatic cancer risk.
The invention also provides a kit for judging pancreatic cancer risk, which contains a detection reagent used for detecting the gene, mRNA, cDNA, protein or the combination thereof of the pancreatic cancer risk marker. Preferably, the kit contains an antibody or immunoconjugate of the anti-pancreatic cancer risk marker of the invention, or an active fragment thereof; or a primer or primer pair, probe or chip containing mRNA or cDNA specifically amplifying a pancreatic cancer risk marker.
In another preferred embodiment, the kit further comprises a label or instructions.
The main advantages of the invention include:
(1) Compared with the prior imaging technology, the method adopts the blood sample, is more suitable for early screening diagnosis, and has the characteristics of rapidness, convenience and low cost.
(2) Compared with the existing tumor antigen detection method, the marker combination established by the invention has higher specificity and more accurate detection result.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Experimental procedures without specific conditions noted in the following examples, generally followed by conventional conditions, such as Sambrook et al, molecular cloning: the conditions described in the Laboratory Manual (New York: cold Spring Harbor Laboratory Press, 1989), or according to the manufacturer's recommendations. Unless otherwise indicated, percentages and parts are percentages and parts by weight.
Example 1 screening and determination of diagnostic markers for pancreatic cancer
Specifically, the inventors used mRNA expression profiles of pancreatic cancers (cancer tissues and paracancerous tissues) in the TCGA database and the GEO database, grouped the samples according to the pathological stage of pancreatic cancer, and compared the expression profiles of different sample groups to obtain a group of mrnas differentially expressed between pancreatic cancer and normal pancreatic tissue samples. And taking the differential mRNAs as candidates, calculating by using a Support Vector Machine (SVM) model, and on the basis, adopting different algorithms to calculate and screen the molecular markers to obtain a multi-marker combined classifier (containing 2 or more than 2 mRNA markers) with higher classification accuracy. The classifier composed of the mRNA markers can predict whether a sample has pancreatic cancer, and the prediction accuracy of the classifier can reach 93.90 percent at most. Based on the group of mRNA markers, RT-PCR kits can be developed for early screening of pancreatic cancer.
Example 2 verification of marker for pancreatic cancer diagnosis (blood sample)
We collected 229 serum samples that were used to verify the accuracy of the classifier, 131 pancreatic cancers and 98 healthy volunteers.
Example 3 pancreatic cancer diagnostic marker alone
4 genes with obviously high pancreatic cancer positive rate occurrence frequency when used alone in pancreatic cancer samples are selected, and the single use effect in serum is further evaluated.
The results are shown in table 1:
TABLE 1 Effect of markers alone in serum
| Gene | Cut-off value | AUC | Sensitivity (%) | Degree of specificity (%) | Accuracy (%) |
| ZHX2 | ≥1.9 | 0.841 | 97.70％ | 79.90％ | 88.80％ |
| CYYR1 | ≥2.0 | 0.637 | 62.00％ | 64.00％ | 63.00％ |
| COL10A1 | ≥1.9 | 0.801 | 84.50％ | 77.00％ | 80.75％ |
| COL17A1 | ≤1.5 | 0.551 | 40.30％ | 98.00％ | 69.15％ |
ZHX2, CYYR1, COL10A1, and COL17A1 all had good sensitivity, specificity, and accuracy when used alone. Among them, the ZHX2 gene is particularly excellent in the performances such as sensitivity (%), specificity (%), accuracy (%), etc. when used alone.
Example 4 Combined use of pancreatic cancer diagnostic markers
In this example, it was further verified that a combination of multiple pancreatic cancer diagnostic markers detects the effect in a serum sample.
The results are shown in FIGS. 1 to 3, respectively.
FIG. 1 shows the ROC effect of the combination of 4 markers, COL10A1, COL17A1, CYYR1 and ZHX2, in protocol 1.
Wherein, the scoring calculation formula is:
score =3.2 + COL10A1+0.1 + ZHX2-2 + CYYR1-2.5 + COL17A1,
the cut-off values were given as: -1.22
The validation results for 229 samples are:
| rate of accuracy | 93.87％ |
| AUC | 0.975 |
| Sensitivity of the probe | 93.10％ |
| Specificity of | 94.90％ |
FIG. 2 shows the ROC effect of scheme 2 when 3 markers, COL10A1, COL17A1 and CYYR1, were combined.
Wherein, the scoring calculation formula is:
score =3.6 × col10a1-2 × cyyr1-2.8 × col17a1
The cut-off values are given as: -1.58
The validation results for 229 samples are:
| rate of accuracy | 93.90％ |
| AUC | 0.975 |
| Sensitivity of the probe | 93.90％ |
| Specificity of | 93.90％ |
FIG. 3 shows the ROC effect of 2 marker combinations, COL10A1 and ZHX2, in protocol 3.
Wherein, the scoring calculation formula is adopted as follows:
score =4.1 × col10a1-0.2 × zhhx 2-5.8 × col17a1
The cut-off values were given as: -3.75
The validation results for 229 samples are:
| rate of accuracy | 93.01％ |
| AUC | 0.970 |
| Sensitivity of the probe | 93.10％ |
| Specificity of | 92.90％ |
Example 5 detection reagents and applications
In this example, the following detection method and detection reagent were used for detection.
The detection method comprises the following steps:
(1) The collected serum samples were used for total RNA extraction.
(2) Removing genome DNA from the extracted RNA, specifically: the reaction mixture is prepared on ice according to the following components, in order to ensure the accuracy of the preparation of the reaction solution, master Mix is prepared according to the reaction number +2, then the Master Mix is subpackaged into each reaction tube, and finally the RNA sample is added. The reaction steps are as follows: 2min at 42 ℃ and 5min at 4 ℃.
| Reagent | Amount of the composition used |
| 5x gDNA Eraser Buffer | 2.0ul |
| gDNA Eraser | 1.0ul |
| Total RNA | 7.0ul |
| Total | 10.0ul |
(3) And (3) carrying out reverse transcription on the product RNA, specifically: the reaction was prepared on ice. In order to ensure the accuracy of the preparation of the reaction solution, the Master Mix should be prepared in an amount of +2 reaction times and then divided into 10ul portions for each reaction tube. After instantaneous centrifugation and mixing, reverse transcription reaction is carried out immediately. (TB green qPCR method). The reaction steps are as follows: 15min at 37 ℃, 5sec at 85 ℃ and 5min at 4 ℃.
| Reagent | Amount of the composition used |
| Reaction solution of step 1 | 10.0ul |
| PrimeScript RT Enzyme Mix I | 1.0ul |
| RT Prime Mix | 1.0ul |
| 5x PrimeScript Buffer 2(for Real time) | 4.0ul |
| RNase Free dH 2 O | 4.0ul |
| Total | 20.0ul |
(4) And (3) carrying out fluorescence quantitative PCR on the reverse transcription product, which specifically comprises the following steps:
plate dilution, 20ul reverse transcription cDNA template to add 180ul RNase Free dH2O, template dilution 10 times.
| Reagent | Amount of the composition used |
| 10-fold diluted cDNA template | 8.0ul |
| Primer F (10 uM) | 1.0ul |
| Primer R (10 uM) | 1.0ul |
| 2xTB Green Master Mix | 5.0ul |
| Total | 20.0ul |
Fluorescent quantitative PCR instrument, LC480II, reaction step: pre-denaturation: 95 ℃ 30sec, PCR: (95 ℃ C. 5sec,60 ℃ C. 1min,95 ℃ C. Continuos)
The sequences of primers F and R for each marker were as follows:
(5) And substituting the marker gene expression level obtained by the detection into a calculation formula to obtain a detection result.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
SEQUENCE LISTING
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Claims (10)
1. The use of a gene, mRNA, cDNA, protein, or a detection reagent thereof of a pancreatic cancer risk marker for preparing a diagnostic reagent or kit for determining the risk of pancreatic cancer;
wherein the pancreatic cancer risk markers are selected from the group consisting of:
(A) Any one marker selected from A1 to A7, or a combination thereof: (A1) ZHX2; (A2) CYYR1; (A3) GJA4; (A4) GSDME; (A5) LYNX1; (A6) RARP10; (A7) ZNF250.
2. The use of claim 1, wherein the markers of pancreatic cancer risk further comprise any one or a combination of markers selected from group B: (B1) COL10A1; (B2) COL17A1; (B3) CDH3; (B4) CUZD1; (B5) GPT; (B6) SLC45A4; (B7) SQLE.
3. The use of claim 1, wherein the pancreatic cancer risk marker further comprises at least 2 selected from A1 to A7.
4. The use of claim 1, wherein the marker of pancreatic cancer risk is selected from the group consisting of one or more markers from A1 to A7 in combination with one or more markers from B1 to B7.
5. A kit comprising a detection reagent for detecting a gene, mRNA, cDNA, protein, or a combination thereof, of a marker of pancreatic cancer risk,
wherein the pancreatic cancer risk markers are selected from the group consisting of:
(A) A combination of two or more markers selected from A1 to A7;
(B) Selected from the group consisting of one or more markers from A1 to A7 and one or more markers from B1 to B7.
6. A method of detection, comprising the steps of:
(a) Providing a test sample selected from a blood sample;
(b) Detecting the expression quantity of the pancreatic cancer risk marker gene in the detection sample, and marking as C1; and
(c) Comparing the pancreatic cancer risk marker concentration C1 to a control reference value C0;
wherein the pancreatic cancer risk marker is selected from the group consisting of:
(A) Any one marker selected from A1 to A7, or a combination thereof: (A1) ZHX2; (A2) CYYR1; (A3) GJA4; (A4) GSDME; (A5) LYNX1; (A6) RARP10; (A7) ZNF250;
indicating that the risk of pancreatic cancer in the subject is high if the result of detecting the risk of pancreatic cancer in the subject satisfies the following condition:
(1) When a marker is an up-regulated marker in table a in a subject and the expression level of the marker is higher than a reference value or standard value C0, the subject is at high risk of developing pancreatic cancer;
(2) When a marker is a marker down-regulated in table a in a subject and the expression level of the marker is lower than the reference or standard value C0, the subject is at high risk of developing pancreatic cancer.
7. A pancreatic cancer diagnosis apparatus, characterized in that the apparatus comprises:
(a) An input module for inputting pancreatic cancer risk marker data for a blood sample of a subject;
wherein said risk marker gene comprises a gene selected from the group consisting of:
(A) Any one marker selected from A1 to A7, or a combination thereof: (A1) ZHX2; (A2) CYYR1; (A3) GJA4; (A4) GSDME; (A5) LYNX1; (A6) RARP10; (A7) ZNF250;
(b) The processing module is used for calculating the input marker genes according to a preset scoring formula to obtain risk degree scores; and comparing the score to a Cut-off value (Cut-off) to obtain a discrimination result, wherein when the risk score is higher than the Cut-off value (Cut-off), the subject is suggested as a pancreatic cancer patient; when the risk score is below the Cut-off value (Cut-off), suggesting that the subject is a non-pancreatic cancer patient; and
(c) And the output module is used for outputting the diagnosis result.
8. The pancreatic cancer diagnosis apparatus of claim 7, wherein said scoring formula is:
wherein, the Wi is the weighted value of each gene; pi is the expression level of each gene.
9. A method for detecting the expression level of a combination of pancreatic cancer risk markers, comprising the steps of:
(a) Providing a serum sample;
(b) Extracting total RNA of the serum sample;
(c) Reverse transcription of the product RNA obtained in step (b);
(d) Performing fluorescent quantitative PCR on the reverse transcription product obtained in the step (c) so as to obtain the gene expression level of the risk marker;
wherein the risk marker is selected from the group consisting of:
(A) Any one marker selected from A1 to A7, or a combination thereof: (A1) ZHX2; (A2) CYYR1; (A3) GJA4; (A4) GSDME; (A5) LYNX1; (A6) RARP10; (A7) ZNF250.
10. The method of claim 9, wherein in the quantitative PCR in step (d), the upstream and downstream specific primer sequences corresponding to each gene are: 1-28 of SEQ ID NO.
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