CN114990220B - Molecular marker group for early diagnosis of renal clear cell carcinoma - Google Patents
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Abstract
The invention discloses a molecular marker group for early diagnosis of renal clear cell carcinoma, which comprises the following components: mRNA of exosome-derived CUL9 gene, mRNA of exosome-derived KMT2D gene, mRNA of exosome-derived PBRM1 gene, mRNA of exosome-derived PREX2 gene and mRNA of exosome-derived SETD2 gene. The beneficial effects of the invention are as follows: by finding out the mRNA expression profile of the serum exosome related to the kidney cancer and the differential gene related to the kidney cancer, the mRNA in the exosome carries rich genetic information, so that the mRNA can represent tumor characteristics, and then by establishing a kidney cancer diagnosis model, the clinical early diagnosis of the kidney cancer can be guided more accurately, and related theoretical basis is provided for the research and development of a kidney cancer diagnosis kit.
Description
Technical Field
The invention relates to the technical field of marker sets, in particular to a molecular marker set for early diagnosis of renal clear cell carcinoma.
Background
Renal clear cell carcinoma (ccRCC) is one of the most common types of renal cell carcinoma, and its morbidity and mortality tend to increase year by year. The early ccRCC has no obvious manifestation, and after symptoms appear, the tumor enters into the late stage, and the operation and chemoradiotherapy effects are poor, so the early diagnosis is significant to the ccRCC. At present, the diagnosis of ccRCC mainly depends on imaging, and has higher specificity, but it is difficult to screen out tumors with smaller volumes or identify renal sites with undefined properties, so that the missed diagnosis or misdiagnosis of the tumors is caused. While final diagnosis relies on pathological biopsies, tissue biopsies have certain limitations, such as tumor heterogeneity and inability to re-sample during treatment, risk of disseminated metastasis after biopsy stimulation or manipulation is not accelerated, which limit their clinical application. Therefore, there is an urgent clinical need for new and reliable early diagnosis of ccRCC in the precise medical era.
With the continuous penetration of liquid biopsy technology in tumor research, more and more blood molecular markers are applied to clinical diagnosis and even whole-course monitoring. In recent years, research on diagnosis and treatment of diseases by exosomes has become a hot spot in the academic world, and rapid development of exosomes has greatly promoted the progress of biomarkers. Exosomes are small extracellular vesicles with diameters of about 40-160 nm, contain various genetic materials such as proteins, nucleic acids, lipids and the like, and have lipid bilayer which can protect the contents from degradation in circulation and play an important role in maintaining intercellular substances and cell communication. The exosomes derived from the tumor are involved in regulating the occurrence and development of the tumor, and play an important role in the processes of participating in tumor metastasis, immune escape and the like. Recent reports have found that peripheral blood exosome RNA can be used as a valuable molecular marker for cancer screening, but there is currently no study on the early diagnosis of exosome mRNA in ccRCC.
Disclosure of Invention
The invention aims to provide a molecular marker group for early diagnosis of renal clear cell carcinoma, so as to solve the problem that research on early diagnosis of exosome mRNA in ccRCC is lacking in the background art.
To achieve the above object, a first aspect of the present invention provides a molecular marker set for early diagnosis of renal clear cell carcinoma, the marker set comprising:
mRNA of exosome-derived CUL9 gene, mRNA of exosome-derived KMT2D gene, mRNA of exosome-derived PBRM1 gene, mRNA of exosome-derived PREX2 gene and mRNA of exosome-derived SETD2 gene.
Preferably, the mRNA of the CUL9 gene is selected from exons 2 to 4;
Preferably, the mRNA of the KMT2D gene is selected from exon 31 and exon 51;
Preferably, the mRNA of the PBRM1 gene is selected from the group consisting of exons 2, exons 29-30;
Preferably, the mRNA of the PREX gene is selected from exons 36-38;
Preferably, the mRNA of the SETD2 gene is selected from exons 7-8 or 14-15.
Preferably, the exosomes are blood, plasma or serum exosomes.
In a second aspect, the invention provides the use of a marker panel as described above for the preparation of a product for the diagnosis of renal clear cell carcinoma.
Preferably, the diagnosis of renal clear cell carcinoma includes early screening and differential diagnosis of renal clear cell carcinoma.
In a third aspect, the invention provides a product for diagnosing or prognosticating renal clear cell carcinoma, the product comprising a detection reagent for detecting a biomarker as described above;
Preferably, the detection reagent comprises an exosome extraction reagent, a ribonucleic acid extraction reagent, a reverse transcription reagent and a fluorescent PCR reaction solution.
Preferably, the exosome extraction reagent comprises an upstream and a downstream primer for PCR and a detection probe.
In a fourth aspect, the present invention provides a renal clear cell carcinoma early diagnosis system comprising:
An information acquisition module for performing an operation of acquiring subject detection information, including information of the above-described marker group;
And the information analysis module is used for executing a diagnosis model for constructing the subject marker group information, thereby carrying out analysis of early diagnosis of the renal clear cell carcinoma.
A fifth aspect of the present invention provides a computer-readable storage medium having stored thereon a computer program which, when executed by a processor, implements a renal clear cell carcinoma early diagnosis system as described above.
Compared with the prior art, the invention has the beneficial effects that: the peripheral blood is taken as an incision point, so that the clinical transformation is easy; the exosome is used as a 'break-through opening' of the kidney cancer liquid biopsy, and has the characteristics of stability, no wound, real time and repeatability; by finding out the mRNA expression profile of the serum exosome related to the kidney cancer and the differential gene related to the kidney cancer, the mRNA in the exosome carries rich genetic information, so that the mRNA can represent tumor characteristics, and then by establishing a kidney cancer diagnosis model, the clinical early diagnosis of the kidney cancer can be guided more accurately, and related theoretical basis is provided for the research and development of a kidney cancer diagnosis kit.
Drawings
FIG. 1 is a graph showing Ct values read after the reaction of the reaction solution in the fluorescent PCR apparatus is completed in the embodiment of the present invention;
FIG. 2 is a standard graph of copy number of a target gene in an embodiment of the present invention;
FIG. 3 is a graph of ROC of one of the test queues of the present invention;
FIG. 4 is a graph of ROC of one of the test queues of the present invention;
FIG. 5 is a graph of ROC of one of the test queues of the present invention;
FIG. 6 is a graph of ROC of one of the test queues of the present invention;
fig. 7 is a graph of ROC for one of the test queues of the present invention.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and completely with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
For a better understanding of the invention, some terms will now be defined:
the Ct value refers to the number of cycles undergone by the fluorescent signal in each reaction tube when the fluorescent signal reaches a set threshold in the PCR reaction process, wherein C represents Cycle and t represents threshold.
The CUL9 gene is the CULLin 9 gene, and 41 exons are added.
The KMT2D gene is LYSINE METHYLTRANSFERASE D genes, and total 55 exons are contained.
The PBRM1 gene is polybromo genes, and total 33 exons are included.
The PREX gene is phosphatidylinositol-3,4,5-trisphosphate DEPENDENT RAC exchange factor 2 gene, and total 40 exons.
The SETD2 gene is SET domain containing 2,histone lysine methyltransferase genes, and total 21 exons are included.
The invention designs primers aiming at CUL9, KMT2D, PBRM1, PREX2 and SETD2 genes: wherein CUL9 covers exons 2-4; KMT2D covers exons 31, 51; PBRM1 covers exons 2, 29-30; PREX2 covers 36-38 exons; SETD2 covers exons 7-8, 14-15.
Among these, preferred results for exons are: exon 2 of the CUL9 gene sequence; exon 51 of KMT2D gene sequence; exon 2 of the PBRM1 gene sequence; 38 exon of PREX gene sequence; exon 7 of the SETD2 gene sequence.
Example 1
The present embodiment provides a molecular marker set for early diagnosis of renal clear cell carcinoma, the marker set comprising:
mRNA of exosome-derived CUL9 gene, mRNA of exosome-derived KMT2D gene, mRNA of exosome-derived PBRM1 gene, mRNA of exosome-derived PREX2 gene and mRNA of exosome-derived SETD2 gene.
Preferably, the mRNA of the CUL9 gene is selected from exons 2-4.
Preferably, the mRNA of the KMT2D gene is selected from exon 31 and exon 51.
Preferably, the mRNA of the PBRM1 gene is selected from the group consisting of exons 2, 29-30. Preferably, the mRNA of the PREX gene is selected from exons 36-38.
Preferably, the mRNA of the SETD2 gene is selected from exons 7-8 or 14-15.
Preferably, the exosomes are blood, plasma or serum exosomes.
The embodiment also provides application of the marker group in preparation of products for diagnosing renal clear cell carcinoma.
Preferably, the diagnosis of renal clear cell carcinoma includes early screening and differential diagnosis of renal clear cell carcinoma.
The embodiment also provides a product for diagnosing or predicting renal clear cell carcinoma, which comprises a detection reagent for detecting the biomarker;
Preferably, the detection reagent comprises an exosome extraction reagent, a ribonucleic acid extraction reagent, a reverse transcription reagent and a fluorescent PCR reaction solution.
Preferably, the exosome extraction reagent comprises an upstream and a downstream primer for PCR and a detection probe. The present embodiment also provides a renal clear cell carcinoma early diagnosis system, comprising:
An information acquisition module for performing an operation of acquiring subject detection information, including information of the above-described marker group;
And the model establishment information analysis module is used for executing a diagnosis model for constructing the subject marker group information, thereby carrying out analysis of early diagnosis of the renal clear cell carcinoma.
The present embodiment also provides a computer-readable storage medium having stored thereon a computer program which, when executed by a processor, implements a renal clear cell carcinoma early diagnosis system as described above.
Example 2
The main purpose of this embodiment is to establish a method for constructing a ccRCC diagnostic model, where the method at least includes:
1. The fasting peripheral blood of the patient or healthy person was collected in the morning and all samples were centrifuged at 1600 Xg
Serum was isolated for 15 minutes and collected (supernatant) in a 1.5 ml centrifuge tube.
2. Extracting total exosomes in serum with an exosome extraction kit (exoEasy Maxi Kit; QIAGEN company);
3. Then extracting the extracted exosome ribonucleic acid by using a ribonucleic acid extraction Kit (exoRNeasy Serum/Plasma Maxi Kit; QIAGEN company);
4. converting the extracted ribonucleic acid into cDNA by using a reverse transcription kit (PRIMESCRIPTTM RT REAGENT KIT; takara Co.);
5. Sequentially adding cDNA into fluorescent quantitative PCR reaction liquid, adding 2 microliters of cDNA into each tube of reaction liquid, respectively adding primer pairs and detection probes for amplifying CUL9, KMT2D, PBRM1, PREX and SETD2 genes, as shown in the following table 1, then placing the mixed reaction liquid on a fluorescent PCR instrument (ABI 7500 fluorescent PCR instrument; applied Biosystems company), as shown in figure 1, and reading the Ct value of each reaction hole after the reaction is completed;
TABLE 1 Gene-corresponding primers and probes
6. Diluting the standard substance into different concentrations (103, 104, 105, 106, 107), drawing a standard curve by taking the detected CT value as an abscissa and taking the logarithmic value of the copy number of the standard substance as an ordinate, and calculating the copy number of the target gene as shown in figure 2;
7. Before the model is built, the data are subjected to standardized pretreatment by a Z-Score method, and the calculation method is as follows:
①z＝(x-μ)/σ;②μ＝average();③σ＝stdevp()。
Example 3
The main object of the present embodiment is to provide a ccRCC diagnostic model, which includes:
logit (p=ccrcc) = 1.21943 ×kmt2d+1.97072 × PREX2+1.30485, the model incorporates 142 samples (92 ccRCC, 50 healthy persons), as shown in fig. 3, the ROC curve area under AUC:0.836, p < 0.001, sensitivity 78.3%, specificity 90%, indicating that exosome mRNAs have higher discrimination efficacy for ccRCC patients from healthy people.
The model was validated in another cohort (203 samples, 106 ccrccs, 97 healthy people) as shown in fig. 4, area under ROC curve AUC:0.830, p < 0.001, sensitivity 67.0%, specificity 93.8%, indicating that the model can be used for ccRCC screening.
Example 4
The main object of the present embodiment is to provide another ccRCC diagnostic model, which model comprises:
logit (p=ccrcc) = 1.68689 ×cul9-1.16173 ×kmt2d+1.17881 × PREX +0.75145, the model incorporates 179 samples (106 ccRCC, 73 kidney benign lesions, 47 of which are renal solid lesions, 26 kidney cystic lesions), as shown in fig. 5, the ROC curve area under AUC:0.816, p < 0.001, sensitivity of 75.5% and specificity of 79.5%, which indicates that exosome mRNAs have better discrimination ability for ccRCC patients and kidney benign lesions patients.
The model was validated in subgroups with area under ROC curve AUC of 0.810 in fig. 6 and 0.832 in fig. 7, respectively, indicating that the model can be used for identification of ccRCC.
According to the embodiment of the invention, through quantitatively detecting the expression of mRNA (KMT 2D and PREX 2) in blood exosomes, renal transparent cell carcinoma patients can be effectively screened out from healthy people, the kit is hopeful to become a novel molecular marker for renal carcinoma, and the missed diagnosis caused by ultrasonic in the prior art can be effectively reduced, so that the early diagnosis rate is improved; the quantitative detection of mRNA (CUL 9, KMT2D and PREX 2) expression in blood exosomes can identify the occupation property of the kidney, effectively predict patients with renal clear cell carcinoma, and is used for overcoming the defect that CT or MRI in the prior art cannot accurately judge the occupation property of various kidneys (fat-deficient hamartoma, eosinophiloma and the like), and avoiding excessive treatment caused by undefined judgment of the occupation property in clinic.
Although embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made therein without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (8)
1. A set of molecular markers for early diagnosis of renal clear cell carcinoma, the set comprising: mRNA of exosome-derived KMT2D gene and mRNA of exosome-derived PREX gene.
2. The set of molecular markers for early diagnosis of renal clear cell carcinoma of claim 1, wherein: the exosomes are blood, plasma or serum exosomes.
3. Use of a marker panel according to any one of claims 1-2 for the preparation of a product for the diagnosis of renal clear cell carcinoma.
4. The use according to claim 3, wherein said diagnosis of renal clear cell carcinoma comprises early screening and differential diagnosis of renal clear cell carcinoma.
5. A product for diagnosing or prognosticating renal clear cell carcinoma, comprising a detection reagent for detecting the molecular marker of claim 1;
the detection reagent comprises an exosome extraction reagent, a ribonucleic acid extraction reagent, a reverse transcription reagent and a fluorescent PCR reaction solution.
6. A product for diagnosing or prognosing renal clear cell carcinoma according to claim 5, characterized in that:
the exosome extraction reagent includes upstream and downstream primers and detection probes for PCR.
7. A renal clear cell carcinoma early diagnosis system, comprising:
An information acquisition module for performing an operation of acquiring subject detection information, including information of the marker set according to any one of claims 1 to 2;
And the model establishment information analysis module is used for executing a diagnosis model for constructing the subject marker group information, thereby carrying out analysis of early diagnosis of the renal clear cell carcinoma.
8. A computer readable storage medium, having stored thereon a computer program which, when executed by a processor, implements the system of claim 7.
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