CN110343762A - Bladder carcinoma marker group and its application - Google Patents
Bladder carcinoma marker group and its application Download PDFInfo
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- CN110343762A CN110343762A CN201910493478.5A CN201910493478A CN110343762A CN 110343762 A CN110343762 A CN 110343762A CN 201910493478 A CN201910493478 A CN 201910493478A CN 110343762 A CN110343762 A CN 110343762A
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- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
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- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
- C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
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- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/112—Disease subtyping, staging or classification
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- C12Q2600/118—Prognosis of disease development
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- C—CHEMISTRY; METALLURGY
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- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/154—Methylation markers
Abstract
The invention discloses bladder carcinoma marker groups, including following gene: HOXA9, ONECUT2, PCDH17, PENK, TWIST1, VIM and ZNF154.The present invention also provides application of the bladder carcinoma marker group in the reagent or kit that preparation is used for Diagnosis of Bladder.The present invention also provides a kind of combinations of reagent, for detecting the methylation level of the bladder carcinoma marker group.Bladder carcinoma marker group of the invention can be used for the early screening of bladder cancer, the parting and/or prognosis prediction of the risk assessment of bladder cancer, bladder cancer occur for subject, improve sensitivity, specificity and the accuracy of diagnosis and detection.It is predicted by accurate risk assessment, bladder carcinoma marker group of the invention can reduce the unnecessary invasive inspection of low-risk (low risk) patient.
Description
Technical field
The invention belongs to molecular biology fields.In particular it relates to bladder carcinoma marker group and its application.More
Body, the present invention relates to the DNA methylation biomarker of bladder cancer and its applications.
Background technique
With the progress of intensification and science and technology that people recognize tumour, many novel tumor markers are found
And it is used for clinical diagnosis.Before 1980, tumor marker is mainly the cell secretas such as some hormones, enzyme, protein, example
The marker that such as carcinomebryonic antigen, first tire antigen can be used as the kinds of tumors such as liver cancer gastric cancer, carbohydrate antigen 125 can be used as ovum
The marker of nest cancer, prostate-specific antigen can be used as prostate cancer marker.However, this kind of tumor markers is sensitive
Degree and specificity have been difficult to meet Present clinical demand.
Bladder cancer is a kind of common and high lethality rate malignant tumour.According to statistics, annual about 429800 of the whole world is new
Increase case and 165100 deaths.Traditional bladder cancer inspection is cystoscopy and cytology biopsy, but cystoscopy
It looks into and belongs to invasive inspection, it is costly and certain pain can be brought to patient, and its result may be by operator's subjective judgement
And bring certain error；And cytology biopsy then haves the defects that sensitivity is low (34% or so).Therefore, Non-invasive detection becomes
One of the important development direction of bladder cancer detection.
More and more evidences show important function of the minor variations of epigenetic regulation in tumour.Epigenetic
Be research gene in the case where DNA sequence dna change does not occur, heritable variation that gene function occurs, and is eventually led to
One Men Xueke of the variation of phenotype.DNA methylation is important epigenetic relevant to many genes activity and bioprocess
Modification.The frequent epigenetic of DNA changes the progress that can lead to cancer, and includes that bladder cancer is associated with many cancers.DNA first
One of the advantage of baseization detection is that it not only can be using tumor tissues, can also be using body fluids such as blood, saliva, urine etc.
Diagnosing tumor is carried out, is realized noninvasive painless.The study found that DNA methylation relevant to bladder cancer can be used for the diagnosis of bladder cancer,
And it can be used as the target spot of bladder cancer treatment.
In consideration of it, still needing to carry out extensive evaluation to the DNA methylation biomarker of bladder cancer at present, finds and be used for bladder
The high sensitivity of cancer Non-invasive detection and the biomarker of high specific.
Summary of the invention
The present inventor recognizes one group of methyl-sensitive gene by extensive research screening, i.e. HOXA9, ONECUT2,
PCDH17, PENK, TWIST1, VIM and ZNF154 gene.In bladder cancer patients, in specific site height occurs for said gene
Methylation.Therefore, the assortment of genes of HOXA9, ONECUT2, PCDH17, PENK, TWIST1, VIM and ZNF154, Ke Yijin are utilized
The risk assessment of bladder cancer, bladder occur for the detection and/or diagnosis of row bladder cancer, early screening, subject including bladder cancer
The parting and/or prognosis prediction of cancer.
The purpose of the present invention is to provide new biomarker groups, are used for bladder cancer Non-invasive detection.In addition, of the invention
Purpose, which also resides in, provides the application of above-mentioned marker group.
In the first aspect of the present invention, bladder carcinoma marker group, including following gene are provided: HOXA9, ONECUT2,
PCDH17, PENK, TWIST1, VIM and ZNF154.
According to a specific embodiment, said gene is hyper-methylation.
On the other hand, the present invention provides the reagent that bladder carcinoma marker group as described above is used for Diagnosis of Bladder in preparation
Or the application in kit.
According to a specific embodiment, above-mentioned Diagnosis of Bladder includes the early screening of bladder cancer, subject's generation wing
The risk assessment of Guang cancer, the parting of bladder cancer and/or prognosis prediction.
On the other hand, the present invention provides a kind of reagent combination, including nucleotide sequence such as SEQ ID NO:1 and SEQ ID
The primer pair 2, nucleotides sequence as shown in SEQ ID NO:3 and SEQ ID NO:4 of primer pair 1, nucleotide sequence shown in NO:2
Arrange primer pair 3, nucleotide sequence such as SEQ ID NO:7 and SEQ ID NO as shown in SEQ ID NO:5 and SEQ ID NO:6:
The primer pair 5, nucleotide sequence as shown in SEQ ID NO:9 and SEQ ID NO:10 of primer pair 4, nucleotide sequence shown in 8
The primer pair 6 as shown in SEQ ID NO:11 and SEQ ID NO:12 and nucleotide sequence such as SEQ ID NO:13 and SEQ
Primer pair 7 shown in ID NO:14, the reagent set are shared in the methylation level for detecting above-mentioned bladder carcinoma marker group.
According to a specific embodiment, reagent combination further includes selected from LC GreenPlus、LC Green、Eva Green
Or the saturated fluorescence dyestuff of SYTO 9.
Preferably, reagent combination includes LC GreenPlusSaturated fluorescence dyestuff.It is demonstrated experimentally that LC GreenPlusIt is saturated glimmering
The sensibility of photoinitiator dye is higher, and detection sensitivity can be improved.
According to a specific embodiment, reagent combination is that bladder cancer occurs for the early screening of bladder cancer, subject
Risk assessment, the parting of bladder cancer and/or the kit of prognosis prediction.
According to a specific embodiment, mentioned reagent box includes the container and operation instruction for accommodating each reagent
Book, wherein indicating test experience step and result judgement standard etc..
On the other hand, the present invention provides the reagent or reagent that reagent combination as described above is used for Diagnosis of Bladder in preparation
Application in box.
According to a specific embodiment, above-mentioned Diagnosis of Bladder includes the early screening of bladder cancer, subject's generation wing
The risk assessment of Guang cancer, the parting of bladder cancer and/or prognosis prediction.
Bladder carcinoma marker group of the invention can be used for the early screening of bladder cancer, the risk of bladder cancer occurs for subject
Assessment, the parting of bladder cancer and/or prognosis prediction, improve sensitivity, specificity and the accuracy of diagnosis and detection.Pass through standard
(positive predictive value 100%, negative predictive value 98%) is predicted in true risk assessment, and bladder carcinoma marker group of the invention can
To reduce the unnecessary invasive inspection of low-risk (low risk) patient.
Reagent combination/kit of the invention has the advantages that easy to operate, saving diagnosis/detection time, result are clear
It is clear reliable.Using reagent combination/kit of the invention, the effect of noninvasive, convenient, efficient quick diagnosis bladder cancer may be implemented
Fruit.
Reagent set of the invention closes strong applicability, is widely portable to scientific experiment and clinical detection.Also, due to this
Reagent combination/kit of invention is suitable for Non-invasive detection, and the acceptance of the unobvious crowd of asymptomatic or symptom is high, can be used for often
Regulator inspection.
In addition, primer specificity designed by the present inventor is strong, expanding effect and detection efficiency, the inspection of acquisition are improved
Surveying result has high confidence level.
Detailed description of the invention
Fig. 1 is the experiment flow schematic diagram for detecting marker methylation level in urine sample.
Fig. 2 is the ratio of bladder cancer patients (44) and non-bladder cancer patients (37) DNA methylation probability in 81 samples
Compared with.Statistical significance examines (student ' s t-test) to determine by student t, wherein *, * *, * * * respectively represent P < 0.05, P <
0.01、P<0.001。
Fig. 3 is using risk score model of the invention to 81 sample queues (44 bladder cancers and 37 normal controls)
Carry out Receiver Operating Characteristics (ROC) curve of bladder cancer prediction, wherein abscissa is specificity, and ordinate is sensitivity.
Fig. 4 be using risk score model of the invention to cancer gene group map (TCGA) queue (412 bladder cancers and
21 normal controls) carry out bladder cancer prediction Receiver Operating Characteristics (ROC) curve, wherein abscissa be specificity, indulge sit
It is designated as sensitivity.
Fig. 5 is that each coefficient takes the subject when upper limit value of its numberical range to work in risk score model of the invention
Indicatrix (ROC).
Fig. 6 is that each coefficient takes the subject when lower limit value of its numberical range to work in risk score model of the invention
Indicatrix (ROC).
Specific embodiment
The present invention is described in further detail with reference to the accompanying drawings and examples.Following embodiment is merely to illustrate this
It invents rather than limits the scope of the invention.Test method without specific conditions in embodiment, usually according to conventional strip
Part, or according to the normal condition proposed by manufacturer.
" Diagnosis of Bladder " described in this specification includes the risk of the early screening of bladder cancer, subject's generation bladder cancer
Assessment, the parting of bladder cancer and/or prognosis prediction.
" marker " described in this specification refers to specific biological characteristic, biochemical characteristics or aspect
Molecular indicator can be used for determining the serious journey presence or absence of specified disease or situation and/or specified disease or situation
Degree.
" high (degree) methylation " described in this specification refers to that there are high methylations, hydroxyl by CpG in a gene order
Methylation, aldehyde methylation or carboxy methylation modification.
" sample " described in this specification or " sample " include (related indication if any disease in the urological system from any individual
Subject) in obtain, be suitable for methylation state of DNA detection substance.It is mixed in the urine of bladder cancer and falls off on a small quantity
Tumour cell.Therefore, sample is preferably urine sample or the urine sample (especially urinary precipitation) by processing.
When carrying out marker methylation assay, urine DNA sample is handled with bisulfite conversion, wherein first does not occur
The Cytosines of base are uracil, and the cytimidine to methylate remains unchanged.
It should be understood that other than the method (high-resolution solubility curve polymerase chain reaction, HRM-PCR) used in addition to the present invention,
Other it is any existing and it is following it is newly developed can be used for detecting/analysis of methylation status/level technology can be applied to
The present invention, for example, MS-PCR (methylation status of PTEN promoter), M-MLPA, pyrosequencing, MALDI-TOF etc..
Embodiment 1
Sample treatment (urine sample)
1) in the urine collection tube for prestoring 600ul EDTA solution, collect 30ml urine, after mixing at 3000g from
The heart 10 minutes；
2) urine DNA is extracted using Qiagen kit；
3) EZ Gold methylating reagent box is used, bisulfite conversion is carried out to urine DNA.
Urine preservation condition: when the holding time was less than 48 hours, 4 DEG C are stored in；Holding time is more than 48 hours, then saves
In -80 DEG C.
Embodiment 2
It is horizontal that HRM-PCR measures gene methylation
High solubility curve polymerase chain reaction (HRM-PCR) experiment is following to be carried out:
1) reagent needed for preparing HRM-PCR (1 reaction):
A.5ul 2X Zymo premix；
B.0.5ul primer, primer sequence is as shown in NO:1~14 SEQ ID；
C.0.5ul LC GreenPlusSaturated fluorescence dyestuff；
D.3ul water；
E.1ul sample, the sample are handled according to the method for embodiment 1；
2) HRM-PCR measurement is carried out, gene methylation level is obtained, reaction step and condition are as follows:
A. pre-activate 10 minutes at 95.0 DEG C；
B. it is denaturalized 15 seconds at 95.0 DEG C, anneals 30 seconds at 60.0 DEG C, extend 15 seconds at 72.0 DEG C, carry out 50 with this
A circulation；
C. it according to following reaction condition, obtains HRM curve: temperature being risen to 95.0 from 72.0 DEG C with 1.6 DEG C/sec of rate
DEG C, and kept for 15 seconds；60.0 DEG C are cooled to again with 0.025 DEG C/sec of rate；Then with 0.025 DEG C/sec of rate from 60.0 DEG C
95.0 DEG C are risen to, is kept for 15 seconds, and be cooled to 60.0 DEG C with 1.6 DEG C/sec of rate.
Embodiment 3
The building of bladder cancer risk score model
1. sample collection
Collect 81 mankind's urine samples, including 44 bladder cancer patients and 37 normal controls.
2. model construction
To the methylation water of 7 selected genes (HOXA9, ONECUT2, PCDH17, PENK, TWIST1, VIM and ZNF154)
Flat to carry out single argument and multivariable logistic regression analysis, building includes the detection model of 7 genes.Using the method for embodiment 2,
The methylation level of 7 genes in each sample is obtained respectively, and the operating process of test experience is as shown in Figure 1.Firstly, carrying out single
Variable logistic regression analysis.As shown in Fig. 2, 7 selected genes are all significant related to bladder cancer.Then multivariable is carried out to patrol
Regression analysis is collected, the regression coefficient of 7 kinds of genes is obtained.
All statistical analysis use (the Statistical Product and Service of SPSS 19.0
Solutions, IBM Corporation, Armonk, New York, the U.S.) and (the R Foundation for of R 3.4.2 editions
Statistical Computing, Vienna, Austria) it carries out.
Based on the methylation level of this 7 genes, creation can be used for bladder cancer detection/diagnosis risk score model: G=
(8.919 × HOXA9 methylation level)+(13.513 × ONECUT2 methylation level)+(13.119 × PCDH17 methylation water
It is flat)+(2.534 × PENK methylation level)+(1.151 × TWIST1 methylation level)+(0.405 × VIM methylation level)+
(0.306 × ZNF154 methylation level).Wherein, the methyl of the gene methylation then gene is detected using HRM-PCR method
Change level is denoted as 1, and the methylation level that the gene methylation then gene is not detected is denoted as -1.
3. result
When G value is higher than -13.709, it is judged as high-risk-type bladder cancer (high risk)；When G value is equal to or less than -13.709
When, it is judged as low risk bladder cancer (low-risk).As shown in figure 3, above-mentioned risk score model carries out the special of Diagnosis of Bladder
Property up to 94.6%, sensitivity shows to make bladder cancer detection/diagnosis with good instruction up to 75.0%, AUC value 89.4%
With.
Embodiment 4
The verifying of bladder cancer risk score model
Utilize the methylation sample information in cancer gene group map (Cancer Genome Atlas, TCGA) database
(412 bladder cancers and 21 normal controls) carry out individual authentication to the risk score model in embodiment 3.When G value be higher than-
When 13.709, it is judged as high-risk-type bladder cancer (high risk)；When G value is equal to or less than -13.709, it is judged as low risk bladder
Cancer (low-risk).
As a result as shown in figure 4, the specificity of bladder cancer detection is up to 91.2%, sensitivity is up to 73.4%, AUC value
85.1%, show that risk score model shows in bladder cancer detection and stablizes.
Embodiment 5
Coefficient range in bladder cancer risk score model
The present inventor, which also studies, compares influence of the coefficient value to model validation in risk score model.According to risk
Rating Model: G=(8.919 × HOXA9 methylation level)+(13.513 × ONECUT2 methylation level)+(13.119 ×
PCDH17 methylation level)+(2.534 × PENK methylation level)+(1.151 × TWIST1 methylation level)+(0.405 ×
VIM methylation level)+(0.306 × ZNF154 methylation level), 95% confidence of each gene methylation horizontal coefficients is provided
Section is listed in table 1.
Table 1.
| Coefficient (95% confidence interval coefficient range) | |
| HOXA9 | 8.919 (1.99~39.964) |
| ONECUT2 | 13.513 (1.128~161.832) |
| PCDH17 | 13.119 (1.51~114) |
| PENK | 2.534 (0.146~43.883) |
| TWIST1 | 1.151 (0.246~5.374) |
| VIM | 0.405 (0.042~3.929) |
| ZNF154 | 0.306 (0.033~2.862) |
1) when each coefficient takes range higher limit, risk score model are as follows: G=(39.964 × HOXA9 methylation level)+
(161.832 × ONECUT2 methylation level)+(114 × PCDH17 methylation level)+(43.883 × PENK methylation level)
+ (5.374 × TWIST1 methylation level)+(3.929 × VIM methylation level)+(2.862 × ZNF154 methylation level).
Using above-mentioned risk score model (coefficient capping value), to 7 genes in above-mentioned 81 urine samples (HOXA9,
ONECUT2, PCDH17, PENK, TWIST1, VIM and ZNF154) methylation level carry out data statistic analysis.When G value is high
When -143.844, it is judged as high-risk-type bladder cancer (high risk)；When G value is equal to or less than -143.844, it is judged as low danger
Type bladder cancer (low-risk).As a result as shown in figure 5, the risk score model carries out the specificity of Diagnosis of Bladder up to 94.6%,
Sensitivity is up to 75.0%, AUC value 89.3%.
2) when each coefficient takes lower range limit, risk score model are as follows: G=(1.99 × HOXA9 methylation level)+
(1.128 × ONECUT2 methylation level)+(1.51 × PCDH17 methylation level)+(0.146 × PENK methylation level)+
(0.246 × TWIST1 methylation level)+(0.042 × VIM methylation level)+(0.033 × ZNF154 methylation level).
Using above-mentioned risk score model (coefficient removes limit value), to 7 genes in above-mentioned 81 urine samples (HOXA9,
ONECUT2, PCDH17, PENK, TWIST1, VIM and ZNF154) methylation level carry out data statistic analysis.When G value is high
When -0.473, it is judged as high-risk-type bladder cancer (high risk)；When G value is equal to or less than -0.473, it is judged as low risk wing
Guang cancer (low-risk).As a result sensitive as shown in fig. 6, the risk score model carries out the specific up to 94.6% of Diagnosis of Bladder
Degree is up to 75.0%, AUC value 89.6%.
Therefore, risk score model can be with are as follows: and G=(m1 × HOXA9 methylation level)+(m2 × ONECUT2 methylates water
It is flat)+(m3 × PCDH17 methylation level)+(m4 × PENK methylation level)+(m5 × TWIST1 methylation level)+(m6 ×
VIM methylation level)+(m7 × ZNF154 methylation level), wherein m1 be 1.99~39.964, m2 be 1.128~
161.832, m3 be 1.51~114, m4 be 0.146~43.883, m5 be 0.246~5.374, m6 be 0.042~3.929, m7
It is 0.033~2.862.
Embodiment 6
The preparation of kit
Reagent preparation box includes: primer sequence as shown in Table 2, and 2 × ZymoTaq qPCR Premix (is purchased from Zymo
Research company), LC GreenPlus(being purchased from BioFire Diagnostics, Inc., salt lake city, the Utah State, the U.S.),
The pure water of RNase-free and DNase-free.
Table 2.
Using the above-mentioned kit prepared, using HRM-PCR method, the methylation level of testing goal gene is obtained
Highly sensitive, specificity and accuracy testing result.
The explanation of above-described embodiment is only intended to understand method and its core concept of the invention.It should be pointed out that for this
For the those of ordinary skill in field, without departing from the principle of the present invention, several improvement can also be carried out to the present invention
And modification, these improvement and modification will also be fallen into the protection scope of the claim of this application.
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Claims (10)
1. bladder carcinoma marker group, including following gene: HOXA9, ONECUT2, PCDH17, PENK, TWIST1, VIM and
ZNF154。
2. bladder carcinoma marker group according to claim 1, the gene are hyper-methylations.
3. bladder carcinoma marker group of any of claims 1 or 2 is in the reagent or kit that preparation is used for Diagnosis of Bladder
Using.
4. application according to claim 3, the Diagnosis of Bladder includes the early screening of bladder cancer, subject's generation wing
The risk assessment of Guang cancer, the parting of bladder cancer and/or prognosis prediction.
5. a kind of reagent combination, including nucleotide sequence primer pair 1, nucleosides as shown in SEQ ID NO:1 and SEQ ID NO:2
Acid sequence primer pair 2, nucleotide sequence such as SEQ ID NO:5 and SEQ ID as shown in SEQ ID NO:3 and SEQ ID NO:4
The primer pair 4, nucleotides sequence as shown in SEQ ID NO:7 and SEQ ID NO:8 of primer pair 3, nucleotide sequence shown in NO:6
Arrange primer pair 5, nucleotide sequence such as SEQ ID NO:11 and SEQ ID as shown in SEQ ID NO:9 and SEQ ID NO:10
The primer pair 7 as shown in SEQ ID NO:13 and SEQ ID NO:14 of primer pair 6 and nucleotide sequence shown in NO:12, institute
Reagent set is stated to share in the methylation level for detecting bladder carcinoma marker group described in claim 1.
6. reagent combination according to claim 5, the reagent combination further includes selected from LC GreenPlus、LC Green、
The saturated fluorescence dyestuff of Eva Green or SYTO9.
7. reagent combination according to claim 5 or 6, the reagent combination includes LC GreenPlusSaturated fluorescence dyestuff.
8. reagent according to claim 5 or 6 combination, the reagent combination is the early screening, tested for bladder cancer
Risk assessment, the parting of bladder cancer and/or the kit of prognosis prediction of person's generation bladder cancer.
9. reagent combination according to claim 8, the kit includes the container for accommodating each reagent, and is used
Specification.
10. application of the reagent combination described in claim 5 or 6 in the reagent or kit that preparation is used for Diagnosis of Bladder.
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110872631A (en) * | 2019-12-26 | 2020-03-10 | 广州市基准医疗有限责任公司 | DNA methylation biomarker combination, detection method and kit |
| CN110964820A (en) * | 2019-12-16 | 2020-04-07 | 中山大学 | Bladder cancer biomarker TJP1 and application thereof |
| CN111826446A (en) * | 2020-03-24 | 2020-10-27 | 亚能生物技术（深圳）有限公司 | Primer, probe and kit for early screening and auxiliary diagnosis of bladder cancer |
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| CN113943799A (en) * | 2020-07-16 | 2022-01-18 | 广州达健生物科技有限公司 | Composition for detecting bladder cancer, kit and application thereof |
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| CN110964820A (en) * | 2019-12-16 | 2020-04-07 | 中山大学 | Bladder cancer biomarker TJP1 and application thereof |
| CN110872631A (en) * | 2019-12-26 | 2020-03-10 | 广州市基准医疗有限责任公司 | DNA methylation biomarker combination, detection method and kit |
| CN111826446A (en) * | 2020-03-24 | 2020-10-27 | 亚能生物技术（深圳）有限公司 | Primer, probe and kit for early screening and auxiliary diagnosis of bladder cancer |
| CN113943799A (en) * | 2020-07-16 | 2022-01-18 | 广州达健生物科技有限公司 | Composition for detecting bladder cancer, kit and application thereof |
| CN113943799B (en) * | 2020-07-16 | 2023-12-15 | 广州达健生物科技有限公司 | Composition for detecting bladder cancer, kit and application thereof |
| CN114686607A (en) * | 2020-12-31 | 2022-07-01 | 深圳华大生命科学研究院 | Application of corynebacteria as urine microbial marker in preparation of related detection products for detecting bladder cancer |
| CN114686607B (en) * | 2020-12-31 | 2023-09-26 | 深圳华大生命科学研究院 | Application of corynebacteria as urine microorganism marker in preparation of related detection products for detecting bladder cancer |
| CN113930509A (en) * | 2021-09-29 | 2022-01-14 | 苏州美汇医药技术有限公司 | Primer probe composition, kit and system for early screening or prognostic monitoring of bladder cancer |
| CN114891886A (en) * | 2022-05-12 | 2022-08-12 | 武汉艾米森生命科技有限公司 | Nucleic acid product and kit for diagnosing bladder cancer and application |
| WO2024066941A1 (en) * | 2022-09-30 | 2024-04-04 | 圣湘生物科技股份有限公司 | Composition for detecting bladder cancer, kit, and use thereof |
| CN117737250A (en) * | 2024-02-21 | 2024-03-22 | 上海金翌生物科技有限公司 | Method and kit for detecting methylation level of bladder cancer biomarker |
| CN117757947A (en) * | 2024-02-21 | 2024-03-26 | 上海金翌生物科技有限公司 | Primer group, probe group, kit and method for detecting methylation level of bladder cancer biomarker |
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