CN105779465A - CDKN2A gene fragment and application of primers of CDKN2A gene fragment in diagnosing tumors - Google Patents
CDKN2A gene fragment and application of primers of CDKN2A gene fragment in diagnosing tumors Download PDFInfo
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Abstract
The invention discloses a CDKN2A gene fragment and application of the primers of CDKN2A gene fragment in diagnosing tumors.By designing an upstream and downstream primer pair, the specific CDKN2A gene fragment is determined, the gene fragment shows remarkable high DNA methylation in tumor patients while showing low DNA methylation in normal people, and statistic differences exist between DNA methylation of tumor patients and that in normal people.Occurrence and development of tumors are tracked with the level changes of DNA methylation of the gene fragment, and thus a novel biomarker is provided for diagnosis, treatment effect monitoring and prognosis improvement judgment of tumors.
Description
Technical field
The invention belongs to gene technology field, be specifically related to the application in the clinical diagnosis of tumor, curative effect monitoring and Index for diagnosis field of the CDKN2A genetic fragment.
Background technology
Tumor (tumor) is a class commonly encountered diseases, frequently-occurring disease, and at present, malignant tumor has become one of the most serious disease of harm human health.The mortality rate of malignant tumor is only second to cardiovascular system diseases and occupies second, and in the trend being gradually increasing, expends substantial amounts of medical resource.Major part tumor is that accumulation, the combined effect gradually changed by gene mutation and epigenetics causes, and its slower development, if can find in early days, it is possible to carry out excision and radical cure, thus the early screening meaning of tumor is very great.The method of existing examination tumor has colonoscopy, feces sDNA inspection, S-CEA (CEA) horizon check etc., but its diagnosis efficiency, accuracy or invasive etc. are very not satisfactory, still have the tumor patient of half to be just found late.Find Tumor biomarkers, be applied to early diagnosis and examination, tumor patient diagnosis and prognosis are had important meaning.
CDKN2A inactivates the tumor suppressor gene that frequency is the highest in the various tumor of the mankind.CDKN2A albumen is Cyclin Dependent Kinase (CDK) mortifier (CDKinhibitor, CKI), with CyclinD1 competitive binding CDK4, and the activity of CDK4 can be suppressed specifically, make Rb gene protein phosphorylation, finally stop cell division.If CDKN2A gene loses normal expression, CDKN2A albumen being made inactive or protein product lacks, cell constantly rises in value, thus leading oncogenic development.Now there are some researches show, CDKN2A gene inactivation is mostly derived from gene and methylates and reticent, and the generation development with tumor that methylates of CDKN2A gene has substantial connection.Therefore, the early diagnosis of tumor, prognosis etc. are all played an important role by detection CDKN2A gene methylation.
But, not yet determine suitable CDKN2A genetic fragment at present, it is possible to by measuring its methylation level, for the biomarker as diagnosing tumor, curative effect monitoring and Index for diagnosis.Therefore, it is necessary to further study in this respect, upstream and downstream primer reasonable in design, location can measure the suitable CDKN2A genetic fragment of its methylation level.
Summary of the invention
The invention discloses a kind of CDKN2A genetic fragment and primer thereof and the application in diagnosing tumor, changed by the level of the DNA methylation of this genetic fragment, tracking of knub develops, and improves for the diagnosis of tumor, curative effect monitoring and prognosis and judges to provide a kind of new biomarker.
In order to realize foregoing invention purpose, the particular content of the present invention is as follows:
A kind of CDKN2A genetic fragment, for the section of DNA sequence on mankind's CDKN2A gene extron 2, length is 273bp, comprises 32 CpG sites, and the sequence of described CDKN2A genetic fragment is as follows:
The specific primer of above-mentioned CDKN2A genetic fragment design, specific as follows:
Forward primer CDKN2A-f:5'-GGTCATGATGATGGGCAG-3'
Downstream primer CDKN2A-r:5'-TTACTACCTCTAATACCCC-3'
Based on the foregoing disclosed, present invention additionally comprises the application in diagnosing tumor of the above-mentioned CDKN2A genetic fragment.
The application in the test kit of diagnosing tumor of the above-mentioned CDKN2A genetic fragment.
The application in diagnosing tumor of the above-mentioned CDKN2A genetic fragment primer.
The application in the diagnostic kit of tumor of the above-mentioned CDKN2A genetic fragment primer.
Meaning of the present invention is in that to devise above-mentioned upstream and downstream primer pair, determine above-mentioned specific CDKN2A genetic fragment, this genetic fragment presents significant high DNA in tumor patient and methylates, and DNA methylation is relatively low in normal person, both have significant difference, thus may be used for tumor diagnose early, curative effect monitoring and Index for diagnosis, the assay method of its methylation level includes mass spectrum, spectrum, electrochemistry or round pcr.
The beneficial effects of the present invention is, disclosed CDKN2A genetic fragment is little, and only 273bp adopts primer provided by the invention and program, only needs a PCR and amplifiable success, is not only easy to operation, saving time, it is possible to be substantially reduced cost.CDKN2A genetic fragment of the present invention can from blood, tissue, cell, body fluid, Excreta type sample obtain, sampling simplicity, applied widely.Therefore, the clinical indices that CDKN2A genetic fragment provided by the invention is improved as diagnosing tumor, therapeutic effect and prognosis, for examination and the diagnosis of tumor, tool has very great significance.
Accompanying drawing explanation
The pcr amplification of Fig. 1 tumor and normal blood CDKN2A genetic fragment
Wherein: M.DNAmarker；1-6 tumor blood；7-12 normal blood
Detailed description of the invention
Below by the specific embodiment of tumor patient and the DNA methylation assay of normal population blood CDKN2A genetic fragment, the invention will be further described.
1) extracting genome DNA and bisulfite process.
Adopt DNA extraction kit to extract the genome DNA of blood sample, and detected purity and the concentration of DNA solution by agarose gel electrophoresis and UV-spectrophotometry.Take the genomic DNA of a certain amount of concentration known, adopt bisulfite conversion reagent box to process, make unmethylated cytosine (C) in DNA be converted into uracil (U), and methylated cytosine remains unchanged.
2) the PCR primer specific design method that of the present invention CDKN2A genetic fragment is described below is as follows:
From GenBank Genbank (http://www.ncbi.nlm.nih.gov/genbank/), (Sequence accession number is NG_007485 to manned CDKN2A gene order total length, referring to sequence table file appended by present specification), choose its exon 2 coding region complete sequence.Blastn method is adopted to determine the positional accuracy of the sequence chosen.Oligo6.54 (www.oligo.net) and PrimerPremier5.0 (www.premierbiosoft.com) is adopted to carry out design of primers and evaluation for CDKN2A gene extron 2 sequence C pG site close quarters.Primer evaluation index mainly adopts whether the G/C content of sequence anneals temperature value, primer dimer and hairpin structure, primer and product and primer contain CpG site etc., finally determine the primer sequence for expanding CDKN2A genetic fragment, particularly as follows: forward primer CDKN2A-f:
5'-GGTCATGATGATGGGCAG-3', downstream primer CDKN2A-r:
5'-TTACTACCTCTAATACCCC-3'。
3) acquisition of CDKN2A genetic fragment.
Genomic DNA after being processed by bisulfite carries out pcr amplification by following procedure after mixing with above-mentioned forward primer, downstream primer, archaeal dna polymerase, PCR reactant liquor: enter circulation after 95 DEG C of denaturation 5min, 95 DEG C of degeneration 30s, 54 DEG C of annealing 60s, 72 DEG C extend 30s, circulate 36 times, 72 DEG C extend 7min, 4 DEG C of preservations.Wherein, described pcr amplification reaction system is as shown in table 1:
The reaction system of table 1PCR amplification
The PCR primer of CDKN2A genetic fragment adopts agarose gel electrophoresis to detect, and uses PCR primer recovery test kit to carry out reclaiming purification.
4) DNA methylation assay of CDKN2A genetic fragment
Adopting 88% formic acid that CDKN2A gene nucleotide fragment is cracked into single base, the content of recycling Isotope Dilution Mass Spectrometry adenine Ade and cytosine Cyt, thus calculating the DNA methylation level of CDKN2A genetic fragment.5) result
(1) pcr amplification result such as Fig. 1 shows, tumor and normal blood all can once amplify CDKN2A genetic fragment, and band is clear, and without non-specific amplification, repeatability is good.Illustrate that CDKN2A genetic fragment provided by the invention obtains simple, easy.
(2) as shown in table 2, by two independent samples t test, find tumor blood CDKN2A genetic fragment DNA methylation level be significantly higher than normal blood (p < 0.05), illustrate CDKN2A genetic fragment provided by the invention and methylate change can as the biomarker of the clinical diagnosis of tumor, curative effect monitoring and Index for diagnosis.
CDKN2A genetic fragment methylation level testing result in table 2 blood DNA
According to above-mentioned experimental result, we are it follows that utilize the specific CDKN2A genetic fragment that CDKN2A genetic fragment upstream and downstream primer disclosed by the invention obtains, according to the characteristic that its methylation level shows, may be used for making reagent, play a role in the diagnosis early of tumor, therapeutic effect and prognosis improve.
Above-described embodiment is except extracting from human blood, it is also possible to be tissue, cell, body fluid, excremental genomic DNA；The genomic DNA extracted is not limited to bisulfite and processes, it is also possible to be restriction enzyme ferment treatment；The routine techniques means related in above-described embodiment are intended merely to the invention detailed description of the invention reproducing applicant, can not be used for limiting the present invention, and protection scope of the present invention is as the criterion with appended claims.
Claims (6)
1. a CDKN2A genetic fragment, for the section of DNA sequence on mankind's CDKN2A gene extron 2, it is characterised in that the length of described CDKN2A genetic fragment is 273bp, comprises 32 CpG sites, and sequence is as follows:
2. the specific primer of CDKN2A genetic fragment according to claim 1 design, it is characterised in that:
Forward primer CDKN2A-f:5'-GGTCATGATGATGGGCAG-3'
Downstream primer CDKN2A-r:5'-TTACTACCTCTAATACCCC-3'
3. CDKN2A genetic fragment application in diagnosing tumor according to claim 1.
4. CDKN2A genetic fragment application in the test kit of diagnosing tumor according to claim 1.
5. CDKN2A genetic fragment primer application in diagnosing tumor according to claim 2.
6. CDKN2A genetic fragment primer application in the diagnostic kit of tumor according to claim 2.
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Cited By (3)
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| CN107058567A (en) * | 2017-05-23 | 2017-08-18 | 宁波市第医院 | A kind of detection kit of auxiliary diagnosis cerebral arteriovenous malformation and its application |
| WO2020228009A1 (en) * | 2019-05-16 | 2020-11-19 | 北京市肿瘤防治研究所 | Method for quantitatively detecting deletion of human cdkn2a gene copy, primers and use thereof |
| CN112708677A (en) * | 2021-01-28 | 2021-04-27 | 长沙深宇生物科技有限公司 | Primer group, kit and method for detecting head and neck tumor gene survival correlation |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107058567A (en) * | 2017-05-23 | 2017-08-18 | 宁波市第医院 | A kind of detection kit of auxiliary diagnosis cerebral arteriovenous malformation and its application |
| WO2020228009A1 (en) * | 2019-05-16 | 2020-11-19 | 北京市肿瘤防治研究所 | Method for quantitatively detecting deletion of human cdkn2a gene copy, primers and use thereof |
| CN113811623A (en) * | 2019-05-16 | 2021-12-17 | 北京市肿瘤防治研究所 | Method for quantitatively detecting copy deletion of human CDKN2A gene, primer and application thereof |
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| CN112708677A (en) * | 2021-01-28 | 2021-04-27 | 长沙深宇生物科技有限公司 | Primer group, kit and method for detecting head and neck tumor gene survival correlation |
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