CN104745700A - Esophageal-cancer-related methylated biomarker and application thereof - Google Patents
Esophageal-cancer-related methylated biomarker and application thereof Download PDFInfo
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Abstract
The invention provides an esophageal-cancer-related methylated biomarker and the application thereof. According to the application of the esophageal-cancer-related methylated biomarker, the peripheral venous blood of the person to be tested is collected by an EDTA vacuum anticoagulant blood vessel, the supernatant plasma is separated, the plasma circulation DNA is extracted by the QIAamp Circulating Nucleic Acid Kit and hydrosulfite modification is performed to the extracted plasma circulation DNA by the EZ DNA Methylation Kit; the methylation frequencies of the CG sites of the esophageal-cancer-related tumor-suppressor genes CASZ1, CDH13 and ING2 in the modified plasma circulation DNA are detected by the mass spectrography, so that biomarkers are obtained; and the biomarkers are used in screening, anticipating, preventing and treating of the esophageal cancer. The esophageal-cancer-related methylated biomarker has the advantages that the esophageal-cancer-related methylated biomarker is rapid, simple, sensitive, specific and non-invasive; moreover, the methylation of the DNA is reversible by using exogenous drugs, so that the research result also has potential application prospect in tumor treatment.
Description
Technical field
The invention belongs to cancer prevention field, particularly relate to a kind of esophageal carcinoma relevant methylate biomarker and application.
Background technology
The esophageal carcinoma is common alimentary system malignant tumour, with south and East Africa, East Asia Region sickness rate the highest.China is one of Esophageal Cancer in High Risk Areas, and sickness rate is higher than the U.S. 20 to 30 times.Except well-known behavior and dietary factors and the esophageal carcinoma occur relevant except, idiogenetics factor also can not be ignored.In recent years, along with molecular biology and deepening continuously to tumor originates mechanism understanding, the abnormal effect in tumour occurs of epigenetic receives publicity day by day.
One of principal mode that epigenetic changes is DNA methylation, and this is a kind of important regulating and controlling mode of mammal epigenetic modification, is also the only natural chemically modified mode of vertebrates DNA.DNA methylation mainly occurs in the gene promoter area of being rich in CG island.Genetic transcription can be caused suppressed after the CG island of promoter region methylates, expressing quantity reduces, and corresponding function declines and even loses.Because DNA methylation pattern also has tumour-specific, may there is different DNA methylation spectrums in namely dissimilar tumour, can be used as the diagnosis of potential Molecular biomarkers for the esophageal carcinoma by identifying that DNA abnormal methylation is composed and built specific library.
Traditional esophagus cancer diagnosis method comprises x-ray, CT, nucleus magnetic resonance, gastroscopy etc., but all there is the low and early stage focus of susceptibility and be difficult to the shortcomings such as discovery.Find quick, easy, sensitive, special method of early diagnosis and become a vital task in current esophageal cancer prevention work.Compared with traditional protein biomarker, it is usually event more early stage in cell carcinogenesis that DNA methylation changes, if the DNA methylation collection of illustrative plates of rational multi objective can be set up, namely adopting Protocols in Molecular Biology to identify this specific variations at the commitment of disease, meaning of the utmost importance will be had to realizing the esophageal carcinoma " three early " undoubtedly.
As far back as eighties of last century the 1970s and 1980s, scientists just has been found that in the peripheral blood of tumour patient to there is a kind of dissociative DNA (cell free DNA) deriving from tumour stove.The effect of dissociative DNA in the diagnosis and prognosis of tumour in recent years comes into one's own day by day, becomes the biomarker that has broad prospect of application.Solid malignant knurl discharges a large amount of DNA by necrocytosis or apoptosis and enters body circulation, and molecular size is between 500bp ~ 30kb.Research in recent years shows, the amount of human peripheral dissociative DNA and the change of matter and disease development in close relations, promise to be a kind of important molecule mark of medical diagnosis on disease, curative effect evaluation and Prognosis scoveillance.The hereditary feature of dissociative DNA is consistent with corresponding tumor tissues height, as there is similar transgenation, microsatellite instability and loss of heterozygosity, and has consistent epigenetic change feature.An important discovery in Circulating DNA research is the abnormal methylation that Circulating DNA simultaneously can be detected in the blood plasma/clear of tumour patient, and the methylation patterns of Peripheral Circulation DNA is consistent with cancerous tissue, this is found to be non-invasive DNA methylation spectrum analysis and provides possibility.
Due to the earliest events that cancer suppressor gene abnormal methylation is tumour generating process, identifying and build methylome library, for esophageal carcinoma early diagnosis and prognosis, there is important using value, especially identifying that in peripheral blood, tumor specific DNA methylome provides clue for finding non-invasive esophagus cancer diagnosis mark especially.Because DNA methylation can pass through external source Set back by drug, thus this result of study also has potential cancer therapeutic applications prospect.
Summary of the invention
The object of the present invention is to provide a kind of esophageal carcinoma relevant methylate biomarker and application, be intended to solve existing esophagus cancer diagnosis method and comprise x-ray, CT, nucleus magnetic resonance, gastroscopy etc. and there is the low and early stage focus of susceptibility and be difficult to the problems such as discovery.
The present invention is achieved in that the relevant biomarker that methylates of a kind of esophageal carcinoma, is biomarker by the specific CG site detected in CASZ1, CDH13 and ING2 esophageal carcinoma suppressor genes correlation frequency that methylates.
The detailed process that this biomarker obtains comprises: adopt EDTA vacuum anticoagulant blood-collecting pipe to gather the peripheric venous blood of person to be measured, be separated upper plasma, adopt QIAamp Circulating Nucleic Acid kit to extract plasma circulation DNA, adopt EZ DNA Methylation Kit to carry out bisulphite modified.Plasma circulation DNA after modification adopts mass spectroscopy to detect methylating of genes involved CG site.
Invention further provides the be correlated with biomarker that methylates of the above-mentioned esophageal carcinoma and suffer from application in the esophageal carcinoma examination, anticipation, control person to be checked.
Auxiliary judgment person to be checked can suffer from the possibility size of the esophageal carcinoma by the frequency that methylates detecting CASZ1, CDH13 and ING2 in sample, the early stage i.e. identifiable design of the esophageal carcinoma occurs patient, contribute to early finding, early diagnosis, early treatment.
Compared to the shortcoming and defect of prior art, the present invention has following beneficial effect:
(1) the present invention is using Peripheral Circulation DNA methylation as biomarker for the early screening of the esophageal carcinoma, anticipation, control, has quick, easy, sensitive, special and noninvasive advantage, has important using value.
(2) in biomarker of the present invention, DNA methylation can pass through external source Set back by drug, and thus this result of study also has potential cancer therapeutic applications prospect.
Embodiment
In order to make object of the present invention, technical scheme and advantage clearly understand, below in conjunction with embodiment, the present invention is further elaborated.Should be appreciated that specific embodiment described herein only in order to explain the present invention, be not intended to limit the present invention.
Embodiment 1 esophageal carcinoma is correlated with the acquisition of biomarker of methylating
1, blood collection
EDTA vacuum anticoagulant blood-collecting pipe is adopted to gather patient peripheric venous blood 3 ~ 5ml on an empty stomach, 3,000 rev/min centrifugal 10 minutes, careful absorption upper plasma is placed in centrifuge tube, recentrifuge 10 minutes, speed 5,000 rev/min, draw upper plasma and be placed in another cryopreservation tube, detect for DNA methylation, sample to be tested can put-80 DEG C of freezen protective.
2, DNA extraction
QIAamp Circulating Nucleic Acid kit is adopted to extract plasma dna.Test kit is by MiniColumns, Tube Extenders, Elution Tubes, VacConnectors, Collection Tubes, Buffer ACL, Buffer ACB, Buffer ACW1, Buffer ACW2, Buffer AVE, Carrier RNA and Proteinase K composition.
3, DNA modification
U.S. EZ DNAMethylation Kit is adopted to carry out bisulphite modified.Test kit comprises M-Dilution Buffer, CT Conversion Reagent, M-Binding Buffer, Zymo-SpinTMICColumn, M-Wash Buffer, M-Wash Buffe, M-Elution Buffer, Collection Tubes.It is for subsequent use that DNA sample after modification puts into-20 DEG C of refrigerators.
4, DNA methylation assay
Design PCR primer, as shown in table 1 below:
The primer sequence of table 1 blood sample DNA methylation assay
Flight mass spectrum method is adopted to detect 7 CG site (CASZ1_CpG_2.3 in CASZ1, CDH13 and ING2 tri-genes; CASZ1_CpG_4; CASZ1_CpG_5; CDH13_CpG_8; ING2_CpG_1.2.3.4; ING2_CpG_5; ING2_CpG_6.7) the frequency that methylates.
If plasma dna fragmentation is serious, then CDH13 gene can adopt the primer in table 2 to increase:
Table 2 is for the primer sequence of the serious blood sample DNA methylation assay of fragmentation
5, result
Correctly so that early stage, result of study was determined judge that cutoff value that rate is the highest is as foundation, comprehensive descision sample to be tested is from the possibility size of patient with esophageal carcinoma.Table 3 to methylate frequency cutoff value reference table for unit point, and table 4 is the accumulative frequency cutoff value reference table that methylates in each gene C G site.
Table 3 unit point methylates frequency cutoff value reference table
The accumulative frequency cutoff value reference table that methylates in each gene C G site of table 4
The application of embodiment 2 biomarker in esophageal carcinoma examination
1, research method
First differential methylation site in DNA methylation chip technology primary dcreening operation human esophageal carcinoma is utilized; Then enlarged sample carries out mass spectroscopy to the methylation sites just sifted out, and compares the consistence of specific gene DNA methylation pattern in human esophageal carcinoma and blood plasma.
Case derives from the patient carrying out Operation on Esophageal Cancer in the People's Hospital of Yangzhong City, requires: (1) is pathological diagnosis foundation in a organized way; (2) histological type is esophageal squamous cell carcinoma; (3) informed consent of patient is obtained; (4) preoperatively radiation and chemotherapy was not accepted.Preoperative employing EDTA vacuum anticoagulant blood-collecting pipe gathers venous blood 5ml, centrifugal rearmounted-80 DEG C of freezen protective.Collect the normal esophageal tissue of distal esophagus naked eyes (distance Ai Zao center more than 5cm) of Ai Zao central tissue and excision in art, be placed in-80 DEG C of cryopreservation.Normal esophageal mucous membrane control tissue, from the crowd participating in gastroscope health check-up, requires without malignant tumour medical history, and gastroscopy confirms without serious stomach, esophagel disease.
First stage chip primary dcreening operation adopts Illumina Human 450K chip, and subordinate phase adopts Maldi-Tof mass spectroscopy (ground substance assistant laser solution ionization time of flight mass spectrometry) to detect tissue and peripheral blood DNA methylates.Sequenom Photographing On-line software (https: //www.mysequenom.com/Tools) is adopted to design methylated primers.For the special primer of each CG site design multi-PRC reaction and single-basic extension extension primer used, consider influencing each other between the PCR primer size that the success ratio of single reaction and multiple reaction produce, choose best combination of primers.For the serum sample that dissociative DNA fragmentation is serious, then adopt multipair primer extension method.
2, result of study
2.1, chip primary dcreening operation
Analyze based on the P value in front 300 sites of chip detection and GO, KEGG and consider that it occurs simultaneously, obtaining 10 potential cancer suppressor genes and verify for the two-stage, as shown in table 5 below:
The abnormal methylation gene that table 5 cDNA microarray goes out
2.2 mass spectroscopy
Adopt the amplified production for 10 genes to comprise altogether 89 CG sites, compare the DNA methylation frequency of human esophageal carcinoma, patient with esophageal carcinoma blood plasma, normal esophageal tissue, as shown in table 6 below:
Table 6 specific gene CG site methylates the difference of frequency in human esophageal carcinoma, peripheral blood and normal control
Filter out 3 esophageal carcinoma suppressor genes correlation (CASZ1, CDH13 and ING2), using the biomarker of frequency as examination and diagnosis of esophageal that methylate in the specific CG site of these 3 genes, sensitivity and specific degree all can reach 100%, as shown in table 7 below:
Table 7 specific gene adds up the difference of frequency in human esophageal carcinoma, peripheral blood and normal control that methylates
The foregoing is only preferred embodiment of the present invention, not in order to limit the present invention, all any amendments done within the spirit and principles in the present invention, equivalent replacement and improvement etc., all should be included within protection scope of the present invention.
Claims (2)
1. the relevant biomarker that methylates of the esophageal carcinoma, is characterized in that, is biomarker by the specific CG site detected in CASZ1, CDH13 and ING2 esophageal carcinoma suppressor genes correlation frequency that methylates.
2. the be correlated with biomarker that methylates of the esophageal carcinoma according to claim 1 suffers from application in the esophageal carcinoma examination, anticipation, control person to be checked.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111534600A (en) * | 2020-06-18 | 2020-08-14 | 广州达健生物科技有限公司 | Esophagus cancer gene methylation detection primer probe combination, kit and application thereof |
| CN113388685A (en) * | 2021-08-08 | 2021-09-14 | 中国医学科学院肿瘤医院 | Methylation marker for diagnosing esophageal cancer |
| CN113403398A (en) * | 2021-08-08 | 2021-09-17 | 中国医学科学院肿瘤医院 | Esophageal cancer methylation prognosis markers and application thereof |
| CN113637754A (en) * | 2021-08-17 | 2021-11-12 | 武汉艾米森生命科技有限公司 | Application of biomarker in diagnosis of esophageal cancer |
| WO2022102742A1 (en) * | 2020-11-16 | 2022-05-19 | 国立大学法人京都大学 | Cell surface marker for high efficiency purification of skeletal muscle lineage cells and skeletal muscle stem cells, and use thereof |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111534600A (en) * | 2020-06-18 | 2020-08-14 | 广州达健生物科技有限公司 | Esophagus cancer gene methylation detection primer probe combination, kit and application thereof |
| WO2022102742A1 (en) * | 2020-11-16 | 2022-05-19 | 国立大学法人京都大学 | Cell surface marker for high efficiency purification of skeletal muscle lineage cells and skeletal muscle stem cells, and use thereof |
| CN113388685A (en) * | 2021-08-08 | 2021-09-14 | 中国医学科学院肿瘤医院 | Methylation marker for diagnosing esophageal cancer |
| CN113403398A (en) * | 2021-08-08 | 2021-09-17 | 中国医学科学院肿瘤医院 | Esophageal cancer methylation prognosis markers and application thereof |
| CN113403398B (en) * | 2021-08-08 | 2023-08-11 | 中国医学科学院肿瘤医院 | Esophageal cancer methylation prognosis markers and application thereof |
| CN113388685B (en) * | 2021-08-08 | 2023-10-31 | 中国医学科学院肿瘤医院 | Methylation markers for diagnosing esophageal cancer |
| CN113637754A (en) * | 2021-08-17 | 2021-11-12 | 武汉艾米森生命科技有限公司 | Application of biomarker in diagnosis of esophageal cancer |
| CN113637754B (en) * | 2021-08-17 | 2023-10-27 | 武汉艾米森生命科技有限公司 | Application of biomarker in diagnosis of esophageal cancer |
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Application publication date: 20150701 |