CN105316343B - The application of KCP gene mutations sequence, detection method and KCP gene mutations in distinguishing kidney stem cell - Google Patents
The application of KCP gene mutations sequence, detection method and KCP gene mutations in distinguishing kidney stem cell Download PDFInfo
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Abstract
Present invention employs the analyses of high-throughput unicellular exon sequencing technologies and stringent bioinformatics, it was found that 1 distinctive notable mutation in kidney stem cell is KCP genes.According to the specific mutations, a kind of method of detection KCP gene mutations is devised, and disclose method of the KCP detection in Gene Mutation for differentiating kidney stem cell.The diagnosis to kidney gene level, parting, establishing for therapy target is contributed to provide reference.
Description
Technical field
The application belongs to field of biological detection, and in particular to the identification and detection of kidney stem cell specific gene mutation,
And application of the mutation in distinguishing kidney stem cell.
Background technology
Currently, finding that the specific gene mutation in specific tumors has been used for the diagnosis of tumour using gene sequencing technology
It is disclosed by the prior art, such as application No. is 201410213970 to be related to gene STAG2 gene mutation sequences, and the STAG2 is prominent
The application of change and its detection method in detecting carcinoma of urinary bladder；Application No. is 201410255625 applications for a patent for invention to be then related to using
In the ERBB signal paths mutation targeting sequencing approach of gall-bladder prognosis evaluation；Application No. is 201410274543 to disclose profit
With mankind's BRAF gene mutation detection primer and probe and its kit.
Clear-cell carcinoma is the highest tumor type of lethality in Patients with Urinary System Tumors.It is extensive with second generation sequencing technologies
Using the result of high-flux sequence discloses, the proteolysis approach (UMPP) caused by the high frequency mutation of vhl gene
The high frequency of inactivation and PBRM1 genes is mutated the disorder that mediated chromatin is adjusted, and jointly promotes the generation of nephrocyte.So
And the mutation for being responsible for the gene level of kidney transfer and drug resistant kidney stem cell is not reported so far.
KCP (kielin/chordin-like protein) is one group of encoding gene in human genome, outer by 48
Aobvious son composition, is located at CR7q32.1.Rich region containing 18 cysteines.KCP can enhance (the bone of BMP mediations
Morphogenetic proteins) signal path.KCP plays an important role in injury of kidney, and the missing of KCP easily causes kidney fibre
Dimensionization.
Invention content
The present invention designs and invents a kind of method of detection KCP gene mutations, and discloses KCP detection in Gene Mutation and be used for
Differentiate the method for kidney stem cell.
In order to explore distinctive mutation in kidney stem cell, we have carried out unicellular disappear to the tumour of a row patients with renal cell carcinoma
Change, airflow classification, the tumor stem cell of sorting acquisition and non-tumor stem cell combination cancer beside organism have then been subjected to list together
Cellular exons are sequenced.Pass through the Exact Analysis of bioinformatics, it was found that 1 distinctive notable mutation.
By obtaining renal cancer tumor sample, peripheral blood or normal control tissue to the patient newly diagnosed, kidney cancer cell is chosen
Purity be more than 85% tissue for DNA extract and be sequenced.Using unicellular flow-sorting methods, sub-elect kidney stem cell and
Non-stem cell.DNA extractions and amplification are carried out to single celled genome using Single Cell Kit, and build DNA library.
Full exon group sequence is captured using SureSelect Human All Exon 50Mb Kit, Illumina companies
HiSeq2000 platforms carry out full sequencing of extron group.Then the full exon group somatic mutation detection of row kidney stem cell, uses
Sanger is sequenced to verify somatic mutation (Fig. 2).The gene being only mutated in kidney stem cell is filtered out, including KCP
Gene.Present invention employs the analyses of high-throughput unicellular exon sequencing technologies and stringent bioinformatics, it was found that kidney
1 distinctive notable mutation (Fig. 3) in cancer stem cell.The beneficial effects of the present invention are devise a kind of detection KCP genes
The method of mutation, and disclose method of the KCP detection in Gene Mutation for differentiating kidney stem cell.Contribute to kidney gene water
The establishment of flat diagnosis, parting, therapy target provides reference.
Description of the drawings
Fig. 1：The general technical route map that technical scheme is implemented；
Fig. 2：Kidney exons mutation spectrogram；
Fig. 3：The peculiar mutator of kidney stem cell；
Fig. 4：PCR fragment sequencing result shows the mutational site of KCP genes；
Fig. 5：The relationship of follow-up experimental verification KCP mutation and patient's life cycle.
Specific implementation mode
1 material of embodiment and instrument
It is prominent to KCP genes of the present invention below in conjunction with specific test examples in order to make technical scheme of the present invention be easy to understand
Become sequence, detection method and KCP gene mutations detecting and differentiating that the application in kidney stem cell is further described.
The operating method of total Test is operated according to the specification of instrument.
1) reagent and instrument
SureSelect Human All Exon50Mb Kit
TruSeq RNA sample reagent preparations box (Illumina companies)
Single Cell Kit (Qiagen companies)
Dual96‐well GeneAmp PCR System9700(Applied Biosystems)
3730x1DNA analyzers (Applied Biosystems)
EpiTect Bisulfite Kit(Qiagen,Hilden,Germany)
HotStar Taq archaeal dna polymerases (Qiagen, Hilden, Germany)
ABI StepOne(Applied Biosystems)
SYBR Premix Ex TaqTMII (TAKARA) reagent
GeneAmp PCR System9700thermal cycler(Life Technologies)。
2) material
By the Chinese member mechanism of genitourinary cancers genome alliance (UCGC), obtained from the patient newly diagnosed
Take renal cancer tumor sample and matched peripheral blood or normal control tissue (adjacent morphologically normal nephridial tissue).According to human relations
System as defined in examination board is managed, patient endorsed informed consent form before recruitment is studied.The detailed clinic of patient
Data.All samples are stored in liquid nitrogen flash freezer and immediately -80 DEG C for further studying after collection.One Yihong of hematoxylin
(HE) stained slice is independently assessed under the microscope by two pathologists.In our current research, we only have chosen
Kidney cancer cell purity be more than 85% tissue for DNA extraction and subsequent sequencing.
The selection criteria of sample:All patients are in the preoperative without radiotherapy or chemotherapy；Sample tissue is all flesh tissue, is cut
It is put into tissue preserration liquid in 30 minutes after lower, and in 4 DEG C of refrigerated overnights, thereafter -80 DEG C of low-temperature storages；It is dyed through HE, tumour
Cell is more than 80% tumor tissues and negative for tumor cells pollution normal kidney tissue.
2 tissue digestion of embodiment and unicellular airflow classification
For tumour and normal sample, -80 DEG C are saved in first with sterile 1640 elution 3 times, 1/6,1/6 be saved in it is more
Polyformaldehyde is fixed, and remainder 2/3 is subtracted broken with sterile scissors, subtracts broken tissue block using the clostridiopetidase A IV resuspension of 12ml-0.15%, together
When be added 200ul it is dual anti-, 2mlFBS.37 DEG C of digestion 2h.
The tissue digested is resuspended with 1ml rifles, being added to the online filtering of solarization of 300 mesh becomes single cell suspension.Cell is hanged
Liquid is added in 50ml centrifuge tubes, is added in 10ml 10%FBS culture mediums and clostridiopetidase A, and then 2.5*103rpm/min is centrifuged
5min.Supernatant is abandoned, PBS is resuspended cell, washed once.2.5*103rpm/min centrifuges 5min.
Achromophil blank control cell is reserved, antibody response liquid, CD1331 are then first configured:200 dilution CD45,
CD311:Tumour and normal structure is resuspended with the sterile antibody diluent prepared in 200 dilutions, the 1h of shaking reaction on ice.2.5*
103rpm/min is centrifuged, and 5min collects cell, and PBS resuspensions washed once, and 2.5*103rpm/min, centrifugation 5min collects cell.
Cell is resuspended in 1ml serum free mediums, prepares flow cytometer detection and sorting.For tumor sample, sort respectively the CD133 positives and
In the kidney stem cell and kidney non-stem cell to 96 orifice plates of CD133 feminine genders, each hole setting 1 cell of sorting.For normal
Kidney cancer cell, sort the cell of CD45 and CD31 feminine gender to 96 orifice plates, same each hole setting sorts 1 cell.After sorting
Cell be placed in dry ice immediately, freeze at -20 DEG C overnight.
The extraction and sequencing of 3 unicellular genomic DNA of embodiment
DNA extractions and amplification are carried out to single celled genome using Single Cell Kit, and build DNA library.
According to the experiment flow that Agilent Technologies specifications provide, using SureSelect Human All
Exon 50Mb Kit capture full exon group sequence.Microarray dataset used in full sequencing of extron group is Illumina public affairs
The HiSeq2000 platforms of department, sequencing mode are double end sequencings, sequencing reading length 100bp.Finally three kinds of cell types are distinguished
10 cells are sequenced, cell category and number are shown in Table 1.
Table 1
The full exon group somatic mutation detection of 4 kidney stem cell of embodiment
After removing the low quality sequence containing sequence measuring joints and comprising five or more unknown bases, we are soft using BWA
Filtered comparing to ginseng is examined genome (b37), and is counted to comparison result by part.Comparison rate is not less than
96%, mean depth all covers 74% or more in 130X or more, coverage in 91% or more, 10X.
Using the Data Detection snp information of GATK pairs of 30 cells, and timing is being done, is using two samples of 3N and 3T
The mixed data set of snp does soft filtering, removes the sites false positive snp, and obtained snp results are it is considered that be reliable snp knots
Fruit.
Use the unicellular snp results after correction.For the result of 20 tumour cells, it is believed that not less than two
Snp present in cell is relatively reliable, is used in combination these results to filter out snp present in not less than two normal cells, and just
Snp present in normal line and staff control.As the somatic mutation of this tumour cell, (concrete outcome is shown in figure to final remaining snp
2)。
Embodiment 5 is sequenced to verify somatic mutation using Sanger
For the gene mutation of sequencing out, we devise the primer of DNA profiling, in each single celled DNA level
To verify the accuracy of sequencing.By verification, verification rate is 186/192=96.35%.
Kidney genescreen known to embodiment 6
Each cancer kind related gene of the discovery of countries in the world research institution is preserved in ICGC databases.By these information
It is captured from database.Including mutator (being shown in Table 2, KCNA3, MUC4 and CSMD3) known to three kidneys.
Table 2
The 7 peculiar mutation of kidney stem cell of embodiment
Those genes being only mutated in kidney stem cell are screened, and calculate the conspicuousness of mutation.Obtain following gene.
KCP is just among them (concrete outcome is shown in Fig. 3).
The discriminating that KCP is mutated in 8 kidney stem cell of embodiment
For the position of KCP being mutated in the genome：chr7:128547482T<A
KCP‐F：GACAGCAGTGTCACTCAAGC
KCP‐R：CTTTCTCATCCTGCCTCATT
Reaction condition：95 DEG C of 5min, 40 cycles, cycle are internal：95℃30s,60℃30s,72℃30s.Extend 72 DEG C
10min.Primer size 364bp.
Company is sent to be sequenced amplified production link cloning vector selection positive colony, sequencing result is as shown in figure 4, i.e. KCP
The base T mutation in 128547482 sites on gene become A)
Ratio of the embodiment 9KCP gene mutations in kidney case
To 57 tissue digestion and unicellular stream are carried out without the clinical Operated Specimens of chemotherapy or the patients with renal cell carcinoma of radiotherapy
Formula sorts, and obtains kidney stem cell.The genome of kidney stem cell and sequencing are extracted, sequencing result examines genome progress with ginseng
Statistics is compared, it is found that KCP mutates in the kidney stem cell of 13 patients, mutation rate 22.8%.
Table 3
The relationship of embodiment 10KCP mutation and patient's life cycle
It is tested and is found by follow-up, patient's Sulfurless fixative of kidney stem cell KCP mutation is 7-22 months, and middle position is without tumor
Life cycle is 14.5 months, and kidney stem cell is 15-26 months without patient's Sulfurless fixative that KCP is mutated, and middle position is survived without tumor
Phase is 20.5 months.There are the patients with renal cell carcinoma Sulfurless fixatives of KCP mutation to be obviously shortened, and is more easy to compared with no KCP mutation patients with renal cell carcinoma multiple
It sends out (specifically referring to Fig. 5).Assessment to prognosis of patients with renal cell carcinoma recurrence is contributed to the detection of KCP.
<110>Lee's Chong
<120>KCP gene mutations sequence, detection method and KCP gene mutations answering in distinguishing kidney stem cell
With
<160> 2
<170> PatentIn version 3.5
<210> 1
<211> 20
<212> DNA
<213>It is artificial synthesized
<400> 1
GACAGCAGTG TCACTCAAGC 20
<210> 1
<211> 20
<212> DNA
<213>It is artificial synthesized
<400> 1
CTTTCTCATC CTGCCTCATT 20
Claims (3)
1. a kind of KCP (kielin/chordin-like protein) mutator, which is characterized in that the KCP bases with wild type
Because comparing, chr7 is sported:128547482T<A.
2. the primer of one group of amplification KCP mutators described in claim 1, which is characterized in that upstream primer sequence is：5’-
GACAGCAGTGTCACTCAAGC-3 ', downstream primer sequence 5 '-CTTTCTCATCCTGCCTCATT-3 '.
3. the primer described in mutator described in claim 1 or claim 2 is used to prepare detection kidney prognosis recurrence examination
Purposes in agent box.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2003089659A1 (en) * | 2002-04-16 | 2003-10-30 | The Regents Of The University Of California | Methods or renal cell carcinoma prognosis and treatment selection with carbonic anhydrase ix |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2003089659A1 (en) * | 2002-04-16 | 2003-10-30 | The Regents Of The University Of California | Methods or renal cell carcinoma prognosis and treatment selection with carbonic anhydrase ix |
Non-Patent Citations (2)
| Title |
|---|
| Kielin/Chordin-Like Protein Attenuates both Acute and Chronic Renal Injury;Abdul Soofi, et al.;《Journal of the American Society of Nephrology Jasn》;20131231;第24卷;第897-905页 * |
| Single-Cell Exome Sequencing Reveals Single-Nucleotide Mutation Characteristics of a Kidney Tumor;Xun Xu, et al.;《Cell》;20120302;第148卷;第886-895页 * |
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