CN106018640A - Method for rapid screening and identification of tumor biomarkers and application - Google Patents
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Abstract
The invention provides a HPLC-TOF-MSMS based metabolomic method for rapid screening and identification of tumor biomarkers and application. The specific steps include: collection and pretreatment of biological samples from tumor patients and normal people; acquisition of the biological samples' HPLC-TOF-MS and HPLC-TOF-MSMS data; HPLC-TOF-MS data processing, multivariate statistical analysis and differential metabolite screening; HPLC-TOF-MSMS data processing and differential metabolite identification; SPSS analysis for further confirmation of a group of differential compounds as tumor biomarkers; and quantitative analysis of the tumor biomarkers. The invention provides a method for rapid screening and identification of tumor biomarkers, the method has the advantages of short time and high accuracy, etc., is not only suitable for screening and identification of tumor patients' biomarkers, but is also suitable for screening and identification of the biomarkers of other metabolic diseases, like diabetes, uremia and depression, etc.
Description
Technical field
The present invention relates to life sciences and analytical chemistry field, be specifically related to a kind of based on HPLC-TOF-MS and HPLC-
The metabolism group method of TOF-MSMS is for rapid screening, qualification tumor biomarker and application thereof.
Background technology
Tumor (Tumor), especially malignant tumor, have a strong impact on the health of the mankind and threatened the life of the mankind.
Within 2014, tumor registration annual report shows, it is 22% that people suffers from the probability of malignant tumor in life.National malignant tumor sickness rate is
235.23/10 ten thousand (male 268.65/10 ten thousand, and women 200.21/10 ten thousand), Chinese population standardized rate (win bit rate) 184.58/10
Ten thousand.City acceptance of the bid sickness rate 187.53/10 ten thousand；Rural area acceptance of the bid sickness rate 181.10/10 ten thousand.National malignant tumor mortality rate
It is 148.81/10 ten thousand (male 186.37/10 ten thousand, and women 109.42/10 ten thousand), win bit rate 113.92/10 ten thousand.City acceptance of the bid death
Rate 109.21/10 ten thousand；Rural area acceptance of the bid mortality rate 119.00/10 ten thousand.Pulmonary carcinoma, women with breast cancer, gastric cancer, hepatocarcinoma, the esophageal carcinoma, knot are straight
Intestinal cancer, cervical cancer are the malignant tumor that China is common, and worldwide, the M & M of malignant tumor goes out to present
Cumulative year after year trend, and surmounted cardiovascular and cerebrovascular disease in 2010 and become the rank the first disease of position of whole world mortality rate and kill
Hands.Speculate that the year two thousand twenty malignant tumor increases number of the infected newly and is up to about 16,000,000 according to World Health Organization (WHO), relative to
The newly-increased number of the infected of 2000 10000000 will have the increase of more than 50%.Malignant tumor has become a global publilc health
Problem, so the research carrying out malignant tumor is compeled at the tip of the brow.
The early diagnosis of tumor is one of effective way improving its Overall survival, so can use in the urgent need to novel strategy
In the biomarker of screening early diagnosis of tumor and molecular diagnosis is converted to clinical practice from experimentation.But, pernicious
Tumor is a kind of multifactor participation, causes the complex disease of body each systemic-function Balance disorders, in generation and the development of tumor
During, each component of body can produce the disorder influencing each other, interacting in structure, function and form, the metabolism of body
Product can occur corresponding dynamically change therewith.The generation of the tumour-specific metabolite cover all kinds biomolecule reported
Thank, such as carbohydrate metabolism, lipid metabolism, amino acid metabolism, nucleotide metabolism etc..Research shows, relative to normal cell, tumor cell goes out
Modern times thank to the change of spectrum, glucose absorption rate increases and strengthens with glycolysis, and synthetic DNA polymerase and rna polymerase activity are the most relatively
Normal structure is high, and protein anabolism and catabolism all strengthen, and anabolism exceedes catabolism, even just can capture
The often protein breakdown products of tissue, the protein that synthesis tumor itself needs, cause body to be in cachectic states.Tumor is thin
Born of the same parents' not only metabolism is vigorous, and the generation of tumor and development also be unable to do without microenvironment about, and the surrounding that tumor growth is depended on for existence is micro-
Environment is mainly some key metabolites, such as glucose, nutrient and the vegetative growth factor.Near tumor cells is acyclic acidic
Border, the reason constituting this environment is that tumor cell carries out glycolysis under aerobic conditions, produces substantial amounts of lactic acid, meanwhile, tumor
Cell peripheral environmental induction vascular endothelial cell growth factor (VEGF) great expression, the blood capillary formation that VEGF induction is new, for
Tumor brings more nutrition, promotes that it grows.Visible, tumor occurs and the early stage of development changes closely related with metabolism network.
Organism metabolism product is present in the body fluid such as tissue, blood, urine, saliva, carries out the metabolite composition of these biological specimens
Detection and analysis, it may be appreciated that malignant tumor occurs and material adjoint in evolution changes and energy variation, and finds pernicious
Tumor occurs and abnormal metabolism thing in evolution, and is applied to the early diagnosis of malignant tumor.
Existing early diagnosis of tumor associated biomarkers is mainly based on gene, protein matter.Genomics and
Proteomics is respectively from gene and the mechanism of protein layer viewpoint tumor, and the most intracellular many activities are all sent out
Raw in metabolism aspect.Along with group learns progressively going deep into of research, researcher is gradually recognized, the change of genome not necessarily can obtain
To expressing, system is not produced impact.The concentration of some albumen can raise due to the change of external condition, but due to this egg
Bai Keneng does not possess activity, thus system is not produced impact.The disappearance of certain gene or albumen can be by other genes or egg
White existence and be compensated, the net result of final reaction is zero.The metabolite of little molecule is only this sequence of events
Termination fruit, it can reflect the state of living things system more accurately.Globality that metabolism group is had, can be quantitative and can be pre-
Survey Journal of Sex Research and demonstrate big advantage, from the dynamic metabolic pathway of body, occur to malignant tumor and each stage of development is equal
There is an applications well prospect, especially contribute to the biomarker of early diagnosis of tumor and tumor pattern classification and pathology divides in screening
Significant advantage is had in type.
Summary of the invention
Goal of the invention
It is an object of the invention to set up a kind of metabolism group method based on HPLC-TOF-MSMS for knubble biological mark
Remember the screening of thing, identify and apply, have an advantage in that by the biological specimen of high-volume tumour patient and normal person is carried out
HPLC-TOF-MS and HPLC-TOF-MSMS analyzes, in conjunction with multivariate statistical analysis for the screening of tumor biomarker and mirror
Fixed.
Technical scheme
For achieving the above object, the technical solution used in the present invention is as follows.
1, the biological specimen of the tumour patient and normal person that carry out metabonomic analysis in advance is grouped.To the sample often organized
This carries out merging in equal-volume pipettes (or etc. quality weigh) and organizes respectively, and the most often group sample at least takes plural single
Biological specimen merges, and is often organized the merging sample of sample, and merging sample equal-volume (quality) of each group is mixed,
To quality control sample.And according to analysis purpose, each sample and merging sample are carried out metabolite extraction (as tissue samples uses
Chloroform/methanol/aqueous systems or methanol/water system are extracted；Plasma/serum sample takes methanol or acetonitrile system precipitation egg
In vain；Saliva, urine are directly centrifuged) obtain being available for the sample of HPLC-TOF-MS and HPLC-TOF-MSMS analysis sample introduction.Utilize
The biological specimen of tumour patient and normal person is acquired by HPLC-TOF-MS, for multivariate statistical analysis.
2, utilize HPLC-TOF-MSMS that the biological specimen of tumour patient and normal person is acquired, for screening
Difference metabolite is identified.The standard substance bought are carried out HPLC-TOF-MS and HPLC-TOF-MSMS to analyze for right simultaneously
Difference metabolite carries out qualitative and quantitative analysis.
3, the initial data gathering HPLC-TOF-MS utilizes MassHun ter Quantitative Analysis to enter
The automatic blob detection of row and chromatographic deconvolution, derive the CSV. file arranged with relative molecular mass, retention time and peak height three, according to
Packed compressed for be uploaded to after ZIP. file metabolism group online treatment software MetaboAnalyst 3.0 (http: //
Www.metaboanalyst.ca/MetaboAnalyst/) carry out peak alignment, filter is made an uproar and standardization.
4, the file after MetaboAnalyst 3.0 standardization utilizes SIMCA-P software to carry out principal component analysis
(principal component analysis, PCA) and orthogonal partial least squares discriminant analysis (orthogonal
Projection on latent structures discriminant analysi s, OPLS-DA).Utilize in PLS-DA
VIP value size screening difference metabolite.
5, the authentication method of difference metabolite is: (1) utilizes HPLC-TOF-MSMS second order ms fragment to combine Human
Metabolome Database (http://www.hmdb.ca/) and METLIN (https: //metlin.scripps.edu/
Index.php) the second order ms fragment ion in is compared.(2) the one-level fragment of combined standard product, secondary ion fragment and
Retention time carries out qualitative analysis to difference metabolite.
6, SPSS is utilized to analyze the difference metabolite identified, further screening tumor biomarker and ROC
(receiver operating characteri st ic curve is called for short ROC curve) is analyzed.
7, the quantitative analysis of tumor biomarker.
Beneficial effect
The method by carrying out first mass spectrometric and second mass analysis combines existing online, off-line and divides to large number of biological specimen
Analysis software also combines existing network data base, screens and identify difference metabolite, utilizes the SPSS software difference to screening simultaneously
Metabolite is analyzed to identify tumor biomarker further, and the data cycle is short, detection range width, method favorable reproducibility to have process
Etc. advantage, it is suitable for tumor or the screening of other metabolism class disease biomarker and qualification.
Accompanying drawing explanation
Fig. 1 metabolism group based on HPLC-TOF-MSMS methods analyst flow chart；
The BPC figure of the HPLC-TOF-MS of Fig. 2 tumour patient and normal person；
Fig. 3 tumour patient and the 3D-PCA of normal person；
Fig. 4 tumour patient and the 3D-PLS-DA of normal person；
The VIP figure of the PLS-DA of Fig. 5 tumour patient and normal person；
The BPC figure of Fig. 6 uracil and two kinds of standard of physical product of pseudouracil；
Isomers in differentiation compound is identified (as a example by uracil and pseudouracil by Fig. 7 based on standard substance；
Upper figure is first mass spectrometric, and figure below is second order ms)；
Differentiation compound is identified and (with glycine betaine is by Fig. 8 second order ms based on HPLC-TOF-MSMS fragment ion
Example, upper figure is first mass spectrometric, and figure below is second order ms)；
Fig. 9 SPSS analysis process；
Figure 10 ROC curve.
Detailed description of the invention
A kind of metabolism group method based on HPLC-TOF-MSMS for tumour patient urine biology marker screening,
Identify and application comprises the following steps.
1, the collection of sample
Collect tumour patient and normal person stage casing urina sanguinis 10mL, 1O centrifuge tube of subpackage, each centrifuge tube 1mL ,-80 DEG C of guarantors
Deposit.
2, the pretreatment of sample
Taking-80 DEG C of urine sample 1mL thaw at RT preserved, 10000-15000r/min is centrifuged 1O-20min, takes supernatant
0.6mL, controlling Fmoc-glycine concentration in urine is 1 μm ol/L, is HPLC-TOF-MS and HPLC-TOF-MSMS sample.
Quality control samples is prepared according to the control method of above-mentioned Quality control samples.Tumour patient and normal person biological specimen 50-
60% is used for setting up multivariate statistical analysis model, screening differentiation compound and biomarker as training set, and 20-25% makees
For checking collection for that optimize multivariate statistical analysis model and biomarker, the sample of 20-25% as test set to swollen
The susceptiveness of tumor biomarker, specificity detect.
3, the HPLC-TOF-MS of sample gathers
Flowing phase: A=O.1% formic acid water, B=O.1% formic acid acetonitrile, elution requirement: 0-6min, 5-10%B；6-
11min, 10-20%B；11-12min, 20%-100%B；12-18min, 100%B.Chromatographic column is Inertsil ODS-3C18
Post, its a size of 250mm × 4.6mm, i.d.5 μm, sampling volume 10 μ L, column temperature 25 DEG C, flow velocity 1mL/min.Mass spectrum yin, yang from
Subpattern condition: nitrogen is used as to be dried gas, nitrogen temperature 325 DEG C, flow velocity 12L/min, atomization air pressure 35psi；Capillary voltage:
Cation 4000V, anion 3500V；Fragmentation voltage: 100V；Separator voltage 60V；Quality acquisition range: zwitterion pattern
It is 0.05-1KDa.
4, the HPLC-TOF-MSMS of sample gathers
The same HPLC-TOF-MS of HPLC and MS condition.MSMS applied voltage is 20V.
5, the process of HPLC-TOF-MS data
Original HPLC-TOF-MS data separate MassHunter Quan ti tative Analysis carries out the inspection of automatic peak
Survey and chromatographic deconvolution, extract absolute peak tall and big in 10000, derive and arrange with relative molecular mass, retention time, peak height three
CSV. file, tumour patient and normal person are respectively put into two files, both of these documents are clamped and are condensed to ZIP. files passe
Carrying out peak alignment to online MetahoAnalyst 3.0, filter and make an uproar and standardization, wherein mass deviation 0.01Da, during reservation
Between deviation 0.5min, data filtering mode be Interquantile range (IQR), Data scaling mode be Pareto
Scaling, obtains the standardized data of HPLC-TOF-MS.
6, HPLC-TOF-MS data metabonomic analysis and the screening of difference metabolite
The standardized data of HPLC-TOF-MS is uploaded to SIMCA-P12.0 and carries out PCA and PLS-DA analysis, PCA and PSL-
DA all uses first three main constituent to be analyzed.The result of PCA and PLS-DA such as accompanying drawing.The size of the VIP value of PLS-DA is used for
Evaluate the size of metabolite difference, it is considered that the compound of VIP >=2 is taken as difference metabolite.
7, difference metabolite is identified by second order ms fragment based on HPLC-TOF-MSMS and retention time.Citing
As follows
1. the qualification of isomerss based on standard substance, as a example by uracil and pseudouracil, pseudouracil go out peak
Time is 3.7min, and the appearance time of uracil is 5.3min, although the mass spectrographic fragment ion of its one-level is the same, but its two grades
Mass spectrographic fragment ion is different.
2. identify based on HPLC-MSMS second order ms fragment ion, as a example by valine and glycine betaine, valine and
The relative molecular mass of glycine betaine is 117.079, and under cation mode, its one-level mass ions fragment is 118.0863, but
It is to be by the second order ms fragment ion of inquiry Human Metabo lome Database and METLIN discovery valine
55.0547,57.0576,59.0503 and 72.0581 (second order ms voltage 20V), and the second order ms fragment ion of glycine betaine
It is 58.0660 and 59.0703 (second order ms voltage 20V), finds to go out peak at 2.87min by comparison second order ms fragment ion
First mass spectrometric fragment ion be the compound of 118.0863 be glycine betaine rather than valine.
8, the SPSS of difference metabolite analyzes and is used for confirming that tumor biomarker and ROC analyze.Comprise the steps:
1. two independent sample T inspection: the difference metabolite identified above is carried out the most respectively T inspection, judges each one by one
Material between two groups of biological specimens average whether there were significant differences；
2. binomial logistic regression analysis: the above average difference metabolite that there were significant differences is carried out binomial in the lump
Logistic regression analysis, by introduce forward method, backward scalping method or backward step by step filter method carry out independent variable screening, it is thus achieved that
One group of tumor biomarker, obtains the recurrence side of disease pathogenetic logistic prediction optimal models according to regression coefficient (B)
Journey；
3. Receiver operating curve (ROC) analyzes.Logistic (P) value obtained with above-mentioned regression equation is drawn and is subject to
Examination person's performance curve, the transverse and longitudinal coordinate of ROC curve represents specificity and sensitivity, the effective ROC of this inspection respectively
Its area under curve of curve (area under curve, be called for short AUC) should between 0.5-1.0, this inspection of the biggest explanation of AUC
Diagnostic is the biggest.Optimal marginal value is the most permanent by means of " outstanding mounting index ", i.e. sensitivity+specificity-1, and this index takes
Point corresponding during big value is exactly best cut point, utilize the coordinate figure of above-mentioned ROC curve can try to achieve the sensitivity of each coordinate points+
Specificity-1, the point that its maximum is corresponding is exactly optimal marginal value point.The biomarker of confirmation is bent to utilize above method to draw
Under line, area is more than 90%, and the diagnostic of the biomarker illustrating to utilize above method to be screened is higher.
9, the quantitative analysis of biomarker.Specifically comprise the following steps that
1. the preparation of variable concentrations biomarker solution；
2. HPLC-TOF-MS and HPLC-TOF-MSMS of variable concentrations standard substance gathers；
3. the standard curve of biomarker is set up according to the mass spectrographic peak height of HPLC-TOF-MS, simultaneously to its stability, essence
Density, average recovery, detection line, quantitative limit are analyzed.As we detect the standard curve of a kind of biomarker
For y=4634.5x, (with a height of vertical coordinate of mass spectra peak, with the concentration of every kind of nucleosides material as abscissa, correlation coefficient is
0.9902), detection be limited to 0.114692929 μM, be quantitatively limited to 0.382309763 μM, precision O.58%, stability
6.23%, average recovery is 95.0%.
Claims (8)
1. tumour patient and normal person's biological sample difference screening compound, qualification comprise the steps:
A () tumour patient and the collection of normal person's biological specimen, pretreatment obtain HPLC-TOF-MS and HPLC-TOF-MSMS sample
Product；
HIPLC-TOF-MS collection, multivariate statistical analysis and the differentiation compound of (b) tumour patient and normal person's biological specimen
Screening；
C the HPLC-TOF-MSMS of () tumour patient and normal person's biological specimen gathers, analyzes and the qualification of differentiation compound；
The step that 2.SPSS screens tumor biomarker further is as follows:
A the T inspection of () tumour patient and normal person's biological specimen differentiation compound two independent sample, for screening at two groups of samples
Between distribution of mean value there is the differentiation compound of significant difference；
B the average difference metabolite that there were significant differences between above group is carried out binomial logistic regression analysis by () in the lump, pass through
Introduce forward method, backward scalping method or backward step by step filter method carry out independent variable screening, it is thus achieved that one group of tumor biomarker,
To regression coefficient (B), and thus obtain the regression equation of disease pathogenetic logistic prediction optimal models；
C () draws the ROC curve of one group of tumor biomarker according to logistic (P) value, calculate AUC and according to " especially stepping on
Index " determine optimal marginal value.
3. utilize standard substance, by Criterion curve, tumor biomarker carried out quantitative analysis, determine tumour patient and
The absolute content of this material in normal person's biological specimen.
4. the 50-60% of tumour patient and normal person's biological specimen as training set be used for setting up multivariate statistical analysis model,
Screening differentiation compound and biomarker, 20-25% as checking collection for that optimize multivariate statistical analysis model and raw
Substance markers thing, susceptiveness, the specificity of tumor biomarker are detected by the sample of 20-25% as test set.
5. the biological specimen in claim 1 can be tissue, blood, urine or saliva, with Fmoc-glycine as internal standard, is inside marked on
Final concentration in sample controls in 1-10 μm ol/L.
6. the HPLC-TOF-MS data in claim 1 combine Metaboanalyst and SIMCA-P carry out peak alignment, filter make an uproar,
Utilizing the VIP of PLS-DA to screen difference metabolite after standardization, its HPLC-TOF-MS condition is as follows:
(a) HPLC condition: flowing phase: A=0.1% formic acid water, B=0.1% formic acid acetonitrile, elution requirement: 0-6min, 5-10%
B；6-11min, 10-20%B；11-12min, 20%-100%B；12-18min, 100%B；
(b) Mass Spectrometry Conditions: nitrogen is used as to be dried gas, nitrogen temperature 325 DEG C, flow velocity 12L/min, atomization air pressure 35psi；Capillary tube
Voltage: cation 4000V, anion 3500V；Fragmentation voltage: 100V；Separator voltage 65V；Quality acquisition range: negative and positive from
Subpattern is 0.05-1KDa.
7. the HPLC-TOF-MSMS data in claim 1 are for the qualification of difference metabolite, and HPLC-TOF-MSMS condition is such as
Under: second order ms applied voltage is 10V, 20V or 30V；It is 0.03-1KDa that second order ms gathers fragment ion.
8. this method is not only suitable for the screening of tumor biomarker, qualification, is also suitable for other metabolism class disease simultaneously
The screening of biomarker, qualification, such as diabetes, uremia, depression etc..
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| CN110850072A (en) * | 2019-11-08 | 2020-02-28 | 郑州大学第一附属医院 | Screening method and application of liver cancer anion marker |
| CN115985497A (en) * | 2022-12-16 | 2023-04-18 | 首都医科大学附属北京地坛医院 | System for predicting prognosis of non-operation treatment primary liver cancer patient mainly based on platelet/spleen major-diameter ratio |
| CN115985497B (en) * | 2022-12-16 | 2023-08-08 | 首都医科大学附属北京地坛医院 | System for predicting prognosis of patient with non-operative treatment primary liver cancer based on platelet/spleen aspect ratio value |
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