CN107589263A - A kind of small molecule mark for indicating lung cancer lymphatic metastasis and the application in terms of diagnosis - Google Patents
A kind of small molecule mark for indicating lung cancer lymphatic metastasis and the application in terms of diagnosis Download PDFInfo
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Abstract
The invention discloses a kind of small molecule mark for indicating lung cancer lymphatic metastasis and the application in terms of diagnosis, a kind of composition for being used to indicate lung cancer lymphatic metastasis is disclosed, including at least phosphatidylinositols (18:3/0:0)；Preferably, said composition includes phosphatidylinositols (18:3/0:0), lysophosphatidyl choline (18:And phenylalanine 1).Phosphatidylinositols (18:3/0:0) the single AUC for diagnosing lymphatic metastasis and the non-lymphatic metastasis of lung cancer is 0.803, has medium accuracy；Serum paraoxonase acyl inositol (18:3/0:0), lysophosphatidyl choline (18:1) and phenylalanine to combine for the AUC of diagnosing lymphatic metastasis and the non-lymphatic metastasis of lung cancer be 0.937, there is higher accuracy, the sensitivity and specificity at excellent diagnostics critical value are more than 0.9.Serum paraoxonase acyl inositol (18 is proved in the further checking that independent sample is concentrated:3/0:0), lysophosphatidyl choline (18:1) combine with phenylalanine and be up to 95% for the degree of accuracy of diagnosing lymphatic metastasis and the non-lymphatic metastasis of lung cancer, there is higher clinical value.
Description
Technical field
The invention belongs to accurate diagnostic field, it is related to diagnosis marker and diagnostic kit, and in particular to one kind indication lung
The small molecule mark of cancer lymphatic metastasis and the application in terms of diagnosis.
Background technology
Lung cancer is a kind of common malignant tumour, and its morbidity and mortality is occupied first of various malignant tumours, and is in hold
Continuous ascendant trend.Advanced lung cancer may occur in which the transfer of each different organs, can cause corresponding symptom, usually bring pole to patient
Big pain, or even threaten life.Wherein, lung cancer lymphatic metastasis is most commonly seen.The invisible pole of lung cancer lymphatic metastasis
By force, golden hour window has been missed when being made a definite diagnosis by pathological diagnosis without any sign in early days.
The goldstandard that lung cancer lymphatic metastasis is made a definite diagnosis is pathological examination, and this method specificity is high, but with traumatic, no
It is easy for patients to accept, and certain difficulty be present in materials.Imageological examination is that current lung cancer diagnosing lymph node metastatsis relies primarily on
Means, but cost is high, and minimal disease is not easy to detect, it is impossible to meet the requirement of lung cancer lymphatic metastasis early diagnosis.
The exception of blood serum tumor markers is easy to detect often earlier than the exception of iconography, and repeatability is strong, and expense is low,
May all have prompting meaning for the exception without clinically relevant patient with sympotoms, any one mark.Therefore, applicant is intended to
Find the mark that can be used for indicating lung cancer lymphatic metastasis.
The content of the invention
It is an object of the invention to provide a kind of small molecule mark for indicating lung cancer lymphatic metastasis and in terms of diagnosis
Application.
Above-mentioned purpose of the present invention technical scheme is that：
Phosphatidylinositols (18:3/0:0), lysophosphatidyl choline (18:1) or phenylalanine is used to indicate lung cancer lymph node
The clinical application of transfer.
A kind of composition for being used to indicate lung cancer lymphatic metastasis, including at least phosphatidylinositols (18:3/0:0).
Preferably, described composition includes phosphatidylinositols (18:3/0:0), lysophosphatidyl choline (18:And benzene 1)
Alanine.
It is highly preferred that described composition also includes internal standard L-2- chlorophenylalanines.
Application of any of the above-described composition in terms of the diagnostic kit of indication lung cancer lymphatic metastasis is prepared.
Beneficial effects of the present invention：
In ROC curve analysis, area is bigger under ROC curve, and its diagnostic value is bigger.When AUC is 0.5, i.e., anticipated without diagnosis
Justice；AUC represents that accuracy rate of diagnosis is relatively low at 0.5~0.7；AUC represents that diagnostic accuracy is medium at 0.7~0.9；AUC
During ＞ 0.9, represent that diagnosis has higher accuracy.Phosphatidylinositols (18:3/0:0) it is single to be used for diagnosing lymphatic metastasis
AUC with the non-lymphatic metastasis of lung cancer is 0.803, has medium accuracy；Serum paraoxonase acyl inositol (18:3/0:0), haemolysis
Phosphatidyl choline (18:1) combine with phenylalanine and be for the AUC of diagnosing lymphatic metastasis and the non-lymphatic metastasis of lung cancer
0.937, there is higher accuracy, the sensitivity and specificity at excellent diagnostics critical value are more than 0.9.In independent sample
The further checking concentrated proves serum paraoxonase acyl inositol (18:3/0:0), lysophosphatidyl choline (18:1) join with phenylalanine
The degree of accuracy shared in diagnosing lymphatic metastasis and the non-lymphatic metastasis of lung cancer is up to 95%, has higher clinical diagnosis
Value.
Brief description of the drawings
Fig. 1 is serum paraoxonase acyl inositol (18:3/0:0) individually diagnosing lymphatic metastasis and the non-lymphatic metastasis of lung cancer
ROC curve；
Fig. 2 is serum hemolysis phosphatidyl choline (18:1) individually diagnosing lymphatic metastasis and the non-lymphatic metastasis of lung cancer
ROC curve；
Fig. 3 is the ROC curve of the independent diagnosing lymphatic metastasis of Serum Phenylalanine and the non-lymphatic metastasis of lung cancer；
Fig. 4 is serum paraoxonase acyl inositol (18:3/0:0), lysophosphatidyl choline (18:1), phenylalanine Combining diagnosis lung
The ROC curve of cancer lymphatic metastasis and the non-lymphatic metastasis of lung cancer.
Embodiment
The essentiality content of the present invention is further illustrated with reference to embodiment.
Embodiment 1：Accuracy of the small molecule mark to indication lung cancer lymphatic metastasis
First, material and method
1st, research object
The non-lymphatic metastasis group case of lung cancer lymphatic metastasis group, lung cancer be in March, 2015 in December, 2016 in south
The patient of capital drum tower hospital hospitalization, lung cancer lymphatic metastasis group totally 60, wherein man 34, female 26, age 38-72
Year, average age 45 years old；The non-lymphatic metastasis group case of lung cancer totally 100, wherein man 62, female 38, age 35-70 year,
Average age 43 years old.All cases are through clinical and definitive pathological diagnosis.The non-lymphatic metastasis group disease of lung cancer lymphatic metastasis group, lung cancer
Example is divided into two groups at random, and one group is training set, and another group is checking collection, and group result is as follows.
2nd, instrument and reagent
High Performance Liquid Chromatography/Mass Spectrometry instrument：Agilent 1200 (G6410A), Agilent companies of the U.S.；Ultrapure water system：
Milli-Q, Millipor companies of the U.S.；Automatic fluid injector：Agilent companies of the U.S.；Methanol, acetonitrile, formic acid, isopropyl
Alcohol, Sigma Co., USA, it is chromatographically pure or mass spectrum rank.
3rd, sample collection and pretreatment
The selected personnel's empty stomach blood specimen 3ml of collection static 1h solidifications layering, centrifugation in the heparin tube containing liquaemin
(3000rpm10min), take supernatant to dispense to centrifuge tube, it is stand-by to be stored in -80 DEG C of refrigerators.
The serum sample thaw at RT of Cord blood is mixed, takes 100 μ L serum to be put into centrifuge tube, adds 300 μ L acetonitriles
Rock and mix 15s, be stored at room temperature 15min, 10000rpm centrifugation 10min (4 DEG C), take the μ L of supernatant 200, blown at room temperature with nitrogen
Instrument dries up, 50 μ L acetonitrile/waters solvents (3 of residue:1) redissolve, 13000rpm centrifugation 10min (4 DEG C), take supernatant to add 50 μ L
Concentration is standby to be mixed after 0.02mg/mL L-2- chlorophenylalanine internal standards.
The preparation of Quality Control (QC) sample.For the stability of viewing test method, one is all added respectively after every 6 serum
Individual QC samples.QC sample preparation methods are：The serum sample that room temperature shakes up defrosting takes 5 μ L, adds methanol and acetonitrile 1:1 mixed liquor
L-2- chlorophenylalanines are added as internal standard.Remaining processing is same as above.
4th, HPLC-MS analysis conditions
Chromatographic condition：Chromatographic column selects ZorbaxSB-C18 posts (4.6mm × 100mm, 3.5 μm).Column temperature maintains 45 DEG C,
It is that A is the aqueous formic acid of volumetric concentration 0.1% to flow phase composition, and B is the formic acid acetonitrile solution of volumetric concentration 0.1%；Gradient elution
Condition：0~3min is 0~30%B phases, and B is phase linear in 2min increases to 60%, 5~10min linear changes to 90%B phases, so
100%B phases are linearly increasing in 10~12min and keep 3min afterwards；Flow velocity 1.0mL/min；The μ L of single sample introduction 10.Mass spectrum bar
Part：Using ESI, under positive ion mode：Capillary voltage 4KV, electron energy 3eV, be delayed solution 5min, ion source temperature 115
DEG C, dry 350 DEG C, dry gas stream speed 9L/min, reference charge-mass ratio (m/z) 80-900, quality full scan scope 100- of temperature degree
1000, sweep time 0.03s.
5th, data processing and statistical analysis
Calculate phosphatidylinositols (18 in each sample:3/0:0), lysophosphatidyl choline (18:1) and phenylalanine mass spectrum
The ratio of total ion current peak area and the mass spectrum total ion current peak area of internal standard L-2- chlorophenylalanines, the ratio is each sample
Middle phosphatidylinositols (18:3/0:0), lysophosphatidyl choline (18:1) and phenylalanine relative amount.Using SPSS 16.0
Software carries out statistical analysis to data, and normality distribution inspection is analyzed with 1-sampleK-S, compared between the group of each index content
Examined compared with One-wayANOVALSD methods, the comparison of Positive rate uses chi-square criterion, and selection variables are returned simultaneously with Logistic
Regression equation is established, ROC curve analysis is carried out to new variables and each single index.
2nd, experimental result
1st, each group serum paraoxonase acyl inositol (18:3/0:0), lysophosphatidyl choline (18:1) contain with the relative of phenylalanine
Amount compares
Group difference it was found that, 3 kinds of Tumor Marker Levels are significantly higher than lung cancer in lung cancer lymphatic metastasis group serum
Non- lymphatic metastasis group (P ＜ 0.01), phosphatidylinositols (18 in lung cancer lymphatic metastasis group sample:3/0:0) 6-8 times is raised,
Lysophosphatidyl choline (18:1) 1.5-2.5 times is raised, phenylalanine raises 2-3 times, phosphatidylinositols (18:3/0:0) raise
It is the most notable.
2nd, serum paraoxonase acyl inositol (18:3/0:0), lysophosphatidyl choline (18:1) ROC curve with phenylalanine divides
Analysis
Area is bigger under ROC curve, and its diagnostic value is bigger.When AUC is 0.5, i.e., without diagnostic significance；AUC 0.5~
When 0.7, represent that accuracy rate of diagnosis is relatively low；AUC represents that diagnostic accuracy is medium at 0.7~0.9；During AUC ＞ 0.9, represent to examine
It is disconnected to have higher accuracy.With the softwares of SPSS 16.0 in training set by lung cancer lymphatic metastasis group and the non-lymph node of lung cancer
Transfer group serum paraoxonase acyl inositol (18:3/0:0), lysophosphatidyl choline (18:1) relative amount with phenylalanine is made respectively
ROC curve, as shown in Fig. 1-3 and table 1.
The serum paraoxonase acyl inositol (18 of table 1:3/0:0), lysophosphatidyl choline (18:1) and the single ROC of phenylalanine is bent
Line analysis
As a result
| Detect mark | AUC | Standard error | 95%CI | P |
| Phosphatidylinositols (18:3/0:0) | 0.803 | 0.029 | 0.762~0.845 | 0.03 |
| Lysophosphatidyl choline (18:1) | 0.635 | 0.038 | 0.594~0.676 | 0.00 |
| Phenylalanine | 0.682 | 0.035 | 0.643~0.728 | 0.01 |
From Fig. 1-3 and table 1, serum paraoxonase acyl inositol (18:3/0:0) it is single for when indicating lung cancer lymphatic metastasis
With medium accuracy, serum hemolysis phosphatidyl choline (18:1) or phenylalanine is single for indicating lung cancer lymphatic metastasis
When there is relatively low accuracy.
3rd, three mark joint indication lung cancer lymphatic metastasis model structures and ROC curve analysis
In training set, using lung cancer, whether lymphatic metastasis is dependent variable, serum paraoxonase acyl inositol (18:3/0:0), haemolysis
Phosphatidyl choline (18:1) relative amount with phenylalanine is independent variable, establishes Logistic regression models.Respectively join in model
Several fitting results are shown in Table 2.Therefore the model obtained is represented by Logit=-3.562+2.694 × phosphatidylinositols (18:3/
0:0)+1.319 × lysophosphatidyl choline (18:1)+1.867 × phenylalanine.
The Logistic Regression Model Simulator parameters of 2 three mark joint indication lung cancer lymphatic metastasis of table
| Variable | Coefficient | Standard error | Wald is examined | P values | OR values |
| Phosphatidylinositols (18:3/0:0) | 2.694 | 0.09 | 23.583 | 0.00 | 1.03 |
| Lysophosphatidyl choline (18:1) | 1.319 | 0.05 | 17.955 | 0.00 | 0.98 |
| Phenylalanine | 1.867 | 0.07 | 20.172 | 0.00 | 2.01 |
| Intercept | -3.562 | 0.47 | 32.085 | 0.01 | 0.22 |
The model passes through likelihood ratio test, and this regression model has statistical significance (P ＜ 0.01).With ROC curve method pair
Above-mentioned model carries out value of diagnosis, as a result as shown in Figure 4.
As seen from Figure 4, area is 0.937 under the ROC curve, serum paraoxonase acyl inositol (18:3/0:0), hemolytic phosphatidyl
Choline (18:1) combine with phenylalanine for indicating that lung cancer lymphatic metastasis has higher accuracy, excellent diagnostics critical value
(1.474) sensitivity and specificity at place are more than 0.9.
4th, the degree of accuracy of three mark combination indication lung cancer lymphatic metastasis of further checking is concentrated in checking
Concentrated in checking, respectively by serum paraoxonase acyl inositol (18 in each sample:3/0:0), lysophosphatidyl choline (18:
1) relative amount with phenylalanine substitutes into above-mentioned regression model, obtains the regressand value of each sample, regressand value is higher than excellent diagnostics
Critical value 1.474 is predicted as lung cancer lymphatic metastasis, and the non-lymph of lung cancer is predicted as less than the excellent diagnostics critical value 1.474
Carry down shifting, the degree of accuracy is 95% (76/80).
In summary, phosphatidylinositols (18:3/0:0) it is single to be used for diagnosing lymphatic metastasis and the non-lymph node of lung cancer
The AUC of transfer is 0.803, has medium accuracy；Serum paraoxonase acyl inositol (18:3/0:0), lysophosphatidyl choline (18:
1) and phenylalanine to combine for the AUC of diagnosing lymphatic metastasis and the non-lymphatic metastasis of lung cancer be 0.937, have higher
Accuracy, the sensitivity and specificity at excellent diagnostics critical value are more than 0.9.Further tested what independent sample was concentrated
Card proves serum paraoxonase acyl inositol (18:3/0:0), lysophosphatidyl choline (18:1) combine with phenylalanine for diagnosing
The degree of accuracy of lymphatic metastasis and the non-lymphatic metastasis of lung cancer is up to 95%, has higher clinical value.
Embodiment 2：Diagnostic kit
A kind of diagnostic kit for being used to indicate lung cancer lymphatic metastasis in early days, including phosphatidylinositols (18:3/0:0)、
Lysophosphatidyl choline (18:1), phenylalanine and L-2- chlorophenylalanines, phosphatidylinositols (18:3/0:0), hemolytic phosphatidyl
Choline (18:1), phenylalanine carries out qualitative positioning, the ammonia of L-2- chlorobenzenes third as reference substance to target compound in test serum
Acid is added in test serum sample to lysophosphatidyl choline (18 as internal standard:1), phosphatidylinositols (18:3/0:0), benzene
Alanine relative quantification.
The effect of above-described embodiment indicates that the essentiality content of the present invention, but the protection of the present invention is not limited with this
Scope.It will be understood by those within the art that technical scheme can be modified or equivalent substitution,
Without departing from the essence and protection domain of technical solution of the present invention.
Claims (5)
1. phosphatidylinositols (18:3/0:0), lysophosphatidyl choline (18:1) or phenylalanine is used to indicate that lung cancer lymph is carried down
The clinical application of shifting.
A kind of 2. composition for being used to indicate lung cancer lymphatic metastasis, it is characterised in that：Including at least phosphatidylinositols (18:3/
0:0)。
3. composition according to claim 2, it is characterised in that：Including phosphatidylinositols (18:3/0:0), lysophosphatide
Phatidylcholine (18:And phenylalanine 1).
4. the composition according to Claims 2 or 3, it is characterised in that：Also include internal standard L-2- chlorophenylalanines.
5. any compositions of claim 2-4 answering in terms of the diagnostic kit of indication lung cancer lymphatic metastasis is prepared
With.
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