CN106501516B - A kind of reagent and system for postoperative gastric cancer prognosis and chemosensitivity assessment - Google Patents
A kind of reagent and system for postoperative gastric cancer prognosis and chemosensitivity assessment Download PDFInfo
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Abstract
The present invention provides a kind of reagents assessed for postoperative gastric cancer prognosis and chemosensitivity, the reagent includes the first antibody for detecting CD3, detects the first antibody of CD8, detects the first antibody of CD45RO, detect the first antibody of CD66b and the secondary antibody of horseradish peroxidase-labeled.The expression for invading edge and tumor center in gastric cancer sample by the antigen of the above-mentioned 4 kinds of first antibodies of comprehensive analysis achievees the purpose that predict that patient undergos surgery prognosis and chemosensitivity after tumor resection.The present invention provides a kind of methods of assessment postoperative gastric cancer prognosis and chemosensitivity, and the method for the invention is highly developed, operating process is easy, it is intuitive, be easy to repeat, can be completed by common technician.It is as a result objective and accurate using the semi-automatic image quantitative analysis of human assistance, it is better than artificial semi-quantitative analysis.The method can assess postoperative gastric cancer prognosis and chemosensitivity implementations well through the invention.
Description
Technical field
The present invention relates to a kind of reagents and system of assessment postoperative gastric cancer prognosis and chemosensitivity.
Background technology
Gastric cancer (Gastric cancer, GC) is one of most common malignant tumour in the world, and incidence ranked fourth, extremely
The rate of dying ranked second.Only in Chinese kainogenesis Patients with Gastric Cancer 679,000 in 2015, mortality of gastric carcinoma patient 498,000 is serious to add
The acute whole world, especially Chinese Disease Spectrum.Transfer easily occurs for gastric cancer and chemotherapy is insensitive, is lead to its poor prognosis important
Reason.Effective prediction patients with gastric cancer postoperative prognosis and chemosensitivity, can select suitable treatment crowd and mode,
Strong support is provided for effective treatment.According to TNM (tumor, node, metastasis) systems and tissue typing to gastric cancer into
Capable clinical stages is most common prediction prognosis at present and formulates the reference standard of therapeutic scheme.However, a large amount of research hair
Even existing clinical stages is identical, the consistent patient of therapeutic scheme, their Clinical Outcome also has prodigious difference.Due to passing
The effect that Clinicopathologic Diagnosis and single molecular marker judge patient's Postoperative determination and chemosensitivity of uniting is relatively low, therefore
The kit that polymolecular marker is used in combination will be new R＆D direction.
As " eternal incurable wound ", its occurrence and development is a multi-step, multifactor process to malignant tumour.
The result of the interaction for progressing to tumor parenchymal cells and interstitial cell of tumour.Tumour associated fibroblast cell is immunized thin
Born of the same parents, including monocyte, lymphocyte, neutrophil leucocyte etc. are mesenchyma stroma of tumors important components.In this unique microenvironment, exempt from
While removing tumour, tumour cell is contacted by cell and is secreted a series of means such as shla molecule and exempted from epidemic disease cell
Epidemic disease editor changes the phenotype and function of immunocyte, and then immunologic escape occurs.In the relevant research knot of cancer largely delivered
Fruit shows that tumor tissues immunocyte is infiltrated generates important function to the clinical prognosis and chemotherapy effect of tumour patient, and swollen
Reaction of the invasion transfer of tumor depending on host immune system.Immunophenotyping based on tumour immunity scoring is quick to prognosis and chemotherapy
The predictive value of perception may be better than the current routine clinical clinicopathologic stage system used.
The principle that immunohistochemistry is combined using antigen and antibody specificity makes chromogenic reagent to detect by chemical reaction
The presence of antigen in tissue specimen, and can be positioned, quantitative analysis.Immunohistochemistry has been widely used for clinical disease at present
Reason diagnosis is a kind of intuitive, reliable detection means.Moreover, it with the rapid development of Digital image analysis technique, calculates
Machine auxiliary pathological diagnosis and analysis be gradually taken seriously and apply, and have many advantages, such as it is efficient, objective, accurate.
Due to stomach organization have it is significantly heterogeneous, and positioned at the active immune response in invasion edge also with disease
Disease progression is closely related.Therefore, stomach organization position used by molecular labeling analyte detection is very important.Conventional method is only
General detection tumor tissues, and the difference of the immune response of invasion edge and tumor center is ignored, the result of study of large sample
Showing to invade some immunity related molecular markers in edge has the effect of prior prediction gastric cancer prognosis and chemotherapeutic efficacy
Power.Therefore related mark in two positions can be detected simultaneously to tumor center by detection molecules marker position being divided into invasion edge
Remember the expression of object.
Invention content
It is pre- that a kind of assessment postoperative gastric cancer is provided it is an object of the invention to overcome in place of the shortcomings of the prior art
Afterwards with the reagent of chemosensitivity, the present invention provides the reagents in the examination for preparing assessment postoperative gastric cancer prognosis and chemosensitivity
Purposes in agent box, the present invention also provides a kind of systems assessed for postoperative gastric cancer prognosis and chemosensitivity.
To achieve the above object, the technical solution taken：One kind is assessed for postoperative gastric cancer prognosis and chemosensitivity
Reagent, the reagent include detect CD3 first antibody, detect the first antibody of CD8, detect the first antibody of CD45RO,
Detect the first antibody of CD66b and the secondary antibody of horseradish peroxidase-labeled.
Preferably, the first antibody of the detection CD3 is clone SP7, and the first antibody of the detection CD8 is clone
The first antibody of SP16, the detection CD45RO are clone UCHL1, the first antibody of the detection CD66b.
Preferably, the secondary antibody with horseradish peroxidase-labeled is the Anti-TNF-α of mountain sheep anti mouse/rabbit igg
Body.
The present invention provides reagents described above in the kit for preparing assessment postoperative gastric cancer prognosis and chemosensitivity
In purposes.
It is used in combination the present invention provides CD3, CD8, CD45RO and CD66b and is preparing assessment postoperative gastric cancer prognosis and chemotherapy
Purposes in the kit of sensibility.
The present invention provides a kind of systems of assessment postoperative gastric cancer prognosis and chemosensitivity, including：
Data input module is used for the result input model computing module of patient's molecular indexes, the molecular indexes packet
Include CD3IM、CD3CT、CD8IM、CD45ROCTAnd CD66bIM, wherein IM, which is represented, invades edge, and CT represents tumor center；
Model computation module, including immune Rating Model are used for the result according to patient's molecular indexes and immune scoring
Model calculates the immune scoring IS of patientGCAs a result；
As a result output module, for judging whether patient obtains significant existence and benefit according to immune appraisal result；Work as trouble
Person ISGC<When 0, patient, which receives chemotherapy, cannot obtain existence benefit；As patient ISGCWhen >=0, patient receive chemotherapy can obtain it is aobvious
The existence of work benefits.
Further, patient's molecular indexes the result is that by molecular indexes positive signal and molecular indexes positive signal
Threshold value comparison after obtain, molecular indexes positive signal is more than or equal to the threshold value of molecular indexes positive signals, molecular indexes
As a result it is high expression, is indicated with number 1；Molecular indexes positive signal is less than the threshold value of molecular indexes positive signal, molecular indexes
Result be low expression, 0 indicated with number；CD3IM,CD3CT,CD8IM,CD45ROCTAnd CD66bIMThe threshold value of positive signal is distinguished
It is 118,61,86,76 and 59；The numerical value of the molecular indexes positive signal is the positive cell under 200 powered microscope fields
Number；
The immune scoring IS of patientGC=(0.149 × CD3IM)+(0.021×CD3CT)+(0.044×CD8IM)+(0.096×
CD45ROCT0.173 × CD66b of)-(IM)。
The expression at edge and tumor center is invaded in gastric cancer sample by the antigen of the above-mentioned 4 kinds of first antibodies of comprehensive analysis
Level achievees the purpose that predict that patient undergos surgery prognosis and chemosensitivity after tumor resection.
Main advantages of the present invention are：
(1) system of the present invention is highly developed, operating process is easy, it is intuitive, be easy to repeat, it is equal by common technician
It can complete.
(2) the semi-automatic image quantitative analysis of human assistance is utilized, it is as a result objective and accurate, it is better than artificial semi-quantitative analysis.
(3) system can assess postoperative gastric cancer prognosis and chemosensitivity implementations well through the invention.
Description of the drawings
Fig. 1 is immunohistochemical staining result of 4 kinds of first antibodies in gastric cancer in the embodiment of the present invention 1；
Fig. 2 be in the embodiment of the present invention 1 in training group (N=125) and test group (N=126) 1,3,5 year after predicting surgical
Disease-free survival and whole survivorship curve after the ROC curve and predicting surgical of disease-free survival rate；
Fig. 3 be the embodiment of the present invention 1 in internal validation group (N=228) and external certificate group (N=300) predicting surgical
Disease-free survival and whole survivorship curve after the ROC curve and predicting surgical of 1,3,5 year disease-free survival rate afterwards；
Fig. 4 is that IS is detected in patients with gastric cancer in the embodiment of the present invention 1GCA high and low group patient receives chemotherapy and not receiving
The disease-free survival for the treatment of and whole survivorship curve.
Specific implementation mode
To better illustrate the object, technical solutions and advantages of the present invention, below in conjunction with specific embodiment to the present invention
It is described further.
Embodiment 1
First, the present invention dyes 9 kinds of markers and screens, and 9 kinds of molecular marked compounds are detected using the method for immunohistochemistry
Expression in 251 paraffin sections of gastric cancer for receiving resection (while including normal portions, invasion edge and tumor center),
And analyze the positive of the different molecular labels respectively in normal portions, invasion edge and tumor center using specialized image software
It counts, the cut off value of each molecular marked compound is obtained with X-title softwares, obtains the expression of each molecular marked compound, from
And obtain 27 molecular indexes.251 patients with gastric cancer random divisions are training group and test group, respectively 125 and 126,
Model is established with training group, whether the model established with test group verification is suitable.In training group, returned using LASSO COX
The method of model obtains 5 molecular indexes and establishes gastric cancer immunity scoring (ImmunoScore of GC, ISGC).5 molecular indexes
Respectively CD3IM,CD3CT,CD8IM,CD45ROCTAnd CD66bIM；Wherein IM (invasive margin) represents invasion edge, CT
(core of tumor) represents tumor center.The coefficient obtained using this 5 molecular indexes combination LASSO COX regression models
Calculate the immune scoring (IS of each patientGC), calculation formula ISGC=(0.149 × CD3IM)+(0.021×CD3CT)+(0.044
×CD8IM)+(0.096×CD45ROCT0.173 × CD66b of)-(IM).In order to simplify the use of kit, with X-title softwares
It is 0 to choose cut off value, and patient is divided into ISGCIt is high and two groups low.Survival analysis shows to utilize ISGCThe nothing of the two groups of patients obtained
Sick survival rate and the significant difference (P of overall survival<0.001).In multifactor COX analyses, ISGCIt can be used as independent pre-
Factor (the P for surveying disease-free survival and integrally surviving<0.001；As shown in table 1).In test group, incorporate 228 Patients with Gastric Cancer
Internal verification group, the external certificate group example for incorporating 300 Patients with Gastric Cancer have also obtained similar result (as shown in table 1).Institute
With ISGCIt can be effective for the prediction of postoperative gastric cancer prognosis.
Secondly, survival analysis showed in II phases and III phase patients with gastric cancer, ISGCHigh patient, which receives chemotherapy, to be obtained
Significant existence benefits (P<0.05), ISGCLow patient, which receives chemotherapy, can not obtain existence benefit (as shown in Figure 3).Institute
With ISGCThe chemosensitivity that can predict patients with gastric cancer provides help for choosing clinical therapeutic regimen.
1 multiplicity of table and relevant factor of surviving
External certificate group (N=300)*:300 Patients with Gastric Cancer data come from No.1 Hospital Affiliated to Zhongshan Univ..
Note：COX proportional hazards regression models；There is significant difference (P in single factor analysis<0.05) index be included in mostly because
Element analysis；HR, Hazard ratio；CI, confidence interval.
Reagent of the present invention for assessing postoperative gastric cancer prognosis and chemosensitivity, including the first of detection CD3 are anti-
Body, the first antibody for detecting CD8, the first antibody for detecting CD45RO and the first antibody for detecting CD66b, it is anti-based on 4 kind first
Body can detect that clearly positive signal (as shown in Figure 1) assesses postoperative gastric cancer prognosis in stomach organization paraffin section
And chemosensitivity, specific steps include following 3 part：
(1) Samples detection
1. choosing 228 includes the stomach organization wax stone at invasion edge and tumor center, and ensures without large stretch of necrosis；
2. obtain 4 μm of paraffin section 4, in 65 DEG C of roasting pieces 2 hours, take out, it is slightly cold；
3. being dewaxed 2 times, every time 10 minutes with dimethylbenzene at room temperature；
4. wash away dimethylbenzene in 100% ethyl alcohol, then pass through 95% ethyl alcohol, 80% ethyl alcohol, 70% ethyl alcohol successively, every time 5
Minute；
5. being washed in distilled water 5 minutes；
6. using 0.3%H2O2Close endogenous peroxidase activity, room temperature 10 minutes；
7. being washed in distilled water 4 times, every time 5 minutes；
8. antigen retrieval：The repairing condition of synantigen is not as shown in table 2
The source of 2 different antibodies of table and specific experiment condition
CB, citrate buffer solution
9. room temperature natural cooling 30 minutes；
It is washed in 10.PBS buffer solutions 4 times, every time 3 minutes；
11. being added dropwise respectively first antibody (referring to table 2) on 4 histotomies, 4 DEG C are incubated 12 hours；
It is washed in 12.PBS buffer solutions 4 times, every time 5 minutes；
13. the secondary antibody of horseradish peroxidase-labeled is added dropwise, 37 DEG C are incubated 30 minutes；Including two kinds of secondary antibodies,
It is the polyclonal antibody (being purchased from Dako companies, article No. K5007) of mountain sheep anti mouse/rabbit igg respectively.
It is washed in 14.PBS buffer solutions 4 times, every time 3 minutes；
15. dropwise addition DAB color developing agents, room temperature, specific time are as shown in table 2；
16. being washed in distilled water 4 times, every time 5 minutes；
17. haematoxylin is redyed, room temperature 2 minutes；
18. being washed in distilled water 4 times, every time 5 minutes；
It is washed in 19.PBS buffer solutions 3 minutes；
20. being washed in tap water 3 minutes；
21. drying, mounting.
(2) image analysis
1. under 200 times of visuals field respectively obtain invasion edge and tumor center each two kinds of picture, resolution ratio be 2560 ×
1920；
2. using analysis software identification positive signal (brown), negative cells core (blue), white space (white)；
3. drawing the region (region of interest, ROI) for needing to analyze manually；
4. analyzing molecules index：Including CD3IM,CD3CT,CD8IM,CD45ROCTAnd CD66bIM；
5. the computational methods of molecular indexes positive signal：The numerical value of molecular indexes positive signal is 200 powered microscope fields
Under positive cell number；
6. final result is the average value of a variety of photos.
(3) interpretation of result
1. molecular indexes positive signal is compared with its threshold value, the result of molecular indexes is divided into low expression and high expression
It two kinds, is indicated respectively with number 0 and 1；Molecular indexes positive signal is more than or equal to its threshold value, and the result of molecular indexes is high table
It reaches, is indicated with number 1；Molecular indexes positive signal is less than its threshold value, and the result of molecular indexes is low expression, is indicated with number 0.
CD3IM,CD3CT,CD8IM,CD45ROCTAnd CD66bIMThe threshold value of positive signal is respectively that 118,61,86,76 and 59 (200 show
Positive cell number under microscope fields).The threshold value of molecular indexes is the flat of the positive cell number under 200 powered microscope fields
Mean value, be by each patient slices count average positive number of cells after, in training group with X-title softwares according to patient
DFS (disease-free survival rate) generate best cutoff values (threshold value).
2. calculating the immune scoring IS of patientGC=(0.149 × CD3IM)+(0.021×CD3CT)+(0.044×CD8IM)+
(0.096×CD45ROCT0.173 × CD66b of)-(IM)；Wherein IM represents invasion edge, and CT represents tumor center.
3. judging the immune scoring IS of patientGCHeight with it is low：As patient ISGC<When 0, it is believed that patient belongs to low ISGCGroup；Work as trouble
Person ISGCWhen >=0, it is believed that patient belongs to high ISGCGroup.
The result shows that：In this group of patient, prediction patient 1,3,5 years disease-free survivals ROC curve detection AUC be respectively
(as shown in Figure 2).Survival analysis shows the disease-free survival rate and overall survival there were significant differences (P of two groups of patients<0.001；
As shown in Figure 3).In multifactor COX analyses, patient ISGCIt can be as independent prediction disease-free survival and the index integrally survived (P<
0.001；As shown in table 1).Survival analysis shows in II phases and III phase patients with gastric cancer, ISGCHigh patient receives chemotherapy can
It obtains significant existence and benefits (P<0.05；As shown in Figure 4), ISGCLow patient, which receives chemotherapy, can not obtain existence benefit
(as shown in Figure 4).So ISGCThe chemosensitivity that can predict patients with gastric cancer provides help for choosing clinical therapeutic regimen.
Finally, it should be noted that the above embodiments are merely illustrative of the technical solutions of the present invention rather than is protected to the present invention
The limitation of range is protected, although being explained in detail to the present invention with reference to preferred embodiment, those skilled in the art should
Understand, technical scheme of the present invention can be modified or replaced equivalently, without departing from the essence of technical solution of the present invention
And range.
Claims (1)
1. a kind of system assessed for postoperative gastric cancer prognosis and chemosensitivity, which is characterized in that including：
Data input module, for by the result input model computing module of patient's molecular indexes, the molecular indexes to include
CD3IM、CD3CT、CD8IM、CD45ROCTAnd CD66bIM, wherein IM, which is represented, invades edge, and CT represents tumor center；
Model computation module, including immune Rating Model, are used for the result according to patient's molecular indexes and immune Rating Model
Calculate the immune scoring IS of patientGCAs a result；Patient's molecular indexes the result is that by molecular indexes positive signal and molecular indexes
It being obtained after the threshold value comparison of positive signal, molecular indexes positive signal is more than or equal to the threshold value of molecular indexes positive signal, point
The result of sub- index is high expression, is indicated with number 1；Molecular indexes positive signal is less than the threshold value of molecular indexes positive signal,
The result of molecular indexes is low expression, is indicated with number 0；CD3IM,CD3CT,CD8IM,CD45ROCTAnd CD66bIMPositive signal
Threshold value is respectively 118,61,86,76 and 59；The numerical value of the molecular indexes positive signal is the sun under 200 powered microscope fields
Property number of cells；The immune scoring IS of patientGC=(0.149 × CD3IM)+(0.021×CD3CT)+(0.044×CD8IM)+(0.096
×CD45ROCT0.173 × CD66b of)-(IM)；
As a result output module, for judging whether patient obtains significant existence and benefit according to immune appraisal result；As patient ISGC
<When 0, patient, which receives chemotherapy, cannot obtain existence benefit；As patient ISGCWhen >=0, patient, which receives chemotherapy, can obtain significant life
Deposit benefit.
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| CN107641653B (en) * | 2017-10-20 | 2021-02-19 | 南方医科大学南方医院 | Application of MACC1-AS1 probe in preparation of diagnostic reagent for predicting clinical prognosis of gastric cancer |
| CN109086572A (en) * | 2018-07-24 | 2018-12-25 | 南方医科大学南方医院 | It is a kind of for assessing the reagent and method of postoperative gastric cancer prognosis and chemotherapy side effect |
| CN109342742A (en) * | 2018-11-28 | 2019-02-15 | 中山大学孙逸仙纪念医院 | A kind of kit for Prognosis in Breast Cancer judgement |
| US20220236276A1 (en) * | 2019-06-03 | 2022-07-28 | Inserm (Institut National De La Santé Et De La Recherch Médicale | Methods for modulating a treatment regimen |
| CN111024944B (en) * | 2019-12-13 | 2023-06-23 | 北京市神经外科研究所 | Kit for predicting pituitary adenoma radiotherapy sensitivity or resistance through molecular markers |
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