CN117269495B - Marker protein combination for molecular typing of prostatic cancer proteins and application thereof - Google Patents
Marker protein combination for molecular typing of prostatic cancer proteins and application thereof Download PDFInfo
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- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
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Abstract
The invention belongs to the technical field of biomedicine, and particularly relates to a marker protein combination for molecular typing of prostatic cancer proteins and application thereof. The marker protein combination provided by the invention comprises three, two or one of a lipid metabolism protein combination, a glycometabolism protein combination and an immune metabolism protein combination; the lipid metabolism protein combination comprises 10 characteristic proteins, the glycometabolism protein combination comprises 9 characteristic proteins, and the immune metabolism protein combination comprises 20 characteristic proteins. The prostate cancer marker protein combination provided by the invention can be used for molecular typing of prostate cancer, and when any protein combination is used for typing, the AUC reaches more than 95%. The prostate cancer marker protein combination can be used for screening or diagnosing the prostate cancer of a subject, judging the prognosis situation of the prostate cancer, and assisting in treating the prostate cancer, and has clinical popularization value.
Description
Technical Field
The invention belongs to the technical field of biomedicine, and particularly relates to a marker protein combination for molecular typing of prostatic cancer proteins and application thereof.
Background
Prostate cancer (PCa) is a malignant tumor occurring on the prostate epithelium, the most common malignant tumor of the urogenital system of chinese males, and the current incidence rate has been the first malignant tumor of the urogenital system of chinese males.
Prostate cancer is clinically divided into two categories, metastatic and localized prostate cancer. Among them, patients with metastatic prostate cancer have lost the opportunity of radical treatment, and clinically, targeting drug therapies such as Androgen Receptor (AR) pathway inhibitors and PARP inhibitors are the main treatment. And patients with localized prostate cancer have had the opportunity to gain greater survival benefit through local treatment modalities such as radical surgery or radiation therapy. However, studies have shown that prostate cancer exhibits a high degree of heterogeneity at all clinical biology, histopathology and molecular profiling levels, resulting in significant differences in therapeutic response among different patient populations. In clinical practice, it was found that a part of patients had a high recurrence rate after local treatment, while another part of patients did not show significant survival benefit compared to active follow-up, with the problem of oversherapy. Therefore, at present, the diagnosis mode for clinically classifying the risk of the patient based on clinical indexes such as serum Prostate Specific Antigen (PSA) concentration, pathological Gleason score, tumor clinical stage and the like is difficult to effectively distinguish different crowds with heterogeneity in localized prostate cancer patients, so that more accurate diagnosis and treatment cannot be guided. Therefore, there is a need to find new diagnostic criteria for guiding accurate diagnosis and treatment of different feature groups of prostate cancer in clinic.
Disclosure of Invention
The invention aims to provide a marker protein combination for molecular typing of prostate cancer proteins, which is used for distinguishing prostate cancer patient groups with obvious heterogeneity, carrying out molecular typing on prostate cancer and providing basis for targeting accurate diagnosis and treatment of prostate cancer.
The present invention provides a marker protein combination for the molecular typing of a prostate cancer protein, the marker protein combination comprising three, two or one of a lipid metabolism protein combination, a glycometabolism protein combination and an immune metabolism protein combination;
the lipid metabolism protein combination includes ALOX15, AGR2, KBTBD3, HCCS, ANAPC4, ZGPAT, PRKD3, GALNT4, POLR2E, and FOLH1;
the glycometabolism protein combination includes ALCAM, MB, ECI2, PTBP2, MAL2, ITGAE, GGCT, FASN, and EXTL2;
The immune metabolism protein combination comprises SLC43A1、PEX1、RUNDC1、AAAS、KLHL25、TUT7、SAP30BP、PTPRD、SPAG1、GFAP、MTREX、NT5C1A、GTPBP6、NIPBL、DDX59、AHCYL2、SPAG9、SART1、KAT8 and KIF15.
The invention also provides application of the marker protein combination in preparation of a prostatic cancer protein molecular parting product.
Preferably, the protein molecular typing comprises three, two or one of a lipid metabolism subtype, a sugar metabolism subtype and an immune subtype;
The proteins detected by the lipid metabolism subtype are ALOX15, AGR2, KBTBD3, HCCS, ANAPC4, ZGPAT, PRKD3, GALNT4, POLR2E and FOLH1;
Proteins detected by the glycometabolism subtypes are ALCAM, MB, ECI2, PTBP2, MAL2, ITGAE, GGCT, FASN and EXTL2;
Proteins detected by the immune subtype are SLC43A1、PEX1、RUNDC1、AAAS、KLHL25、TUT7、SAP30BP、PTPRD、SPAG1、GFAP、MTREX、NT5C1A、GTPBP6、NIPBL、DDX59、AHCYL2、SPAG9、SART1、KAT8 and KIF15.
The invention also provides application of the marker protein combination in preparation of products for screening or diagnosing prostate cancer.
The invention also provides application of the marker protein combination in the technical scheme in preparation of a product for judging the prognosis situation of a prostate cancer subject.
The invention also provides application of the marker protein combination in preparing a product for assisting in treating the prostate cancer.
Preferably, the product comprises reagents for detecting the combined expression level of the marker proteins.
Preferably, the marker protein combination expression level comprises the protein expression level of the marker protein combination.
The invention also provides a kit for molecular typing of the prostate cancer protein, which comprises a reagent for detecting the marker protein combination in the technical scheme.
The beneficial effects are that:
The marker protein combination for the molecular typing of the prostatic cancer protein provided by the invention comprises three, two or one of a lipid metabolism protein combination, a glycometabolism protein combination and an immune metabolism protein combination; the lipid metabolism protein combination includes ALOX15, AGR2, KBTBD3, HCCS, ANAPC4, ZGPAT, PRKD3, GALNT4, POLR2E, and FOLH1; the glycometabolism protein combination includes ALCAM, MB, ECI2, PTBP2, MAL2, ITGAE, GGCT, FASN, and EXTL2; the immune metabolism protein combination comprises SLC43A1、PEX1、RUNDC1、AAAS、KLHL25、TUT7、SAP30BP、PTPRD、SPAG1、GFAP、MTREX、NT5C1A、GTPBP6、NIPBL、DDX59、AHCYL2、SPAG9、SART1、KAT8 and KIF15. The prostate cancer marker protein combination provided by the invention can be used for molecular typing of prostate cancer, and when any protein combination is used for typing, the AUC reaches more than 95%. The prostate cancer marker protein combination can be used for screening or diagnosing the prostate cancer of a subject, judging the prognosis situation of the prostate cancer, and assisting in treating the prostate cancer, and has clinical popularization value.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are required to be used in the embodiments will be briefly described below.
FIG. 1 is a graph showing the results of clustering of 145 cases of prostate cancer patients;
FIG. 2 is a graph showing the results of survival analysis of prostate cancer patients with 3 protein subtypes;
FIG. 3 is a molecular characterization of 3 protein subtypes extracted using GSEA pathway enrichment; wherein metabolism is a metabolic pathway, proliferation is a proliferation pathway, and immune is an immune pathway;
FIG. 4 shows the results of screening 3 protein subtypes characteristic proteins;
FIG. 5 shows the results of an accuracy test for typing of prostate cancer patients using 3 protein subtypes.
Detailed Description
The present invention provides a marker protein combination for the molecular typing of a prostate cancer protein, the marker protein combination comprising three, two or one of a lipid metabolism protein combination, a glycometabolism protein combination and an immune metabolism protein combination;
the lipid metabolism protein combination includes ALOX15, AGR2, KBTBD3, HCCS, ANAPC4, ZGPAT, PRKD3, GALNT4, POLR2E, and FOLH1;
the glycometabolism protein combination includes ALCAM, MB, ECI2, PTBP2, MAL2, ITGAE, GGCT, FASN, and EXTL2;
The immune metabolism protein combination comprises SLC43A1、PEX1、RUNDC1、AAAS、KLHL25、TUT7、SAP30BP、PTPRD、SPAG1、GFAP、MTREX、NT5C1A、GTPBP6、NIPBL、DDX59、AHCYL2、SPAG9、SART1、KAT8 and KIF15.
The invention also provides application of the marker protein combination in preparation of a prostatic cancer protein molecular parting product.
In the present invention, the protein molecular typing preferably includes three, two or one of a lipid metabolism subtype, a sugar metabolism subtype and an immune subtype, and more preferably a lipid metabolism subtype, a sugar metabolism subtype and an immune subtype.
In the present invention, the protein detected by the lipid metabolism subtype is preferably ALOX15, AGR2, kbdbd 3, HCCS, ANAPC4, ZGPAT, PRKD3, GALNT4, POLR2E and FOLH1;
In the present invention, the proteins detected by the glycometabolism subtypes are preferably ALCAM, MB, ECI2, PTBP2, MAL2, ITGAE, GGCT, FASN, and EXTL2;
In the present invention, the proteins detected by the immune subtype are preferably SLC43A1、PEX1、RUNDC1、AAAS、KLHL25、TUT7、SAP30BP、PTPRD、SPAG1、GFAP、MTREX、NT5C1A、GTPBP6、NIPBL、DDX59、AHCYL2、SPAG9、SART1、KAT8 and KIF15.
The invention detects 145 cases of prostate cancer patient operation specimens through proteomics technology; patients were then cluster-typed by NMF (non-negative matrix factorization) and finally divided into 3 protein subtypes: lipid metabolism subtypes (denoted subtype 1), glycometabolism subtype (denoted subtype 2) and immune subtype (denoted subtype 3); carrying out GSEA (GSEA) pathway enrichment on 3 protein subtype patients to extract the molecular characteristics of each subtype, and finding that subtype 1 is a metabolic subtype and mainly metabolizes lipid; subtype 2 is also a metabolic subtype, predominantly sugar metabolism; subtype 3 is the immune subtype; and then screening 3 molecular subtype characteristic proteins and carrying out accuracy detection, wherein the result shows that subtype 1 is screened to obtain 10 characteristic proteins, subtype 2 is screened to obtain 9 characteristic proteins, and subtype 3 is screened to obtain 20 characteristic proteins. Specifically, the characteristic proteins of subtype 1 are ALOX15, AGR2, kbdbd 3, HCCS, ANAPC4, ZGPAT, PRKD3, GALNT4, POLR2E and FOLH1; characteristic proteins of subtype 2 are ALCAM, MB, ECI2, PTBP2, MAL2, ITGAE, GGCT, FASN and EXTL2; the characteristic proteins of subtype 3 are SLC43A1、PEX1、RUNDC1、AAAS、KLHL25、TUT7、SAP30BP、PTPRD、SPAG1、GFAP、MTREX、NT5C1A、GTPBP6、NIPBL、DDX59、AHCYL2、SPAG9、SART1、KAT8 and KIF15, and when any characteristic protein combination is used for typing, the AUC reaches more than 95%.
The invention also provides application of the marker protein combination in preparation of products for screening or diagnosing prostate cancer.
The invention also provides application of the marker protein combination in the technical scheme in preparation of a product for judging the prognosis situation of a prostate cancer subject.
The invention also provides application of the marker protein combination in preparing a product for assisting in treating the prostate cancer.
In the present invention, the product preferably comprises an agent for detecting the combined expression level of the marker proteins; the marker protein combination expression level preferably comprises the protein expression level of the marker protein combination. Based on the marker protein combination, the invention can accurately type the prostate cancer patients by detecting the protein expression level of the marker protein combination, and based on the typing result, the prognosis situation of the prostate cancer patients can be judged, and the example result shows that the prognosis effect of the subtype 2 prostate cancer patients is the worst, the prognosis effect of the subtype 3 prostate cancer patients is the best (p=0.0049), and the marker protein combination provided by the invention has great significance for screening subjects, diagnosing and prognosis situation judgment of the prostate cancer and auxiliary treatment of the prostate cancer.
The invention also provides a kit for molecular typing of the prostate cancer protein, which comprises a reagent for detecting the marker protein combination in the technical scheme.
For further explanation of the present invention, a marker protein combination for molecular typing of prostate cancer proteins and its use, provided in the present invention, will be described in detail with reference to the accompanying drawings and examples, which should not be construed as limiting the scope of the present invention.
Example 1
1. Detecting 145 cases of prostate cancer patient surgical specimens by proteomics technology; patients were then cluster-typed by NMF (non-negative matrix factorization) (reference Yuan Y,Van Allen E M,Omberg L,et al.Assessing the clinical utility of cancer genomic and proteomic data across tumor types[J].Nature biotechnology,2014,32(7):644-652.), wherein the clinical information of prostate cancer patients is shown in table 1 and the typing results are shown in figure 1.
Table 1 clinical information of prostate cancer patients
Note that: in table 1, bcr=0 indicates no recurrence, and bcr=1 indicates recurrence.
As can be seen from FIG. 1, 145 prostate cancer patients were ultimately classified into 3 protein subtypes, labeled subtype 1 (Subgroup 1), subtype 2 (Subgroup 2), and subtype 3 (Subgroup 3).
2. The 3 subtypes of prostate cancer patients in step 1 were followed post-operatively by reference Yuan Y,Van Allen E M,Omberg L,et al.Assessing the clinical utility of cancer genomic and proteomic data across tumor types[J].Nature biotechnology,2014,32(7):644-652, for survival analysis, and the results are shown in figure 2.
The ordinate in fig. 2 represents the survival rate without biochemical recurrence, and it can be seen from fig. 2 that subtype 2 has the lowest survival rate without biochemical recurrence, the worst prognosis, and subtype 3 has the highest survival rate without biochemical recurrence, and the best prognosis. There were significant differences between subtype 1, subtype 2 and subtype 3, p=0.0049.
3. GSEA pathway enrichment was performed on the 3 protein subtypes of step1, and the molecular characteristics of each subtype were extracted, and the results are shown in FIG. 3.
As can be seen from fig. 3, the subtype 1 patient has more protein involved in lipid metabolism pathways in the tumor, and the subtype 1 patient has the tumor metabolism mainly including lipid metabolism (Lipid metabolic subtype); the protein content related to sugar metabolism pathways is more in the tumor of the subtype 2 patient, and the tumor metabolism of the subtype 2 patient is mainly sugar metabolism (Carbohydrate metabolic subtype); the subtype 3 patient has more protein content related to Immune pathways in the tumor, the subtype 3 patient has more Immune cell infiltration, and the subtype 3 patient tumor belongs to an Immune subtype (Immune subtype).
4. Referring to Yachida S,Mizutani S,Shiroma H,et al.Metagenomic and metabolomic analyses reveal distinct stage-specific phenotypes of the gut microbiota in colorectal cancer[J].Nature medicine,2019,25(6):968-976,, screening the characteristic proteins of 3 molecular subtypes in the step 1 through a random forest machine learning algorithm, and constructing a protein molecular typing model of the prostate cancer, wherein the result is shown in fig. 4.
As can be seen from fig. 4, subtype 1 is screened for 10 characteristic proteins, specifically: ALOX15, AGR2, KBTBD3, HCCS, ANAPC4, ZGPAT, PRKD3, GALNT4, POLR2E, and FOLH1;
subtype 2 is screened to obtain 9 characteristic proteins, which are specifically: ALCAM, MB, ECI2, PTBP2, MAL2, ITGAE, GGCT, FASN and EXTL2;
Subtype 3 was screened for 20 characteristic proteins, specifically ：SLC43A1、PEX1、RUNDC1、AAAS、KLHL25、TUT7、SAP30BP、PTPRD、SPAG1、GFAP、MTREX、NT5C1A、GTPBP6、NIPBL、DDX59、AHCYL2、SPAG9、SART1、KAT8 and KIF15.
5. The accuracy of the typing of the characteristic protein of step 4 was verified with reference Yachida S,Mizutani S,Shiroma H,et al.Metagenomic and metabolomic analyses reveal distinct stage-specific phenotypes of the gut microbiota in colorectal cancer[J].Nature medicine,2019,25(6):968-976,, and the results are shown in fig. 5.
As can be seen from fig. 5, the AUC of all 3 subtypes reached 95% or more, with the AUC of subtype 1 being 95.75%, the AUC of subtype 2 being 99.46%, the AUC of subtype 3 being 98.48%, the AUC of Micro (Micro average) being 97.16%, and the AUC of Macro (Macro average) being 97.14%. The screened protein molecules can be used for accurately carrying out molecular typing on the prostate cancer.
According to the above, the prostate cancer marker protein composition provided by the invention can be used for molecular typing of prostate cancer, screening or diagnosing prostate cancer for a subject, judging prognosis of prostate cancer, and assisting in treating prostate cancer, and has clinical popularization value.
Although the foregoing embodiments have been described in some, but not all, embodiments of the invention, it should be understood that other embodiments may be devised in accordance with the present embodiments without departing from the spirit and scope of the invention.
Claims (4)
1. A protein combination for molecular typing of a prostate cancer protein, wherein the protein combination comprises a lipid metabolism protein combination, a glycometabolism protein combination, and an immune metabolism protein combination;
the lipid metabolism protein combination includes ALOX15, AGR2, KBTBD3, HCCS, ANAPC4, ZGPAT, PRKD3, GALNT4, POLR2E, and FOLH1;
the glycometabolism protein combination includes ALCAM, MB, ECI2, PTBP2, MAL2, ITGAE, GGCT, FASN, and EXTL2;
The immune metabolism protein combination comprises SLC43A1、PEX1、RUNDC1、AAAS、KLHL25、TUT7、SAP30BP、PTPRD、SPAG1、GFAP、MTREX、NT5C1A、GTPBP6、NIPBL、DDX59、AHCYL2、SPAG9、SART1、KAT8 and KIF15.
2. Use of the protein combination of claim 1 for the preparation of a molecular typing product for prostate cancer;
The protein molecular typing includes lipid metabolism subtype, sugar metabolism subtype and immunity subtype;
The proteins detected by the lipid metabolism subtype are ALOX15, AGR2, KBTBD3, HCCS, ANAPC4, ZGPAT, PRKD3, GALNT4, POLR2E and FOLH1;
Proteins detected by the glycometabolism subtypes are ALCAM, MB, ECI2, PTBP2, MAL2, ITGAE, GGCT, FASN and EXTL2;
Proteins detected by the immune subtype are SLC43A1、PEX1、RUNDC1、AAAS、KLHL25、TUT7、SAP30BP、PTPRD、SPAG1、GFAP、MTREX、NT5C1A、GTPBP6、NIPBL、DDX59、AHCYL2、SPAG9、SART1、KAT8 and KIF15.
3. Use of a combination of proteins according to claim 1 for the preparation of a product for determining the prognosis of a prostate cancer subject.
4. The use according to claim 2 or 3, wherein the product comprises an agent for detecting the combined expression level of the proteins.
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