CN117089617A - Application of CADPS2 as marker in preparation of product for prognosis risk assessment of patients with multiple myeloma - Google Patents
Application of CADPS2 as marker in preparation of product for prognosis risk assessment of patients with multiple myeloma Download PDFInfo
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
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- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/118—Prognosis of disease development
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- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/158—Expression markers
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Abstract
The application discloses an application of CADPS2 as a marker in preparing a product for prognosis risk assessment of patients with multiple myeloma. The application analyzes the expression level of CADPS2 in bone marrow cells of patients with primary diagnosis and alleviation of multiple myeloma and healthy donors by an RT-qPCR method, and discovers that the expression level of the gene in MM patients is obviously higher than that of normal controls and possibly related to clinical course of disease. The clinical significance of this gene was subsequently explored and high expression of this gene was found to be an independent risk factor for low Progression Free Survival (PFS) in MM patients. The CADPS2 has important value in the diagnosis and prognosis of multiple myeloma.
Description
Technical Field
The application belongs to the technical field of medical detection, and particularly relates to application of CADPS2 serving as a marker in preparation of a product for prognosis risk assessment of patients with multiple myeloma.
Background
Multiple Myeloma (MM) is a malignant disease of abnormal proliferation of clonal plasma cells, which is frequently found in the elderly and is a common malignancy at position 2 of the blood system in many countries, accounting for about 10% of hematological malignancies. Common symptoms of MM include manifestations of myeloma-related organ dysfunction, i.e. "CRAB" symptoms (increased blood calcium, kidney dysfunction, anemia, bone disease), and target organ damage-related manifestations of amyloidosis. During the past twenty years, the application of medicines such as proteasome inhibitors, immunomodulators, anti-CD 38 monoclonal antibodies, targeted B cell maturation antigen (B cell maturation antigen, BCMA) treatment and the like, the treatment mode of MM patients is greatly changed, and the survival time of the patients is obviously prolonged; and with the combined application of three or four medicines, the curative effect response of patients is obviously deepened, more patients can achieve complete remission (complete remission, CR), the CR rate of primary treatment patients is from 10% (thalidomide and dexamethasone treatment) to 95% (Lei Tuoyou monoclonal antibody, carfilzomib, lenalidomide and dexamethasone) reported nowadays, and the same trend exists in relapse/refractory MM patients. However, even if complete remission is achieved, most patients still recur, suggesting that the patients still remain tumor cells, while the previous evaluation system is not suitable for the current new treatment mode, in terms of prognosis layering and efficacy judgment, cytogenetic indexes and biochemical indexes are often relied on, and specific molecular biological markers are lacking.
The CADPS2 (calcium dependent secretion activator 2) gene encodes a member of the calbindin family of secretion activators that function as calbindins to regulate the extracellular secretion of synapses and dense core vesicles in neurons and neuroendocrine cells. It was found that the presence of aberrant selective cleavage of the CADPS2 mRNA in certain autistic patients resulted in the loss of exon 3, thereby resulting in the dysfunction of the CADPS2 protein, leading to a disturbed release of neurotrophic factors, which may be a causative factor in increased susceptibility to autism.
Disclosure of Invention
It is an object of the present application to provide a novel use of CADPS2 as a marker.
The present application provides the use of CADPS2 as a marker in any one of the following (a 1) - (a 12):
(a1) Preparing a product for diagnosing or aiding in diagnosing multiple myeloma;
(a2) Preparing a product for screening or assisting in screening patients with multiple myeloma;
(a3) Preparing a product for assessing or aiding in assessing prognosis of a patient with multiple myeloma;
(a4) Preparing a product for assessing or aiding in assessing the progression-free survival of a patient with multiple myeloma;
(a5) Preparing a product for assessing or aiding in assessing the progression free survival of a patient with multiple myeloma;
(a6) Preparing a product for assessing or aiding in assessing the progression of a disease (risk of recurrence) in a patient with multiple myeloma;
(a7) Diagnosing or aiding in the diagnosis of multiple myeloma;
(a8) Screening or aiding in screening patients with multiple myeloma;
(a9) Assessing or aiding in assessing prognosis of a patient with multiple myeloma;
(a10) Assessing or aiding in assessing progression-free survival of a patient with multiple myeloma;
(a11) Assessing or aiding in assessing the progression free survival of a patient with multiple myeloma;
(a12) The disease progression (recurrence risk) of the patients with multiple myeloma is evaluated or assisted in evaluation.
Another object of the present application is to provide a novel use of a substance for detecting the expression level of CADPS 2.
The present application provides the use of a substance for detecting the expression level of CADPS2 in any one of the following (a 1) to (a 12):
(a1) Preparing a product for diagnosing or aiding in diagnosing multiple myeloma;
(a2) Preparing a product for screening or assisting in screening patients with multiple myeloma;
(a3) Preparing a product for assessing or aiding in assessing prognosis of a patient with multiple myeloma;
(a4) Preparing a product for assessing or aiding in assessing the progression-free survival of a patient with multiple myeloma;
(a5) Preparing a product for assessing or aiding in assessing the progression free survival of a patient with multiple myeloma;
(a6) Preparing a product for assessing or aiding in assessing the progression of a disease (risk of recurrence) in a patient with multiple myeloma;
(a7) Diagnosing or aiding in the diagnosis of multiple myeloma;
(a8) Screening or aiding in screening patients with multiple myeloma;
(a9) Assessing or aiding in assessing prognosis of a patient with multiple myeloma;
(a10) Assessing or aiding in assessing progression-free survival of a patient with multiple myeloma;
(a11) Assessing or aiding in assessing the progression free survival of a patient with multiple myeloma;
(a12) The disease progression (recurrence risk) of the patients with multiple myeloma is evaluated or assisted in evaluation.
It is still another object of the present application to provide a kit whose function is any one of the following (c 1) to (c 6):
(c1) Diagnosing or aiding in the diagnosis of multiple myeloma;
(c2) Screening or aiding in screening patients with multiple myeloma;
(c3) Assessing or aiding in assessing the risk of prognosis of a patient with multiple myeloma;
(c4) Assessing or aiding in assessing progression-free survival of a patient with multiple myeloma;
(c5) Assessing or aiding in assessing the progression free survival of a patient with multiple myeloma;
(c6) The disease progression (recurrence risk) of the patients with multiple myeloma is evaluated or assisted in evaluation.
The kit provided by the application comprises a substance for detecting the expression level of the CADPS 2.
In any of the above applications or kits, the agent that detects the amount of expression of the CADPS2 gene may be an agent that detects the amount of expression of the CADPS2 gene, an agent that detects the amount of expression of mRNA encoded by the CADPS2 gene, or an agent that detects the amount of protein encoded by the CADPS2 gene.
Further, the substance for detecting the expression level of the CADPS2 gene may be a reagent and/or an instrument required for detecting the expression level of the CADPS2 gene by a method in the prior art, such as a reagent and/or an instrument required for detecting the expression level of the gene by high throughput sequencing, a reagent and/or an instrument required for detecting the expression level of the gene by quantitative PCR, or a reagent and/or an instrument required for detecting the expression level of the gene by a northern hybridization technique.
The substance for detecting the protein content encoded by the CADPS2 gene may be a reagent and/or an instrument required for detecting the protein content by a method in the prior art, such as a reagent and/or an instrument required for detecting the protein content by mass spectrometry or a related technique thereof, or a reagent and/or an instrument required for detecting the protein content by an immunohybridization technique, or a reagent and/or an instrument required for detecting the protein content by an ELISA technique, or a reagent and/or an instrument required for detecting the protein content by a protein chip or a test paper.
The substance for detecting the expression amount of mRNA encoded by the CADPS2 gene can include specific amplification primers and/or probes for detecting the mRNA of the CADPS2 gene. In one embodiment of the application, the specific amplification primers used to detect the CADPS2 gene mRNA consist of a single stranded DNA molecule as shown in sequence 1 and a single stranded DNA molecule as shown in sequence 2. The probe used to detect the CADPS2 gene mRNA is a single-stranded DNA molecule shown in sequence 3, the 5 'end of the probe can be labeled with a fluorescent reporter group (e.g., FAM), and the 3' end of the single-stranded probe can be labeled with a fluorescence quencher group (e.g., BHQ).
Still further, the expression level is a relative expression level of a reference gene of the CADPS2 gene, and specifically may be a ratio of the expression level of the CADPS2 gene to the expression level of the reference gene. The expression level of the CADPS2 gene and the expression level of the reference gene may be copy numbers obtained from standard curves and CT values.
Still further, the means for detecting the expression level of mRNA encoded by the CADPS2 gene may further comprise specific amplification primers and/or probes for detecting mRNA of the reference gene. The reference gene may specifically be the ABL1 gene. In one embodiment of the present application, the specific amplification primers for detecting the ABL1 gene mRNA consist of a single-stranded DNA molecule shown in sequence 4 and a single-stranded DNA molecule shown in sequence 5; the probe for detecting ABL1 gene mRNA is a single-stranded DNA molecule shown in a sequence 6, wherein the 5 '-end of the probe can be marked with a fluorescence reporting group (such as FAM), and the 3' -end of the single-stranded probe can be marked with a fluorescence quenching group (such as BHQ).
The kit can also comprise a data processing device A; a module is arranged in the data processing device A; the module has the following functions: diagnosing whether the testee is a multiple myeloma patient according to the relative expression level of the CADPS2 in the marrow mononuclear cells of the testee: if the relative expression level of CADPS2 in the subject's bone marrow mononuclear cells is greater than that of a healthy control, the subject is or is suspected of being a patient with multiple myeloma; otherwise, the subject is not or suspected of not being a multiple myeloma patient.
The kit may further comprise a data processing device B; a module is arranged in the data processing device B; the module has the following functions: assessing the prognostic risk of a multiple myeloma patient based on the relative expression level of CADPS2 in bone marrow mononuclear cells of the multiple myeloma patient: the risk of prognosis for patients with multiple myeloma in the low expression set of CADPS2 is lower or candidates for patients with multiple myeloma in the low expression set of CADPS 2.
The kit may further comprise a data processing device C; the data processing device C is internally provided with a module; the module has the following functions: assessing the progression-free survival of the multiple myeloma patients based on the relative expression of CADPS2 in bone marrow mononuclear cells of the multiple myeloma patients: the progression free survival of the patients with multiple myeloma in the low expression set of CADPS2 is higher than or candidates for patients with multiple myeloma in the high expression set of CADPS 2.
The kit may further comprise a data processing device D; a module is arranged in the data processing device D; the module has the following functions: assessing the progression free survival time of the multiple myeloma patient based on the relative expression of CADPS2 in bone marrow mononuclear cells of the multiple myeloma patient: the progression free survival time of the patients with multiple myeloma in the CADPS2 low expression group is longer than or a candidate for multiple myeloma patients longer than the CADPS2 high expression group.
The kit may further comprise a data processing device D; a module is arranged in the data processing device D; the module has the following functions: assessing the disease progression of the multiple myeloma patient based on the relative expression of CADPS2 in the bone marrow mononuclear cells of the multiple myeloma patient: multiple myeloma patients in the CADPS2 low expression group have a lower risk of relapse than or a candidate for multiple myeloma patients in the CADPS2 high expression group.
The above-described high and low CADPS2 expression sets can be determined as follows: taking isolated bone marrow of a group to be detected consisting of a plurality of patients with multiple myeloma without any treatment measures as a specimen, measuring the relative expression quantity of mRNA encoded by a CADPS2 gene in each specimen, arranging the group to be detected according to the sequence from low to high of the relative expression quantity of the mRNA, performing quartering, taking 3/4 of the group to be detected with low expression quantity as a CADPS2 low expression group, and taking the rest 1/4 of the groups to be detected as a CADPS2 high expression group.
In any of the above applications or kits, the nucleotide sequence of the CADPS2 is shown as sequence 9 in the sequence Listing (NCBI Reference Sequence: NM-017954.11).
In the present application, the prognostic risk is a prognostic risk of a patient with primary diagnosis of multiple myeloma. The prognosis risk can be embodied as all or part of the following indexes: progression free survival time, progression free survival rate. The longer the progression free survival, the lower the risk of prognosis; the higher the progression free survival, the lower the risk of prognosis.
The disease progression refers to the risk of relapse after remission in patients with multiple myeloma.
In any of the above applications or kits, the screening or aiding in screening of multiple myeloma patients includes screening or aiding in screening of primary multiple myeloma patients and screening or aiding in screening of relapsing multiple myeloma patients.
In any of the above applications or kits, the multiple myeloma is adult multiple myeloma.
According to the application, the CADPS2 expression level in bone marrow mononuclear cells of the MM patient is analyzed by an RT-qPCR method, and the high expression of the CADPS2 is found to be a risk factor of low Progression Free Survival (PFS) of the MM patient for the first time by combining clinical course and survival data. The CADPS2 has important value in the diagnosis and prognosis of multiple myeloma.
Drawings
FIG. 1 is a graph showing the expression level of CADPS2 in bone marrow cells of a primary and fully palliative MM patient and a healthy donor. Lines represent median and quartile values; * P < 0.0001.
FIG. 2 is a ROC graph of a CADPS2 diagnostic first diagnosis MM.
FIG. 3 is a graph showing the relationship between the expression level of CADPS2 and the clinical course of MM. Expression levels of CADPS2 in bone marrow single nuclear cell specimens of 3 MM patients for initial diagnosis, remission and disease progression.
FIG. 4 is a graph showing the relationship between the expression level of CADPS2 and the progression-free survival of MM prognosis.
Detailed Description
The following detailed description of the application is provided in connection with the accompanying drawings that are presented to illustrate the application and not to limit the scope thereof. The examples provided below are intended as guidelines for further modifications by one of ordinary skill in the art and are not to be construed as limiting the application in any way.
The experimental methods in the following examples, unless otherwise specified, are conventional methods, and are carried out according to techniques or conditions described in the literature in the field or according to the product specifications. Materials, reagents and the like used in the examples described below are commercially available unless otherwise specified.
The CADPS2 gene sequence in the application is shown as a sequence 9 in a sequence table (NCBI Reference Sequence: NM_ 017954.11).
Example 1, use of CADPS2 as a marker in the diagnosis and prognosis of multiple myeloma
1. Study object and method
1. Study object
Bone marrow specimens collected from 142 cases of primary-diagnosis multiple myeloma patients from the institute of hematopathy in the civil hospital at university of Beijing during 1 month to 12 months of 2016 were taken as subjects. The 142 cases of primary diagnosis are 91 cases of patients with multiple myeloma, 51 cases of men and 51 cases of women, the median age is 60 years, and the age range is 36-87 years; among them 115 patients with complete prognosis data, were followed up to death, no follow-up or 8 months 2019. The diagnostic criteria for multiple myeloma refer to guidelines of the national integrated cancer network (NCCN), and the staging is performed according to the Durie-Salmon (D-S) staging system, the International Staging System (ISS) and the revised International staging system (R-ISS). Treatment and efficacy assessments for patients with multiple myeloma are made with reference to the guidelines above. Progression Free Survival (PFS) is defined as the time from the onset of primary treatment to the first occurrence of disease progression, which is an event.
In addition, 96 bone marrow specimens were collected during follow-up of primary patients with multiple myeloma, including 24 bone marrow specimens that were treated to obtain Complete Remission (CR), 26 bone marrow specimens that were treated to obtain Very Good Partial Remission (VGPR), 31 bone marrow specimens that were treated to obtain Partial Remission (PR), 4 disease Stabilization (SD), and 26 bone marrow specimens that were treated to develop disease progression. Normal control bone marrow specimens were obtained from adult healthy volunteers in 46 total.
Specimens used in this study protocol were approved by the ethical committee of the civil hospital at the university of Beijing. All healthy volunteers and patients signed informed consent.
2. Bone marrow mononuclear cell extraction and RT-qPCR
Mononuclear cells in bone marrow specimens were separated using Ficoll lymphocyte separation medium and density gradient centrifugation, and RNA was extracted and reverse transcribed into cDNA. RT-qPCR was performed using cDNA as a template, and a CADPS2 primer pair (the CADPS2 primer pair consists of a CADPS2 upstream primer and a CADPS2 downstream primer, the amplification product size is 110bp, and the nucleotide sequence is shown as sequence 7 in the sequence table) and a CADPS2 probe. And (3) taking cDNA as a template, and performing RT-qPCR by using an ABL1 primer pair (the ABL1 primer pair consists of an ABL1 upstream primer and an ABL1 downstream primer, the size of an amplified product is 124bp, and a nucleotide sequence is shown as a sequence 8 in a sequence table) and an ABL1 probe. The following 10 μl PCR reaction system was configured using PCR Master Mix kit: 5 mu L1×Universal PCR Master Mix; upstream primer 0.9. Mu.M, downstream primer 0.9. Mu.M, probe 0.25. Mu.M; 150-500ng cDNA, primer sequences and fluorescent probe sequences are shown in Table 1.qPCR was performed using an ABI 7500FAST PCR amplification apparatus under the following reaction conditions: 50℃2min,95℃10min, then 95℃15s,60℃1min for 40 cycles. The copy numbers of CADPS2 and ABL1 were calculated using ABL1 as an internal reference and a standard curve method. Serial dilutions of ABL1 expressing plasmids (see "Gabert J, beilar E, van der Velden VH, bi W, grimwade D, pallysgaard N, et al Standard and quality control studies of" real-time "quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia-a Europe Against Cancer program. Leukemia.2003;17:2318-2357" ABL1 plasmid "herein) (10) 6 、10 5 、10 4 、10 3 、10 2 、10 1 And 10 0 Copy/. Mu.L) and CADPS2 positive bone marrow specimens were used to construct standard quantification curves. The curve threshold is set to 0.082. Obtaining Ct values of ABL1 and CADPS2 through amplification curves of sample reference genes ABL1 and CADPS2 genes and a set threshold (0.082), obtaining copy numbers of the sample ABL1 and the CADPS2 according to an ABL1 standard curve (because the CADPS2 and the ABL1 amplification efficiency are similar and are calculated by referring to the ABL1 standard curve for reducing experimental errors), dividing the copy number of the CADPS2 by the copy number of the ABL1 to obtain the expression quantity of the sample CADPS2, multiplying the result by one hundred percent for consistency with the form of a report sent by clinical routine, and finally representing the result in the form of the copy number of the CADPS 2/the copy number multiplied by the percentage of the ABL1 = the expression quantity of the sample CADPS 2.
Table 1, CADPS2 and ABL1 primers and probe sequences
| Primer(s) | Sequence (5 '-3') |
| CADPS2 upstream primer | 5'-ACCCTACCCTGCTCCATTACAG-3' (sequence 1) |
| CADPS2 downstream primer | 5'-CTCCTCAAATCTTTCTTTTTCTTCCA-3' (sequence 2) |
| CADPS2 probe | 5'-FAM-CTCATGTGCACGGCAACAGGCC-BHQ-3' (sequence 3) |
| ABL1 upstream primer | 5'-TGGAGATAACACTCTAAGCATAACTAAAGGT-3' (sequence 4) |
| ABL1 downstream primer | 5'-GATGTAGTTGCTTGGGACCCA-3' (sequence 5) |
| ABL1 probe | 5'-FAM-CCATTTTTGGTTTGGGCTTCACACCATT-BHQ-3' (sequence 6) |
3. Statistical analysis
Statistical analysis was performed using SPSS25.0, graphpad Prism 7. The difference of the two groups of data is compared, the chi-square test is adopted for classification variable data, the t test or Mann-Whitney U test is adopted for continuous variable data, and the difference of P < 0.05 is statistically significant. Subject work (receiver operating characteristic, ROC) curves were used to evaluate the specificity and sensitivity of diagnostic indicators. The Jooden Index (Youden Index) is used to calculate the cut-off value for the diagnosis. Survival analysis was performed using Kaplan-Meier using log-rank test. The Cox proportional hazards regression model performs multi-factor analysis. P < 0.05 is statistically significant.
2. Results of the study
1. Expression level of CADPS2 in multiple myeloma
142 bone marrow specimens of primary patients with multiple myeloma, 26 bone marrow specimens of multiple myeloma patients who obtained Complete Remission (CR) after treatment (including 24 bone marrow specimens of multiple myeloma patients with primary data and continuous follow-up data and 2 bone marrow specimens of multiple myeloma patients without primary data), and 46 healthy donor control bone marrow specimens were analyzed for CADPS2 expression levels.
The results show that the expression level of CADPS2 in bone marrow cells of primary patients with multiple myeloma (median 272.97%; range 0-3731.21%) is significantly higher than that of patients with complete remission (median 1.23%; range 0.12-75.68%; P < 0.0001) and healthy donor controls (median 3.00%; range 0.27-17.33%; P < 0.0001). While there was no significant difference in expression levels between the fully relieved patient and healthy donor (p=0.586) (fig. 1).
ROC curve analysis showed that the area under the curve (area under the curve, AUC) for the CADPS2 diagnostic MM was 0.961 (95% confidence interval 0.931-0.990; p < 0.0001; fig. 2), with a maximum approximate bench index corresponding to a CADPS2 expression level of 20.58%. With this being the diagnostic threshold for MM, the CADPS2 over-expression rate in the initial MM was 93.66%.
2. The CADPS2 expression level is correlated with the clinical course of multiple myeloma
To further investigate the relationship of CADPS2 to the clinical course of adult multiple myeloma, analysis of the levels of CADPS2 expression was performed on bone marrow specimens from 3 adult multiple myeloma patients at initial diagnosis, complete remission, and disease progression.
The results showed that the level of CADPS2 expression in bone marrow cells was significantly reduced compared to the initial diagnosis of bone marrow cells at complete remission, whereas the level of CADPS2 expression in bone marrow cells was significantly increased compared to complete remission of bone marrow cells at disease progression (recurrence) (FIG. 3).
3. Relationship of CADPS2 expression levels to general clinical characteristics of multiple myeloma
142 patients initially diagnosed with multiple myeloma are divided into a high CADPS2 expression group and a low CADPS2 expression group according to the upper quarter of the CADPS2 expression level (514.00%) as follows: determining the relative expression quantity of the CADPS2 in each patient bone marrow specimen, arranging the groups to be tested according to the sequence from low to high of the relative expression quantity of the CADPS2, performing quartering, taking 3/4 of the groups to be tested with low expression quantity as a CADPS2 low expression group, taking the rest 1/4 of the groups to be tested as a CADPS2 high expression group, and analyzing the relation between the expression level of the CADPS2 and the general clinical characteristics of the multiple myeloma.
The results showed that the R-ISS stage at the initial visit was more prone to stage III (p=0.027) for the patients in the cals 2 high expression group, while the cals (2.75 mmol/L, p=0.012), the bone marrow plasma cell fraction was higher (p=0.021), and the peripheral blood leukocytes were higher (p=0.010) for the patients in the cals 2 high expression group. In addition, patients in the CADPS2 high expression group were more prone to high risk cytogenetic markers (P=0.000) associated with poor prognosis (Table 2).
TABLE 2 relationship between CADPS2 expression levels and general clinical characteristics of adult primary multiple myeloma
4. Relationship of CADPS2 expression level to prognosis of patients with multiple myeloma
Survival analysis was performed on 115 patients with multiple myeloma with prognostic information by Kaplan-Meier method, and according to the above step 3, the patients were divided into two groups (CADPS 2 high expression group and CADPS2 low expression group) according to the relative expression amount of the CADPS2, and it was found that 48 month Progression Free Survival (PFS) was 5.86% and 25.51% in the CADPS2 high expression group (N=29) patient and the CADPS2 low expression group (N=86) patient, respectively, and the CADPS2 high expression group patient had a shorter progression free survival time (median 17.47 months vs.25.83 months; P=0.02; FIG. 4). To further clarify the effect of CADPS2 on prognosis, the following factors were included in the multi-factor analysis, as the factors affecting MM prognosis were more numerous: ISS stage (I/II vs.iii), CADPS2 expression level at initial diagnosis (. Gtoreq.vs. < 514%), hematopoietic stem cell transplantation (vs. no). The results show that high expression of CADPS2 is an independent risk factor for progression-free survival (Table 3).
TABLE 3 multifactorial analysis of Progression Free Survival (PFS) in adult multiple myeloma patients
The present application is described in detail above. It will be apparent to those skilled in the art that the present application can be practiced in a wide range of equivalent parameters, concentrations, and conditions without departing from the spirit and scope of the application and without undue experimentation. While the application has been described with respect to specific embodiments, it will be appreciated that the application may be further modified. In general, this application is intended to cover any variations, uses, or adaptations of the application following, in general, the principles of the application and including such departures from the present disclosure as come within known or customary practice within the art to which the application pertains. The application of some of the basic features may be done in accordance with the scope of the claims that follow.
Claims (10)
- Use of cadps2 as a marker in any one of the following (a 1) - (a 12):(a1) Preparing a product for diagnosing or aiding in diagnosing multiple myeloma;(a2) Preparing a product for screening or assisting in screening patients with multiple myeloma;(a3) Preparing a product for assessing or aiding in assessing prognosis of a patient with multiple myeloma;(a4) Preparing a product for assessing or aiding in assessing the progression-free survival of a patient with multiple myeloma;(a5) Preparing a product for assessing or aiding in assessing the progression free survival of a patient with multiple myeloma;(a6) Preparing a product for evaluating or aiding in evaluating progression of a disease course in a patient with multiple myeloma;(a7) Diagnosing or aiding in the diagnosis of multiple myeloma;(a8) Screening or aiding in screening patients with multiple myeloma;(a9) Assessing or aiding in assessing prognosis of a patient with multiple myeloma;(a10) Assessing or aiding in assessing progression-free survival of a patient with multiple myeloma;(a11) Assessing or aiding in assessing the progression free survival of a patient with multiple myeloma;(a12) The disease course of the patients with the multiple myeloma is evaluated or assisted in evaluation.
- 2. Use of a substance for detecting the expression level of CADPS2 in any one of the following (a 1) to (a 12):(a1) Preparing a product for diagnosing or aiding in diagnosing multiple myeloma;(a2) Preparing a product for screening or assisting in screening patients with multiple myeloma;(a3) Preparing a product for assessing or aiding in assessing prognosis of a patient with multiple myeloma;(a4) Preparing a product for assessing or aiding in assessing the progression-free survival of a patient with multiple myeloma;(a5) Preparing a product for assessing or aiding in assessing the progression free survival of a patient with multiple myeloma;(a6) Preparing a product for evaluating or aiding in evaluating progression of a disease course in a patient with multiple myeloma;(a7) Diagnosing or aiding in the diagnosis of multiple myeloma;(a8) Screening or aiding in screening patients with multiple myeloma;(a9) Assessing or aiding in assessing prognosis of a patient with multiple myeloma;(a10) Assessing or aiding in assessing progression-free survival of a patient with multiple myeloma;(a11) Assessing or aiding in assessing the progression free survival of a patient with multiple myeloma;(a12) The disease course of the patients with the multiple myeloma is evaluated or assisted in evaluation.
- 3. Use according to claim 1 or 2, characterized in that: the substance for detecting the expression level of the CADPS2 comprises reagents and/or instruments for detecting the expression level of the CADPS2 in the bone marrow mononuclear cells.
- 4. A use according to any one of claims 1-3, characterized in that: the reagent for detecting the expression amount of the CADPS2 in the bone marrow mononuclear cells comprises a specific amplification primer and/or a probe for detecting the mRNA of the CADPS2 gene.
- 5. The use according to claim 4, characterized in that: the specific amplification primer consists of a single-stranded DNA molecule shown in a sequence 1 in a sequence table and a single-stranded DNA molecule shown in a sequence 2 in the sequence table;the probe is a single-stranded DNA molecule shown in a sequence 3 in a sequence table.
- 6. A kit comprising a substance that detects the amount of expression of a CADPS 2; the function of the kit is any one of the following (c 1) - (c 6):(c1) Diagnosing or aiding in the diagnosis of multiple myeloma;(c2) Screening or aiding in screening patients with multiple myeloma;(c3) Assessing or aiding in assessing the risk of prognosis of a patient with multiple myeloma;(c4) Assessing or aiding in assessing progression-free survival of a patient with multiple myeloma;(c5) Assessing or aiding in assessing the progression free survival of a patient with multiple myeloma;(c6) The disease course of the patients with the multiple myeloma is evaluated or assisted in evaluation.
- 7. The kit of claim 6, wherein: the substance for detecting the expression level of the CADPS2 comprises reagents and/or instruments for detecting the expression level of the CADPS2 in the bone marrow mononuclear cells.
- 8. The kit according to claim 6 or 7, wherein: the reagent for detecting the expression quantity of the CADPS2 in the marrow mononuclear cells comprises a specific amplification primer and/or a probe and a probe for detecting the mRNA of the CADPS2 gene.
- 9. The kit of claim 8, wherein: the specific amplification primer consists of a single-stranded DNA molecule shown in a sequence 1 in a sequence table and a single-stranded DNA molecule shown in a sequence 2 in the sequence table;the probe is a single-stranded DNA molecule shown in a sequence 3 in a sequence table.
- 10. The use according to any one of claims 1 to 5 or the kit according to any one of claims 6 to 9, characterized in that: the nucleotide sequence of the CADPS2 gene is shown as a sequence 9 in a sequence table.
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