CN113512589B - Application of PRUNE1 gene detection in prognosis of multiple myeloma patients - Google Patents
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Abstract
The invention relates to application of PRUNE1 gene detection in prognosis of multiple myeloma patients, belonging to the technical field of biological medicines. The invention provides an application of detecting the copy number of PRUNE1 gene in prognosis of multiple myeloma patients with 1q21 amplification, which predicts the prognosis of the patients by detecting the copy number of PRUNE 1. Through PRUNE1 gene copy number analysis, the survival prognosis of MM patients accompanied with 1q21gain (CKS 1B gain) is better layered, and clinicians are assisted to better judge the prognosis of the patients so as to make more refined clinical diagnosis and treatment strategies.
Description
Technical Field
The invention relates to an application of PRUNE1 gene detection in prognosis of multiple myeloma patients, belonging to the technical field of biological medicines.
Background
Multiple Myeloma (MM) is a hematological malignancy that results from the abnormal proliferation of clonal plasma or plasmablasts in the bone marrow and the secretion of large amounts of ineffective monoclonal antibodies. MM is very heterogeneous and the disease is currently considered incurable. Chromosomal 1q21 copy number amplification (1 q21 Gain) is one of the most common cytogenetic abnormalities in MM, particularly in non-white ethnic patient populations. According to literature reports, about 30-50% of the initial MM patients can detect 1q21Gain, and the positive rate of the patients with relapse refractory MM can even reach 70%. However, despite such high positive rates, the prognostic value status of 1q21Gain in MM remains controversial until now. Therefore, there is a need in the art for a method of determining the prognosis of MM patients.
Disclosure of Invention
The invention aims to solve the technical problem of carrying out prognosis stratification on MM patients accompanied by 1q21 Gain.
In order to solve the problems, the technical scheme adopted by the invention is to provide an application of detecting the copy number of PRUNE1 gene in the prognosis of MM patients accompanied by 1q21Gain, and the prognosis of the patients is predicted by detecting the copy number of PRUNE 1.
Preferably, the copy number of PRUNE1 is measured in CD138+ plasma cells of MM patients accompanied by 1q21 Gain.
The invention provides application of detecting PRUNE1 gene copy number in prognosis of MM patients accompanied by 1q21Gain, in particular to application in preparing a detection kit or a gene probe for predicting prognosis of MM patients.
Compared with the prior art, the invention has the following beneficial effects:
according to the application of PRUNE1 gene copy number detection in MM patient prognosis accompanied with 1q21 amplification, through PRUNE1 gene copy number analysis, the survival prognosis of MM patients accompanied with 1q21gain (CKS 1 Bgain) can be better layered, and clinicians can be assisted to better judge the prognosis of patients, so that more refined clinical diagnosis and treatment strategies can be formulated.
Drawings
FIG. 1 is a graph of a one-factor survival analysis combined with Lasso regression analysis; the prognostic significance of the RNA expression value of the coding gene on chromosome 1q21 on the survival of MM patients accompanied by 1q21Gain was clarified.
After RNA expression values of 215 coding genes on chromosome 1q21 are combined with Survival data (Overall Survival, OS and disease-Free Progression, progression Free Survival, PFS) of a patient accompanied by 1q21gain in MMRF Coompass to carry out single-factor Survival analysis, further carrying out Lasso regression analysis on genes with statistical significance; wherein, the A picture shows that 13 genes have significant statistical significance on OS, and the B picture shows that 5 genes have significant statistical significance on PFS. ( RNA expression values as input independent variables and patient survival values as target dependent variables. The left graph is cross validation, the right graph is linear regression, each curve represents the variation locus of each independent variable coefficient, the ordinate is the value of the coefficient, the lower abscissa is log (lambda), and the upper abscissa is the number of nonzero coefficients in the model at the moment. )
FIG. 2 is a graph showing the correlation between RNA expression values and DNA copy numbers. Pearson correlation plots were performed on RNA expression values of 4 genes selected after multifactor Cox regression analysis and DNA Copy number (CN, copy number) of the gene in the same patient. The numbers in each box represent the correlation coefficient, the boxes with background color represent significant statistical correlation of RNA expression values with the gene DNA copy number of the same patient (p < 0.05), with darker colors having smaller p values.
FIG. 3 is a graph of the analysis of the survival of MM patients with 1q21Gain in the MMRF CoomPass database by using the X-tile software developed by Yale university; among them, the optimal cutoff value of the PRUNE1 gene CN (DNA Copy number, CN, copy number) is CN =4 (Ratio = 2). Single factor survival analysis results suggest: patient OS was significantly shortened (p = 0.046) for PRUNE1 CN ≧ 4. The abscissa is the patient's survival time and the ordinate is the percentage of patients who are alive or lost to visit.
FIG. 4 is a graph of the analysis of the survival of MM patients with 1q21gain in the MMRF CoomPass database by applying the X-tile software developed by Yale university; the optimal cutoff value for the PRUNE1 gene CN is CN =4 (Ratio = 2). Single factor survival analysis results suggest: patients with PRUNE1 CN ≧ 4 had a significant reduction in PFS (p = 0.021). The abscissa is the patient's survival time and the ordinate is the percentage of patients who are alive or lost to visit.
FIG. 5 is a graph of the prognostic survival of a subset of MM patients in the PRUNE1 CN in combination with the 1q21gain FISH probe in predicting the MMRF Coomppass database; (PFS p <0.0001, OS p-Ap-0.0001). The abscissa is the patient survival time and the ordinate is the percentage of patients who survive or are not visited.
FIG. 6 is a graphical representation of significant stratification of PRUNE1 CN conjugated 1q21gain FISH probe in the hematological patient specimens from the secondary Zhongshan hospital, university of Compound Dane, for survival of 1q21gain MM patients; (PFS: p =0.11, os. The abscissa is the patient survival time and the ordinate is the percentage of patients who survive or are not visited.
Detailed Description
In order to make the invention more comprehensible, preferred embodiments are described in detail below with reference to the accompanying drawings:
the invention provides an application of detecting the copy number of PRUNE1 gene in the prognosis of MM patients accompanied by 1q21 Gian, and the prognosis of the patients is predicted by detecting the copy number of PRUNE 1. Copy number of PRUNE1 was determined in CD138+ plasma cells of MM patients accompanied by 1q21 Gain.
The invention provides an application of detecting PRUNE1 gene copy number in MM patient prognosis accompanied by 1q21g Gain, in particular to an application in preparing a detection kit or a gene probe for predicting multiple myeloma patient prognosis.
Examples
1. Selecting a relative Clinical Outcome in MM to Personal Assessment of Genetic Profile (CoMMpass) database supported by Multiple Myelomas Research Foundation (MMRF) in the United states with 1q21gain MM patient (205 bits in total) bone marrow CD138+ plasma cell RNA-seq result for analysis, combining the RNA expression values of 215 coding genes on chromosome 1q21 with the Survival data of the patient (Overall Survival, overtur Survival, OS and disease-Free Progression, progress Free Survival, PFS), and carrying out single-factor Survival analysis and Lasso regression analysis; (for example, as shown in fig. 1, after RNA expression values of 215 coding genes on chromosome 1q21 are combined with survival data of MMRF mammpass patients to perform single-factor survival analysis, further Lasso regression analysis is performed on statistically significant genes, and finally a fig. 13 genes are selected to have significant statistical significance on OS, and 5 genes in a B diagram have significant statistical significance on PFS.) the statistically significant genes are further incorporated into multi-factor survival analysis to find that RNA expression values of FAM72D, PRUNE1 and EFNA3 have significant statistical significance on OS of MM patients accompanied by q11121 gain (p <0.05, table 1), and that FAM72D and themm 4 have significant statistical significance on PFS of MM patients accompanied by 1q21gain (p <0.05, table 2);
table 1.Multivariant cox regression analysis for OS of MM tissues with 1q21gain in MMRF CoMMpas RNA-seq dataset.
*p<0.05
Table 2.Multivariant cox regression analysis for PFS of MM tissues with 1q21gain in MMRF CoMMpas RNA-seq dataset.
*p<0.05
2. The RNA expression values of the 4 genes (FAM 72D, PRUNE1, EFNA3, THEM 4) having the above statistical significance were subjected to Pearson correlation analysis with the DNA Copy Number (CN) of the gene. The results suggest that p >0.05 of FAM72D, which was removed. The RNA expression values of PRUNE1 correlated most strongly with CN values at their DNA level (p < 0.001) and the correlation coefficient R =0.43 (Pearson correlation analysis was performed on RNA expression values of 4 genes selected after multifactorial Cox regression analysis and DNA Copy number (Copy number) of the gene in fig. 2).
3. The results of incorporating the CNs of the above-mentioned 3 genes (PRUNE 1, EFNA3, THEM 4) into a multifactorial survival analysis (multivariate cox regression analysis) suggest that the CN of PRUNE1 DNA has a significant statistical difference in OS of patients accompanied by chromosome 1q21 amplification (p =0.029, hr (95% ci) =47.064 (1.480-1496.300)) (table 3), and that the p-value of the prognostic effect on PFS of patients has not reached 0.05 but still had a significant tendency (p =0.084, hr (95% ci) =20.187 (0.871-606.995)).
Table 3 Multivariant cox regression analysis for OS and PFS of MM substrates with 1q21gain in MMRF Coomppass WES dataset.
*p<0.05
4. By analyzing the survival of MM patients with 1q21gain in MMRF mammpass database using X-tile software developed at yale university, the optimal cutoff for the PRUNE1 gene CN was found to be CN =4 (Ratio =2, i.e. CN of tumor patients divided by CN of normal human this gene). Single factor survival analysis results suggest: both the OS (FIG. 3, p = 0.046) and PFS (FIG. 4, p = 0.021) of PRUNE1 CN ≧ 4 patients were significantly shortened. ( The optimal cutoff value for the PRUNE1 gene CN in fig. 3 is CN =4 (Ratio = 2). Single factor survival analysis results suggest: patient OS with PRUNE1 CN ≧ 4 was significantly shortened (p = 0.046). The optimal cutoff value for the PRUNE1 gene CN in fig. 4 is CN =4 (Ratio = 2). Single factor survival analysis results suggest: patients with PRUNE1 CN ≧ 4 had significantly shortened PFS (p = 0.021). )
5. All analyzable MM patients in the MMRF mammpass database (total 712 patients) were divided into 3 groups: (1) 1q21gain FISH probe is negative, and PRUNE1 CN is less than or equal to 3; (2) 1q21gain FISH probe positive, PRUNE1 CN is less than or equal to 3; (3) 1q21gain FISH probe positive, PRUNE1 CN > 3. The results suggest that PRUNE1 in combination with 1q21gain FISH probe could well predict the prognostic survival of this subset of MM patients in the MMRF Coompass database (e.g., PFS p <0.0001, OS p < -0.0001 in FIG. 5; PRUNE1 CN in combination with 1q21gain FISH probe could well predict the prognostic survival of this subset of MM patients in the MMRF Coompass database (PFS p <0.0001, OS p < -0.0001)).
6. And (3) verification set: exon Sequencing (WES) was performed on 25 naive MM patients with 1q21gain, analyzed the CN of PRUNE1 and divided into 3 groups of PRUNE1 CN =2,3, >3 for a single factor survival analysis to validate the above theory, as shown in fig. 6, fig. 6 in patient specimens, PRUNE1 CN in combination with 1q21gain FISH probe still significantly stratifies the MM patient OS of 1q21gain well (PFS: p =0.11, OS p = 0.022.
Further incorporating existing putative MM patient prognostic high risk factors (including del 17p, del 13q14, t (11, 14), t (4, 14)) together with PRUNE1 CN into a multi-factor survival assay, the results suggest that PRUNE1 CN still has significant prognostic significance for OS in this subgroup of patients (see table 4
Table 4.Multivariant cox regression analysis for OS and PFS of MM substrates with 1q21gain in Department of hematology, zhongshan Hospital.
7. Chromosome 1q21 is a fragment in which 215 genes are encoded. The currently accepted FISH probe for detecting the chromosome 1q21Gain is the most authoritative probe with the number of 1q21/CKS 1B. The CDC28 protein kinase regulatory subunit 1B (CDC 28 protein kinase regulatory library 1B, CKS1B) gene is located in the minimal amplification region between 153 and 154Mb on band 1 of long arm 2 of chromosome 1. In other words, the patient clinically diagnosed with chromosome 1q21gain is actually the patient of gene CKS1B gain.
The invention combines the RNA-seq and WES data of a database patient to carry out survival analysis of the patient and correlation analysis of RNA expression level and DNA (deoxyribonucleic acid) CNs, uses CNs of MM patient specimens accompanied by 1q21gain to carry out verification, finally further verifies the function of PRUNE1 gene for promoting cell proliferation or transfer through cell experiments, and finally proves that the PRUNE1 gene can further better stratify the survival prognosis of MM patients accompanied by 1q21gain (CKS 1B gain) and assist clinicians to better judge the prognosis of the patients so as to specify a more refined clinical diagnosis and treatment strategy.
PRUNE1 has 8 exon Coding (CDS) regions, and 3 internal controls were used by default for tumor sample copy number detection, with three replicates per sample. Primers were designed for 11 fragments (containing three internal references) of the PRUNE1 gene, and quantitative PCR detection was performed. Control experiments were performed using normal DNA from normal healthy persons as standards.
Quantitative copy number detection of the predetermined candidate regions was performed using the Sybr green method using the Life technologies 7900 fluorescent RT-PCR detection system. RT-PCR sample experiment requires: the purity of the sample is as follows: OD260/280 should be between 1.8-2.0, OD 260/230 should be above 1.8; sample concentration: the minimum concentration is not lower than 20 ng/mu l; total amount of sample: the total amount of each sample is not less than 300ng; the total detection fragments (including all the reference genes) are increased by 100ng for each fragment increased by more than 5; sample solvent: it was dissolved in distilled water or TE (pH 8.0).
Copy number of PRUNE1 was detected in CD138+ plasma cells of MM patients with 1q21gain to predict patient prognosis.
While the invention has been described with respect to a preferred embodiment, it will be understood by those skilled in the art that the foregoing and other changes, omissions and deviations in the form and detail thereof may be made without departing from the scope of this invention. Those skilled in the art can make various changes, modifications and equivalent arrangements, which are equivalent to the embodiments of the present invention, without departing from the spirit and scope of the present invention, and which may be made by utilizing the techniques disclosed above; meanwhile, any changes, modifications and variations of the above-described embodiments, which are equivalent to those of the technical spirit of the present invention, are within the scope of the technical solution of the present invention.
Claims (3)
1. The application of a reagent for detecting the copy number of PRUNE1 gene in preparing a diagnostic product for prognosis of multiple myeloma patients with 1q21 amplification is characterized in that: by detecting the copy number of PRUNE1, the prognosis of the patient is predicted.
2. The use of claim 1, wherein: the copy number of PRUNE1 was determined in CD138+ plasma cells of MM patients accompanied by 1q21 gain.
3. Application of a reagent for detecting the copy number of PRUNE1 gene in preparing a detection kit or a gene probe for prognosis of multiple myeloma patients with 1q21 amplification.
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| CN110734979A (en) * | 2019-11-14 | 2020-01-31 | 北京大学人民医院(北京大学第二临床医学院) | Application of OC-STAMP as marker for evaluating prognosis risk of multiple myeloma patient |
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| US11141709B2 (en) * | 2016-11-04 | 2021-10-12 | Washington University | Automated exposition of known and novel multiple myeloma genomic variants using a single sequencing platform |
| US20210087638A1 (en) * | 2019-09-23 | 2021-03-25 | Dana-Farber Cancer Institute, Inc. | Next-generation sequencing assay for genomic characterization and minimal residual disease detection in the bone marrow, peripheral blood, and urine of multiple myeloma and smoldering myeloma patients |
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| CN110734979A (en) * | 2019-11-14 | 2020-01-31 | 北京大学人民医院(北京大学第二临床医学院) | Application of OC-STAMP as marker for evaluating prognosis risk of multiple myeloma patient |
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