Model for judging responsiveness of platinum chemotherapeutic drugs and application thereof

Abstract

The invention discloses a model for judging platinum chemotherapeutic drug responsiveness of an ovarian cancer patient, which is characterized in that a homologous recombination repair defect score of a sample is firstly obtained, and a homologous recombination repair defect state of the sample is judged based on a positive threshold value of the homologous recombination repair defect score; and judging the platinum chemotherapeutic drug responsiveness of the ovarian cancer patient in combination with the expression level of the to-be-detected sample gene. When the model is used for judging the responsiveness of the platinum chemotherapeutic drugs of the ovarian cancer patient to be detected, the accuracy is higher than 80%, and compared with the mode that the homologous recombination repair defect state is judged only through the homologous recombination repair defect score, and then the responsiveness of the platinum chemotherapeutic drugs of the ovarian cancer patient is judged, the accuracy is improved by about 11%; the model provided by the invention can be used for accurately judging the responsiveness of the platinum chemotherapeutic drugs of the to-be-detected ovarian cancer patient, so that guidance is provided for clinical use of platinum drugs.

Description

Technical Field

[0001] The present invention relates to the technical field of molecular biology, and in particular to a model for judging the responsiveness of platinum-based chemotherapy drugs and an application thereof. Background Art

[0002] Ovarian cancer (Ovarian Cancer, OV) is a common malignant tumor of the female reproductive system. There is currently no cure for ovarian cancer. The classic treatment is surgery combined with platinum chemotherapy, with an average 5-year survival rate of about 30%. Homologous Recombination Deficiency (HRD) status is a classic biological indicator currently used to predict and evaluate the efficacy of platinum chemotherapy. To a certain extent, it can group patients and expand the proportion of ovarian cancer patients who benefit from it from 20% to 50%.

[0003] Homologous Recombination Repair (HRR) is a DNA double-strand break (DSB) repair pathway based on complementary strand repair in cells. Due to its high fidelity, it is also the preferred repair method in cells. When the HRD state occurs in cells, HRR cannot be used normally, and DSBs will rely on alternative non-homologous end joining (NHEJ), microhomology mediated end joining (MMEJ) and single-strand annealing (SSA) pathways for repair. These methods do not completely rely on the template chain, and are prone to new gene mutations, which ultimately lead to genomic structural instability and cell death.

[0004] Platinum chemotherapy drugs (such as cisplatin, carboplatin, and oxaliplatin) induce DNA double-strand breaks (DSBs) and inhibit tumor cell proliferation by binding to DNA to form complex structures that are not conducive to cell transcription and replication. When ovarian cancer cells cannot use HRR for effective repair due to HRD, the DSBs induced by these drugs will make cancer cells rely on low-fidelity repair pathways for repair, further increasing genomic instability. Because these pathways are not precise enough, errors in the repair process will lead to the accumulation of more mutations, thereby activating intracellular stress responses and programmed death pathways (such as apoptosis), ultimately leading to cancer cell death. When tumor cells are in an HRD state, platinum chemotherapy drugs can more effectively kill them, so judging the patient's HRD status is considered to be an important biological marker for predicting the efficacy of platinum chemotherapy drugs.

[0005] At present, the judgment of HRD status is mainly based on the calculation of the number of loss of heterozygosity (LOH), the number of telomeric allelic imbalance (TAI) and the number of large-scale state transition (LST) by single or multiple, non-weighted or weighted evaluation (HRD score). For example, the FDA-approved test product Myriad CDx (Myriad Genetic Laboratories, Inc.) defines HRD positivity as tumor cells carrying BRCA1 / 2 somatic or germline pathogenic mutations and (or) HRD score ≥ 42. This threshold is set based on the fifth quartile of ovarian and breast cancer samples with BRCA defects. The CDx BRCA LOH (Foundation Medicine, Inc.) test defines HRD positivity as tumor cells carrying BRCA1 / 2 somatic or germline pathogenic mutations and / or LOH scores ≥ 16%.

[0006] These detection indicators have been verified in large-scale clinical studies, but they cannot fully reflect the effects of platinum chemotherapy in the real world, so the accuracy of their judgment of the HRD status of ovarian cancer patient samples needs to be improved. The main reasons include the following two points: (1) This evaluation method only considers the HRD status, but does not consider other factors such as tumor microenvironment, drug transport and efflux, upstream and downstream supplementation or abnormal activation of repair pathways; (2) It does not fully consider the expression of genes involved in the effect of platinum chemotherapy, and the status of these genes may not necessarily be reflected in exome sequencing or HRD status.

[0007] Therefore, a method is currently being developed that can more accurately determine the HRD status of ovarian cancer patient samples to guide the use of platinum-based chemotherapy drugs. Summary of the invention

[0008] The purpose of the present invention is to overcome the above-mentioned deficiencies of the prior art and to provide a model for judging the responsiveness of ovarian cancer patients to platinum-based chemotherapy drugs and its application.

[0009] The first objective of the present invention is to provide an application of a detection reagent in the preparation of a product for determining the responsiveness of platinum-based chemotherapy drugs in homologous recombination repair defect-positive ovarian cancer patients.

[0010] The second objective of the present invention is to provide a detection reagent for use in the preparation of a product for determining the responsiveness of platinum-based chemotherapy drugs in homologous recombination repair defect-negative ovarian cancer patients.

[0011] The third object of the present invention is to provide a detection reagent for use in preparing a product for determining the responsiveness of a platinum-based chemotherapy drug.

[0012] The fourth object of the present invention is to provide a product for determining the responsiveness of platinum-based chemotherapy drugs.

[0013] The fifth object of the present invention is to provide a model for determining the responsiveness of ovarian cancer patients with positive homologous recombination repair deficiency to platinum-based chemotherapy drugs.

[0014] The sixth objective of the present invention is to provide a model for determining the responsiveness of ovarian cancer patients with negative homologous recombination repair deficiency to platinum-based chemotherapy drugs.

[0015] The seventh object of the present invention is to provide a model for determining the responsiveness of platinum-based chemotherapy drugs.

[0016] In order to achieve the above object, the present invention is implemented by the following scheme:

[0017] A detection reagent is used in the preparation of a product for judging the responsiveness of platinum chemotherapy drugs in patients with homologous recombination repair defect-positive ovarian cancer; the detection reagent is a reagent for detecting gene expression levels, and the genes are ANXA4, CD27, GRB7, GSTZ1, SHMT2, TCF15, WARS, GALNT6 and ZFR.

[0018] Preferably, the positive threshold of the homologous recombination repair defect score of the homologous recombination repair defect-negative ovarian cancer patient sample is 38-45.

[0019] More preferably, the positive threshold of the homologous recombination repair deficiency score is 38, 39, 44 or 45.

[0020] Further preferably, the positive threshold of the homologous recombination repair deficiency score is 45.

[0021] Preferably, the platinum drug is cisplatin, carboplatin, oxaliplatin, nedaplatin and / or ethylpropylplatin.

[0022] The present invention also seeks to protect the use of a detection reagent in the preparation of a product for determining the responsiveness of samples from patients with homologous recombination repair-negative ovarian cancer to platinum-based chemotherapy drugs, wherein the detection reagent is a reagent for detecting gene expression levels; the genes are AADAC, ADA, ANXA4, CD27, GJB1, GRB7, GSTZ1, SHMT2, TCF15, WARS, TNFSF11, UBD, GALNT6, PHF20, ZFR and TMEM30B.

[0023] Preferably, the positive threshold of the homologous recombination repair defect score of the homologous recombination repair defect-negative ovarian cancer patient sample is 38-45.

[0024] More preferably, the positive threshold of the homologous recombination repair deficiency score is 38, 39, 44 or 45.

[0025] Further preferably, the positive threshold of the homologous recombination repair deficiency score is 45.

[0026] Preferably, the platinum drug is cisplatin, carboplatin, oxaliplatin, nedaplatin and / or ethylpropylplatin.

[0027] The present invention also seeks to protect the use of a detection reagent in the preparation of a product for determining the responsiveness of ovarian cancer patients to platinum-based chemotherapy drugs, wherein the detection reagent is a reagent for detecting gene expression levels; the genes are AADAC, ADA, ANXA4, CD27, GJB1, GRB7, GSTZ1, SHMT2, TCF15, WARS, TNFSF11, UBD, GALNT6, PHF20, ZFR and TMEM30B.

[0028] The present invention also seeks to protect a product for determining the responsiveness of ovarian cancer patients to platinum-based chemotherapy drugs, characterized in that it contains a detection reagent for detecting the expression level of each gene in a gene combination, wherein the gene combination includes ANXA4, CD27, GRB7, GSTZ1, SHMT2, TCF15, WARS, GALNT6 and ZFR.

[0029] Preferably, the gene combination includes AADAC, ADA, ANXA4, CD27, GJB1, GRB7, GSTZ1, SHMT2, TCF15, WARS, TNFSF11, UBD, GALNT6, PHF20, ZFR and TMEM30B.

[0030] The present invention also claims a model for judging the responsiveness of platinum chemotherapy drugs in homologous recombination repair defect-positive ovarian cancer patients, including a judgment module and a result output module;

[0031] The judgment module judges the responsiveness of ovarian cancer patients to platinum chemotherapy drugs based on the expression levels of the following genes in samples of ovarian cancer patients with positive homologous recombination repair deficiency;

[0032] The genes include ANXA4, CD27, GRB7, GSTZ1, SHMT2, TCF15, WARS, GALNT6 and ZFR genes;

[0033] The result output module is used to output the responsiveness result of the platinum chemotherapy drug obtained by the judgment module.

[0034] Preferably, the platinum drug is cisplatin, carboplatin, oxaliplatin, nedaplatin and / or ethylpropylplatin.

[0035] The present invention also claims a model for determining the responsiveness of platinum chemotherapy drugs in homologous recombination repair defect-negative ovarian cancer patient samples, comprising a determination module and a result output module;

[0036] The judgment module judges the responsiveness of ovarian cancer patients to platinum chemotherapy drugs based on the expression levels of the following genes in samples of homologous recombination repair defect-negative ovarian cancer patients;

[0037] The genes include AADAC, ADA, ANXA4, CD27, GJB1, GRB7, GSTZ1, SHMT2, TCF15, WARS, TNFSF11, UBD, GALNT6, PHF20, ZFR and TMEM30B genes;

[0038] The result output module is used to output the responsiveness result of the platinum chemotherapy drug obtained by the judgment module.

[0039] Preferably, the platinum drug is cisplatin, carboplatin, oxaliplatin, nedaplatin and / or ethylpropylplatin.

[0040] The present invention also claims a model for judging the responsiveness of platinum chemotherapy drugs, comprising a data acquisition module, a judgment module and a result output module;

[0041] The data acquisition module is used to obtain the homologous recombination repair defect score of the ovarian cancer patient sample, and determine the homologous recombination repair defect status of the ovarian cancer patient based on the positive threshold of the homologous recombination repair defect score;

[0042] The judgment module determines the responsiveness of ovarian cancer patients to platinum chemotherapy drugs based on the expression levels of ANXA4, CD27, GRB7, GSTZ1, SHMT2, TCF15, WARS, GALNT6 and ZFR genes in the samples of ovarian cancer patients with positive homologous recombination repair deficiency obtained by the data acquisition module;

[0043] For samples of ovarian cancer patients with negative homologous recombination repair deficiency obtained by the data acquisition module, the expression levels of AADAC, ADA, ANXA4, CD27, GJB1, GRB7, GSTZ1, SHMT2, TCF15, WARS, TNFSF11, UBD, GALNT6, PHF20, ZFR and TMEM30B genes in the samples were combined to determine the responsiveness of ovarian cancer patients to platinum chemotherapy drugs;

[0044] The result output module is used to output the responsiveness result of the platinum chemotherapy drug obtained by the judgment module.

[0045] Preferably, the sample is a sample from an ovarian cancer patient.

[0046] More preferably, the sample is a sample from a patient with high-grade serous ovarian cancer.

[0047] Further preferably, the sample is a sample from a patient with high-grade serous ovarian cancer who has received treatment with platinum-based drugs.

[0048] Preferably, the homologous recombination repair deficiency score in the data acquisition module is a non-weighted sum of a loss of heterozygosity score (LOH score), a telomeric genotype imbalance score (TAI score) and a large-scale structural transfer score (LST score).

[0049] More preferably, scarHRD software is used to calculate the homologous recombination repair deficiency score.

[0050] Preferably, the positive threshold of the homologous recombination repair defect score in the data acquisition module is 38-45.

[0051] More preferably, the positive threshold of the homologous recombination repair deficiency score is 38, 39, 44 or 45.

[0052] Further preferably, the positive threshold of the homologous recombination repair deficiency score is 45.

[0053] Preferably, in the judgment module, for the ovarian cancer patient sample whose homologous recombination repair deficiency status is positive obtained by the data acquisition module, the platinum drug responsiveness of the ovarian cancer patient is judged using Formula I;

[0054] Formula I:

[0055] F1=A0-A1×ANXA4+A2×CD27-A3×GRB7+A4×GSTZ1+A5×SHMT2-A6×TCF15-A7×WARS-A8×GALNT6+A9×ZFR; wherein A0~A9 are obtained by LASSO regression analysis model; ANXA4, CD27, GRB7, GSTZ1, SHMT2, TCF15, WARS, GALNT6 and ZFR shown in formula I are the expression levels of the corresponding genes in ovarian cancer patient samples.

[0056] More preferably, A0-A9 are obtained by a LASSO regression analysis model, and the regularization parameter λ1 of the LASSO regression analysis model is 0.01629.

[0057] Further preferably, when A0~A9 are obtained by the LASSO regression analysis model, LASSO regression analysis is performed in combination with the expression levels of ANXA4, CD27, GRB7, GSTZ1, SHMT2, TCF15, WARS, GALNT6 and ZFR genes in sample set 1 and the responsiveness of ovarian cancer patients to platinum chemotherapy drugs in sample set 1; the samples in the sample set 1 are samples with positive homologous recombination repair deficiency in 196 patients with high-grade serous ovarian cancer with detailed records of the conditions after the use of platinum drugs recorded in the paper (PMID: 21720365).

[0058] More preferably, the samples in the sample set 1 are samples with homologous recombination repair deficiency scores > 45 from 196 patients with high-grade serous ovarian cancer whose conditions after the use of platinum drugs are recorded in detail in the paper (PMID: 21720365).

[0059] More preferably, Formula I is:

[0060] F1=0.256309071612022-0.0194163477558527×ANXA4+0.669038155514554×CD27-0.232859065953763×GRB7+0.178899693365171×GSTZ1+0 .623906367787577×SHMT2-0.368400667169836×TCF15-0.280938533614944×WARS-0.221539503346267×GALNT6+0.672754144414643×ZFR.

[0061] Further preferably, ANXA4, CD27, GRB7, GSTZ1, SHMT2, TCF15, WARS, GALNT6 and ZFR shown in Formula I are the expression levels of the corresponding genes in the samples, and then divided into the upper quartile and the lower quartile after Z-score normalization, the genes in the upper quartile are assigned a value of 2, the genes in the lower quartile are assigned a value of 0, and the genes in the middle quartile are assigned a value of 1.

[0062] More preferably, the Z-score normalization is performed based on the expression level of the corresponding gene in the background sample set, and the background sample set is tumor samples of 196 patients with high-grade serous ovarian cancer with detailed records of the conditions after the use of platinum drugs recorded in the paper (PMID: 21720365).

[0063] Among them, 196 patients with high-grade serous ovarian cancer in the background sample set underwent whole exome sequencing and transcriptome sequencing, and the sequencing data were recorded in the paper (PMID: 21720365).

[0064] Further preferably, for ovarian cancer patient samples with a positive homologous recombination repair deficiency status obtained by the data acquisition module, F1≥0.5 calculated using Formula I, the sample is a sample of ovarian cancer patient sensitive to platinum chemotherapy drugs, otherwise it is a sample of ovarian cancer patient tolerant to platinum chemotherapy drugs.

[0065] Preferably, in the judgment module, for samples whose homologous recombination repair defect status obtained by the data acquisition module is negative, Formula II is used to judge the responsiveness of platinum chemotherapy drugs in ovarian cancer patients;

[0066] Formula II: F2 = B0 + B1 × AADAC + B2 × ADA - B3 × ANXA4 - B4 × CD27 + B5 × GJB1 + B6 × GRB7 + B7 × GSTZ1 + B8 × SHMT2 - B9 × TCF15 + B 10 ×WARS-B 11 ×TNFSF11-B 12 ×UBD-B 13 ×GALNT6-B 14 ×PHF20+B 15 ×ZFR-B 16 ×TMEM30B; among which B0~B 16 Obtained by LASSO regression analysis model; AADAC, ADA, ANXA4, CD27, GJB1, GRB7, GSTZ1, SHMT2, TCF15, WARS, TNFSF11, UBD, GALNT6, PHF20, ZFR and TMEM30B shown in Formula II are the expression levels of the corresponding genes in the samples.

[0067] More preferably, B0~B 16 It is obtained through the LASSO regression analysis model, and the regularization parameter λ2 of the LASSO regression analysis is 0.008965.

[0068] Further preferably, B0~B are obtained by LASSO regression analysis model 16The LASSO regression analysis was performed by combining the expression levels of AADAC, ADA, ANXA4, CD27, GJB1, GRB7, GSTZ1, SHMT2, TCF15, WARS, TNFSF11, UBD, GALNT6, PHF20, ZFR and TMEM30B genes in sample set 2 with the responsiveness of the samples in sample set 2 to platinum chemotherapy drugs; the samples in sample set 2 were homologous recombination repair defect-negative samples from 196 patients with high-grade serous ovarian cancer with detailed records of the conditions after the use of platinum drugs as recorded in the paper (PMID: 21720365).

[0069] More preferably, the samples in the sample set 2 are samples with homologous recombination repair deficiency scores ≤ 45 from 196 patients with high-grade serous ovarian cancer whose conditions after the use of platinum drugs are recorded in detail in the paper (PMID: 21720365).

[0070] More preferably, Formula II is: F2=2.63480181408828+1.75414711832022×AADAC+1.61744050879368×

[0071] ADA-0.335529411791532×ANXA4-2.85124109729058×CD27+0.855056380659892×GJB1+2.55634 098439207×GRB7+0.280308617354185×GSTZ1+0.239486972628679×SHMT2-1.96629329833821×

[0072] TCF15+0.109161478982231×

[0073] WARS-1.82019288788304×TNFSF11-0.108601110679264×UBD-0.0338767735048593×GAL NT6-3.78049656515552×PHF20+1.36369711583015×ZFR-0.536490390878037×TMEM30B.

[0074] Further preferably, AADAC, ADA, ANXA4, CD27, GJB1, GRB7, GSTZ1, SHMT2, TCF15, WARS, TNFSF11, UBD, GALNT6, PHF20, ZFR and TMEM30B shown in Formula II are the expression levels of the corresponding genes in the sample, and then the expression levels are normalized by Z-score and divided into the upper quartile and the lower quartile. The genes in the upper quartile are assigned a value of 2, the genes in the lower quartile are assigned a value of 0, and the genes in the middle quartile are assigned a value of 1.

[0075] More preferably, the Z-score normalization is performed based on the expression level of the corresponding gene in the background sample set, and the background sample set is tumor samples of 196 patients with high-grade serous ovarian cancer with detailed records of the conditions after the use of platinum drugs recorded in the paper (PMID: 21720365).

[0076] Further preferably, for samples whose homologous recombination repair deficiency status obtained by the data acquisition module is negative, F2 calculated by formula II is <0.5, and the sample is a sample of an ovarian cancer patient tolerant to platinum chemotherapy drugs; otherwise, the sample is a sample of an ovarian cancer patient sensitive to platinum chemotherapy drugs.

[0077] Preferably, the sample in any of the above methods is a sample to be tested, and the sample to be tested is a sample from an ovarian cancer patient.

[0078] The present invention also seeks to protect the use of any of the above methods in determining the responsiveness of platinum-based chemotherapy drugs.

[0079] Compared with the prior art, the present invention has the following beneficial effects:

[0080] The present invention provides a model for judging the responsiveness of platinum chemotherapy drugs. The model comprises the following steps: firstly obtaining a homologous recombination repair defect score of a sample, and judging the homologous recombination repair defect state of the sample based on a positive threshold of the homologous recombination repair defect score; for a sample of an ovarian cancer patient whose homologous recombination repair defect state is positive, combining the expression levels of ANXA4, CD27, GRB7, GSTZ1, SHMT2, TCF15, WARS, GALNT6 and ZFR genes of the sample, judging the responsiveness of the sample to platinum chemotherapy drugs; and for a sample whose homologous recombination repair defect state is negative, combining the expression levels of AADAC, ADA, ANXA4, CD27, GJB1, GRB7, GSTZ1, SHMT2, TCF15, WARS, TNFSF11, UBD, GALNT6, PHF20, ZFR and TMEM30B genes of the sample, judging the responsiveness of the sample to platinum chemotherapy drugs. When the model of the present invention is used to judge the responsiveness of the sample to platinum chemotherapy drugs, the accuracy is higher than 80%, which is about 11% higher than the accuracy when using the homologous recombination repair defect score to judge the homologous recombination repair defect state and then judge the responsiveness to platinum chemotherapy drugs; the model of the present invention can accurately judge the responsiveness of ovarian cancer patients to platinum chemotherapy drugs, thereby providing guidance for the clinical use of platinum drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0081] Figure 1 This is a graph showing the accuracy of judging the sensitivity of platinum drugs at various HRD score thresholds in Example 1;

[0082] Figure 2 It is a forest plot of the Cox proportional hazards regression model in Example 1;

[0083] Figure 3 : is the ROC result diagram for judging the responsiveness of platinum chemotherapy drugs in ovarian cancer patients in Example 2; a is the ROC result diagram for judging the responsiveness of platinum chemotherapy drugs in ovarian cancer patients in training set 1 in combination with formula I in Example 2; b is the ROC result diagram for judging the responsiveness of platinum chemotherapy drugs in ovarian cancer patients in validation set 1 in combination with formula I in Example 2; c is the ROC result diagram for judging the responsiveness of platinum chemotherapy drugs in ovarian cancer patients in training set 2 in combination with formula II in Example 2; d is the ROC result diagram for judging the responsiveness of platinum chemotherapy drugs in ovarian cancer patients in validation set 2 in combination with formula II in Example 2;

[0084] Figure 4: is the ROC result graph for judging the responsiveness of platinum drugs in Example 3; a is the ROC result graph for judging the responsiveness of platinum chemotherapy drugs in training set 3 ovarian cancer patients in Example 3; b is the ROC result graph for judging the responsiveness of platinum chemotherapy drugs in validation set 3 ovarian cancer patients in Example 3; c is the ROC result graph for judging the responsiveness of platinum chemotherapy drugs in ovarian cancer patients shown in control group 1 in Example 3. DETAILED DESCRIPTION

[0085] The present invention is further described in detail below in conjunction with the accompanying drawings and specific examples of the specification. The examples are only used to explain the present invention and are not used to limit the scope of the present invention. The test methods used in the following examples are conventional methods unless otherwise specified; the materials and reagents used are reagents and materials that can be obtained from commercial channels unless otherwise specified.

[0086] Example 1 Determination of HRD score threshold and platinum drug responsiveness-related genes

[0087] 1. Experimental Methods

[0088] 1. Determination of HRD score threshold

[0089] (1) Calculation of HRD score

[0090] Samples (196 tumor samples from high-grade serous ovarian cancer patients) and control adjacent cancer samples with detailed records of the use of platinum drugs recorded in an open source paper (PMID: 21720365) were selected as the sample set. All 196 ovarian cancer patients in the sample set had received platinum chemotherapy and recorded the conditions after the use of platinum drugs in detail (whether they were clinically resistant to platinum chemotherapy or not). Patients with efficacy of platinum drugs were recorded as platinum chemotherapy sensitive, and patients with poor efficacy or no therapeutic effect of platinum drugs were recorded as platinum chemotherapy tolerant; all 196 ovarian cancer patients in the sample set underwent whole exome sequencing and transcriptome sequencing, and the sequencing data were recorded in the paper (PMID: 21720365).

[0091] Based on the whole exome sequencing results of each ovarian cancer patient in the sample set, the scarHRD software was used to calculate the heterozygous loss score (LOH), telomere genotype imbalance score (TAI) and large-scale structural transfer score (LST) of each ovarian cancer patient, and the LOH, TAI and LST were summed in an unweighted manner to obtain the homologous recombination repair defect score (HRD score) of each ovarian cancer patient.

[0092] (2) Screening of HRD score threshold

[0093] The HRD score positive threshold was set to each integer value between 30 and 55. When the HRD score of the ovarian cancer patient was ≤ the HRD score positive threshold, the ovarian cancer patient was judged to be a patient tolerant to platinum chemotherapy; when the HRD score of the ovarian cancer patient was > the HRD score positive threshold, the ovarian cancer patient was judged to be a patient sensitive to platinum chemotherapy.

[0094] The exhaustive method was used to calculate the accuracy ACC of judging the platinum drug sensitivity of ovarian cancer patients at each HRD score positive threshold based on the platinum drug sensitivity of ovarian cancer patients' clinical records.

[0095] ACC = number of ovarian cancer patients with accurate judgment of platinum-based drug sensitivity / total number of ovarian cancer patients in the sample set.

[0096] 2. Determination of genes associated with responsiveness to platinum drugs

[0097] Based on the transcriptome sequencing data of 196 ovarian cancer patients in the sample set, the expression level of each gene in each ovarian cancer patient was obtained, and the expression level of each gene was normalized by Z-score based on the expression level of the same gene in each ovarian cancer patient to obtain the standardized expression level of each gene;

[0098] The standardized expression level of each gene was divided into upper and lower quartiles, where genes with standardized expression levels in the upper quartile were recorded as highly expressed genes, genes with standardized expression levels in the lower quartile were recorded as lowly expressed genes, and the rest were recorded as moderately expressed genes. The transcriptome expression level data of 196 ovarian cancer patients in the sample set were obtained.

[0099] The Cox proportional hazard regression model was used to analyze the transcriptome expression levels of 196 ovarian cancer patients in the sample set and the disease-free survival of ovarian cancer patients (including calculation of Wald test significance, statistical significance P-value and relative risk coefficient ratio HR), and P-value < 0.05 was considered statistically significant, and genes that significantly affected the disease-free survival of ovarian cancer patients were obtained.

[0100] 2. Experimental Results

[0101] 1. Determination of HRD score threshold

[0102] The accuracy results of judging the sensitivity of platinum drugs under each HRD score positive threshold are as follows Figure 1As shown, the results showed that when the HRD score positive threshold was between 38 and 45, there were differences in the ACC for judging sensitivity to platinum drugs; and when the HRD score positive threshold was set to 38, 39, 44 or 45, the ACC for judging sensitivity to platinum drugs reached 74.0%, 74.0%, 72.5% and 73.5%, respectively, which were all higher than the ACC when the HRD threshold was 42 (71.9%).

[0103] When the positive threshold of HRD score was 38, the area under the ROC curve (AUC) for judging the sensitivity of platinum drugs was 0.609; when the positive threshold of HRD score was 39, the area under the ROC curve (AUC) for judging the sensitivity of platinum drugs was 0.613; when the positive threshold of HRD score was 44, the area under the ROC curve (AUC) for judging the sensitivity of platinum drugs was 0.629; when the positive threshold of HRD score was 45, the area under the ROC curve (AUC) for judging the sensitivity of platinum drugs was 0.650.

[0104] Therefore, combined with the ACC result value and the corresponding area under the ROC curve AUC, it was determined that the optimal HRD score positive threshold for judging the sensitivity of platinum drugs was set to 45.

[0105] 2. Determination of HRD-related genes

[0106] The results of the analysis based on the transcriptome expression levels of the samples and the disease-free survival of ovarian cancer patients using the Cox proportional hazards regression model showed that the expression levels of AADAC, ADA, ANXA4, CD27, GJB1, GRB7, GSTZ1, HLA.DOA, SHMT2, TCF15, WARS, TNFSF11, UBD, GALNT6, SASH1, PHF20, ZFR, and TMEM30B genes were correlated with the disease-free survival expectation of ovarian cancer patients (P-value < 0.05).

[0107] The forest plot of the above genes in the Cox proportional hazards regression model is as follows: Figure 2 As shown, the forest plot includes the Wald test significance, statistical significance P-value and relative risk coefficient ratio HR.

[0108] Example 2 A method for determining the responsiveness of platinum chemotherapy drugs for non-diagnostic purposes

[0109] 1. Experimental Methods

[0110] 1. Determination of corrective genes for ovarian cancer patients with HRD>45

[0111] (1) Determination of the formula for calculating corrective genes and risk factors

[0112] Among the 196 ovarian cancer patients in the sample set of Example 1, 153 ovarian cancer patients with HRD scores greater than 45 were grouped according to the ratio of training set to validation set = 7:3, and 108 ovarian cancer patients were randomly selected as training set 1, and the remaining 45 ovarian cancer patients were used as validation set 1.

[0113] Taking the transcriptome expression level of ovarian cancer patients in training set 1 as the feature, taking the responsiveness of ovarian cancer patients to platinum chemotherapy drugs in training set 1 as the prediction value, the regularization parameter λ1 of LASSO regression analysis was set to 0.01629, and the genes related to the responsiveness to platinum chemotherapy drugs in ovarian cancer patients with HRD score > 45 and the related weight coefficients of the genes were obtained through LASSO regression analysis, and the risk calculation formula I was obtained.

[0114] (2) Validation of corrective genes and risk calculation formula

[0115] Based on the risk calculation formula I obtained in step (1), the responsiveness of ovarian cancer patients to platinum chemotherapy drugs in training set 1 is determined as follows:

[0116] Substitute the expression values ​​of each characteristic gene of ovarian cancer patients in training set 1 into the risk calculation formula I to calculate the final prediction value F HRD＞45 , and rounded, F HRD＞45 ≥0.5 is recorded as 1, F HRD＞45 <0.5 was recorded as 0.

[0117] F of ovarian cancer patients in training set 1 HRD＞45 When it is 1, it means that the ovarian cancer patient is sensitive to platinum chemotherapy drugs; the F HRD＞45 When it is 0, it indicates that the ovarian cancer patient is resistant to platinum-based chemotherapy drugs.

[0118] The AUC value for judging the responsiveness of ovarian cancer patients to platinum-based chemotherapy drugs in training set 1 was calculated based on the clinical platinum-based chemotherapy resistance of ovarian cancer patients in training set 1 combined with the risk calculation formula I.

[0119] According to the above method, the training set 1 was replaced by the validation set 1, and the AUC value for judging the responsiveness of platinum chemotherapy drugs in ovarian cancer patients in the validation set 1 in combination with the risk calculation formula I was obtained.

[0120] At the same time, combined with the risk calculation formula I obtained in step (1), the responsiveness of 153 ovarian cancer patients with HRD scores >45 among the 196 ovarian cancer patients in the sample set of Example 1 to platinum chemotherapy drugs was determined, and the results were recorded and the ACC value was calculated.

[0121] 2. Determination of corrective genes for ovarian cancer patients with HRD≤45

[0122] (1) Determination of corrective genes and risk calculation formula

[0123] 43 ovarian cancer patients with HRD scores ≤ 45 among the 196 ovarian cancer patients in the sample set of Example 1 were grouped according to the ratio of training set: validation set = 7:3, 31 patient samples were randomly selected as training set 2, and the remaining 12 ovarian cancer patients were used as validation set 2.

[0124] Taking the transcriptome expression level of ovarian cancer patients in training set 2 as the feature, and the responsiveness of ovarian cancer patients to platinum chemotherapy drugs in training set 2 as the prediction value, the regularization parameter λ2 of LASSO regression analysis was set to 0.008965. Through LASSO regression analysis, the genes related to the responsiveness to platinum chemotherapy drugs in samples with HRD score ≤ 45 and the related weight coefficients of the genes were obtained, and the risk calculation formula II was obtained.

[0125] (2) Validation of corrective genes and risk calculation formula

[0126] Based on the risk calculation formula II obtained in step (1), the responsiveness of ovarian cancer patients to platinum chemotherapy drugs in training set 2 is determined as follows:

[0127] Substitute the expression values ​​of each characteristic gene of ovarian cancer patients in training set 2 into the risk calculation formula II to calculate the final prediction value F HRD≤45 , and rounded, F HRD≤45 ≥0.5 is recorded as 1, F HRD≤45 <0.5 was recorded as 0.

[0128] F of ovarian cancer patients in training set 2 HRD≤45 When it is 1, it means that the ovarian cancer patient is sensitive to platinum chemotherapy drugs; the F HRD≤45 When it is 0, it indicates that the ovarian cancer patient is resistant to platinum-based chemotherapy drugs.

[0129] Based on the clinical platinum chemotherapy resistance of ovarian cancer patients in training set 2, the AUC value for judging the responsiveness of platinum chemotherapy drugs in ovarian cancer patients in training set 2 was calculated in combination with risk calculation formula II.

[0130] According to the above method, the training set 2 was replaced by the validation set 2, and the AUC value for judging the responsiveness of platinum chemotherapy drugs in ovarian cancer patients in the validation set 2 in combination with the risk calculation formula II was obtained.

[0131] At the same time, combined with the risk calculation formula II obtained in step (1), the responsiveness of 43 ovarian cancer patients with HRD scores ≤ 45 in the 196 ovarian cancer patients in the sample set of Example 1 to platinum chemotherapy drugs was determined, and the results were recorded and the ACC value was calculated.

[0132] 3. A method for determining the sensitivity of ovarian cancer patients to platinum drugs for non-diagnostic purposes

[0133] (1) A method for determining the sensitivity of a patient with ovarian cancer to platinum drugs for non-diagnostic purposes, comprising the following steps:

[0134] S1. Perform whole exome sequencing with a sequencing depth of 150× on the ovarian cancer patients to be tested, and use scarHRD software to calculate the heterozygous loss score (LOH), telomere genotype imbalance score (TAI) and large-scale structural transfer score (LST) of the ovarian cancer patients to be tested, and perform non-weighted summation of LOH, TAI and LST to obtain the homologous recombination repair defect score (HRD score) of the ovarian cancer patients to be tested, and set the HRD score positive threshold to 45;

[0135] S2. When the homologous repeat repair defect score of the ovarian cancer patient to be tested in step S1 is greater than 45, the risk calculation formula I is used to calculate F HRD＞45 , F HRD＞45 ≥0.5, the ovarian cancer patients to be tested are ovarian cancer patients who are sensitive to platinum-based chemotherapy drugs, otherwise they are ovarian cancer patients who are resistant to platinum-based chemotherapy drugs;

[0136] When the homologous recombination repair deficiency score of the ovarian cancer patient to be tested in step S1 is ≤45, the risk calculation formula II is used to calculate F HRD≤45 , F HRD≤45 ≥0.5, the ovarian cancer patients to be tested are ovarian cancer patients who are sensitive to platinum-based chemotherapy drugs; otherwise, they are ovarian cancer patients who are resistant to platinum-based chemotherapy drugs.

[0137] 2. Experimental Results

[0138] 1. Results of corrective gene determination for ovarian cancer patients with HRD>45

[0139] For ovarian cancer patients with HRD scores > 45, genes associated with patients' responsiveness to platinum chemotherapy drugs based on LASSO regression analysis included ANXA4, CD27, GRB7, GSTZ1, SHMT2, TCF15, WARS, GALNT6, and ZFR. The risk calculation formula I is shown in formula I.

[0140] Formula I:

[0141] F HRD>45=0.256309071612022-0.0194163477558527×ANXA4+0.669038155514554×CD27-0.232859065953763×GRB7+0 .178899693365171×GSTZ1+0.623906367787577×SHMT2-0.368400667169836×TCF15-0.280938533614944×WAR S-0.221539503346267×GALNT6+0.672754144414643×ZFR;

[0142] Among them, ANXA4, CD27, GRB7, GSTZ1, SHMT2, TCF15, WARS, GALNT6 and ZFR in Formula I are the expression levels of the corresponding genes in ovarian cancer patients. After Z-score normalization, the expression levels of the same genes in each ovarian cancer patient in the sample in Example 1 are divided into the upper quartile and the lower quartile. The gene in the upper quartile is assigned a value of 2, the gene in the lower quartile is assigned a value of 0, and the gene in the middle quartile is assigned a value of 1.

[0143] The ROC results of combining formula I to judge the responsiveness of ovarian cancer patients to platinum chemotherapy drugs in training set 1 are as follows Figure 3 As shown in a, the ROC results of combining formula I to judge the responsiveness of platinum chemotherapy drugs in ovarian cancer patients in validation set 1 are as follows Figure 3 b; the results of combining formula I to determine the responsiveness of 153 ovarian cancer patients with HRD scores >45 among the 196 ovarian cancer patients in the sample set of Example 1 are shown in Table 1.

[0144] Table 1 Results of judging the responsiveness of 153 ovarian cancer patients with HRD score >45 to platinum chemotherapy drugs

[0145] HRD score>45 Clinical sensitivity to platinum chemotherapy Clinical platinum chemotherapy resistance Sensitive to platinum chemotherapy 109 22 Platinum chemotherapy tolerance 9 13

[0146] ACC for judging the responsiveness of ovarian cancer patients with HRD score>45 to platinum chemotherapy drugs = (109+13) / (109+22+9+13)×100% = 79.7%.

[0147] 2. Results of corrective gene determination for ovarian cancer patients with HRD≤45

[0148] For ovarian cancer patients with HRD score ≤45, genes associated with patients' responsiveness to platinum chemotherapy drugs based on LASSO regression analysis included AADAC, ADA, ANXA4, CD27, GJB1, GRB7, GSTZ1, SHMT2, TCF15, WARS, TNFSF11, UBD, GALNT6, PHF20, ZFR, and TMEM30B, and the risk calculation formula II was shown in formula II.

[0149] Formula II: F HRD≤45 =2.63480181408828+1.75414711832022×AADAC+1.61744050879368×

[0150] ADA-0.335529411791532×ANXA4-2.85124109729058×CD27+0.855056380659892×GJB1+2.55634 098439207×GRB7+0.280308617354185×GSTZ1+0.239486972628679×SHMT2-1.96629329833821×

[0151] TCF15+0.109161478982231×

[0152] WARS-1.82019288788304×TNFSF11-0.108601110679264×UBD-0.0338767735048593×GAL NT6-3.78049656515552×PHF20+1.36369711583015×ZFR-0.536490390878037×TMEM30B;

[0153] Wherein AADAC, ADA, ANXA4, CD27, GJB1, GRB7, GSTZ1, SHMT2, TCF15, WARS, TNFSF11, UBD, GALNT6, PHF20, ZFR and TMEM30B in Formula II are the expression levels of the corresponding genes in ovarian cancer patients and the expression levels of the same genes in each ovarian cancer patient in the sample in Example 1. After Z-score normalization, they are divided into the upper quartile and the lower quartile. The genes in the upper quartile are assigned a value of 2, the genes in the lower quartile are assigned a value of 0, and the genes in the middle quartile are assigned a value of 1.

[0154] The ROC results of combining formula II to judge the responsiveness of ovarian cancer patients to platinum chemotherapy drugs in training set 2 are as follows Figure 3As shown in c, the ROC results of combining formula II to judge the responsiveness of platinum chemotherapy drugs in ovarian cancer patients in validation set 2 are as follows Figure 3 d; the results of combining Formula II to determine the responsiveness of 43 ovarian cancer patients with HRD scores ≤ 45 among the 196 ovarian cancer patients in the sample set of Example 1 are shown in Table 2.

[0155] Table 2 Results of judging the responsiveness of 43 ovarian cancer patients with HRD score ≤ 45 to platinum-based chemotherapy drugs

[0156] HRD score ≤45 Clinical sensitivity to platinum chemotherapy Clinical platinum chemotherapy resistance Sensitive to platinum chemotherapy 13 4 Platinum chemotherapy tolerance 4 22

[0157] The ACC for judging the responsiveness of ovarian cancer patients with HRD score ≤ 45 to platinum chemotherapy drugs = (13 + 22) / (13 + 4 + 4 + 22) × 100% = 81.4%.

[0158] Example 3 Validation of a method for determining the responsiveness of platinum chemotherapy drugs for non-diagnostic purposes

[0159] 1. Experimental Methods

[0160] The 196 ovarian cancer patients in Example 1 were used as the sample set, the ovarian cancer patients in training set 1 and training set 2 in Example 2 were combined as training set 3 (including 139 ovarian cancer patients), and the ovarian cancer patients in validation set 1 and validation set 2 were combined as validation set 3 (including 57 ovarian cancer patients).

[0161] According to the method for determining the homologous recombination repair deficiency status of ovarian cancer patients for non-diagnostic purposes as shown in Example 2, the responsiveness of ovarian cancer patients to platinum chemotherapy drugs in training set 3 and validation set 3 was determined respectively, and based on whether the ovarian cancer patients in training set 3 and validation set 3 were clinically resistant to platinum chemotherapy, the AUC values ​​for determining the responsiveness of ovarian cancer patients to platinum chemotherapy drugs in training set 3 and validation set 3 using the method shown in Example 2 were calculated.

[0162] An experimental group, a control group 1 and a control group 2 were set up, wherein the experimental group was: the results of judging the platinum drug sensitivity of 196 ovarian cancer patients in the sample set by using the method for judging the platinum drug sensitivity of ovarian cancer patients for non-diagnostic purposes as shown in Example 2.

[0163] Control group 1 was: based on the HRD scores of 196 ovarian cancer patients in the sample set, the HRD score positive threshold was set to 42, and ovarian cancer patients with HRD scores > 42 were judged as HRD positive (HRD existed, sensitive to platinum chemotherapy), and ovarian cancer patients with HRD scores ≤ 42 were judged as HRD negative (HRD did not exist, tolerant to platinum chemotherapy); and the AUC results when the HRD score positive threshold was 42 were calculated.

[0164] Control group 2: Based on the HRD scores of 196 ovarian cancer patients in the sample set, the HRD score positive threshold was set at 45, and ovarian cancer patients with HRD scores > 45 were judged as HRD-positive (HRD exists, sensitive to platinum chemotherapy), and ovarian cancer patients with HRD scores ≤ 45 were judged as HRD-negative (HRD does not exist, tolerant to platinum chemotherapy).

[0165] 2. Experimental Results

[0166] The ROC results of judging the responsiveness of ovarian cancer patients to platinum-based chemotherapy drugs in training set 3 according to the method for judging the responsiveness of ovarian cancer patients to platinum-based chemotherapy drugs for non-diagnostic purposes as shown in Example 2 are as follows: Figure 4 As shown in a, the ROC result of judging the responsiveness of ovarian cancer patients to platinum-based chemotherapy drugs in validation set 3 according to the method for judging the responsiveness of ovarian cancer patients to platinum-based chemotherapy drugs for non-diagnostic purposes as shown in Example 2 is as follows Figure 4 As shown in b, the ROC results of the control group 1 for judging the responsiveness of ovarian cancer patients to platinum-based chemotherapy drugs are as follows Figure 4 As shown in c.

[0167] The results of judging the sensitivity of ovarian cancer patients to platinum drugs in the sample set by the experimental group, control group 1 and control group 2 are shown in Table 3.

[0168] Table 3 Results of the experimental group, control group 1 and control group 2 in judging the sensitivity of ovarian cancer patients to platinum drugs in the sample set

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177] The results showed that when the responsiveness of 196 ovarian cancer patients to platinum chemotherapy drugs in the sample set was judged according to the control group 1, ACC=141 / 196×100%=71.9%<80%; when the responsiveness of 196 ovarian cancer patients to platinum chemotherapy drugs in the sample set was judged according to the control group 2, ACC=144 / 196×100%=73.5%<80%; when the responsiveness of 196 ovarian cancer patients to platinum chemotherapy drugs in the sample set was judged according to the experimental group (i.e., the method for judging the responsiveness of ovarian cancer patients to platinum chemotherapy drugs for non-diagnostic purposes as shown in Example 2), ACC=157 / 196×100%=80.1%>80%.

[0178] The results show that the method shown in Example 2 can effectively improve the accuracy of judging the responsiveness of ovarian cancer patients to platinum-based chemotherapy drugs, and thus more accurately judge whether ovarian cancer patients are sensitive to platinum-based chemotherapy or not, providing guidance for clinical precision medication.

[0179] Example 4 A model for determining the responsiveness of platinum chemotherapy drugs

[0180] A model for judging the responsiveness of Borrell chemotherapy drugs, comprising a data acquisition module, a judgment module and a result output module;

[0181] The data acquisition module is used to obtain the whole exome sequencing data of the ovarian cancer patient to be tested, and use scarHRD software to respectively calculate the heterozygous loss score (LOH), telomere genotype imbalance score (TAI) and large-scale structural transfer score (LST) of the ovarian cancer patient to be tested, and perform non-weighted summation of LOH, TAI and LST to obtain the homologous recombination repair deficiency score (HRD score) of the ovarian cancer patient to be tested, and set the HRD score positive threshold to 45 to obtain the homologous recombination repair deficiency status of the ovarian cancer patient to be tested;

[0182] The judgment module calculates F using the risk calculation formula I shown in formula I for the ovarian cancer patient to be tested whose homologous repeat repair defect status is positive obtained by the data acquisition module. HRD＞45 , F HRD＞45 ≥0.5, the ovarian cancer patients to be tested are ovarian cancer patients who are sensitive to platinum-based chemotherapy drugs, otherwise they are ovarian cancer patients who are resistant to platinum-based chemotherapy drugs;

[0183] Formula I:

[0184] F HRD>45=0.256309071612022-0.0194163477558527×ANXA4+0.669038155514554×CD27-0.232859065953763×GRB7+0 .178899693365171×GSTZ1+0.623906367787577×SHMT2-0.368400667169836×TCF15-0.280938533614944×WAR S-0.221539503346267×GALNT6+0.672754144414643×ZFR;

[0185] Wherein ANXA4, CD27, GRB7, GSTZ1, SHMT2, TCF15, WARS, GALNT6 and ZFR in Formula 1 are the expression levels of the corresponding genes in ovarian cancer patients, and the expression levels of the same genes in each ovarian cancer patient in the sample in Example 1 are subjected to Z-score normalization and divided into the upper quartile and the lower quartile, the gene in the upper quartile is assigned a value of 2, the gene in the lower quartile is assigned a value of 0, and the gene in the middle quartile is assigned a value of 1;

[0186] The judgment module calculates F using the risk calculation formula II shown in formula II for the ovarian cancer patient to be tested whose homologous repeat repair defect status is negative as obtained by the data acquisition module. HRD≤45 , F HRD≤45 ≥0.5, the ovarian cancer patients to be tested are ovarian cancer patients who are sensitive to platinum-based chemotherapy drugs, otherwise they are ovarian cancer patients who are resistant to platinum-based chemotherapy drugs;

[0187] Formula II: F HRD≤45 =2.63480181408828+1.75414711832022×AADAC+1.61744050879368×

[0188] ADA-0.335529411791532×ANXA4-2.85124109729058×CD27+0.855056380659892×GJB1+2.55634 098439207×GRB7+0.280308617354185×GSTZ1+0.239486972628679×SHMT2-1.96629329833821×

[0189] TCF15+0.109161478982231×

[0190] WARS-1.82019288788304×TNFSF11-0.108601110679264×UBD-0.0338767735048593×GAL NT6-3.78049656515552×PHF20+1.36369711583015×ZFR-0.536490390878037×TMEM30B;

[0191] Wherein AADAC, ADA, ANXA4, CD27, GJB1, GRB7, GSTZ1, SHMT2, TCF15, WARS, TNFSF11, UBD, GALNT6, PHF20, ZFR and TMEM30B in Formula II are the expression levels of the corresponding genes in ovarian cancer patients, and the expression levels of the same genes in each ovarian cancer patient in the sample in Example 1 are subjected to Z-score normalization and divided into the upper quartile and the lower quartile, the gene in the upper quartile is assigned a value of 2, the gene in the lower quartile is assigned a value of 0, and the gene in the middle quartile is assigned a value of 1;

[0192] The result output module is used to output the responsiveness result of the platinum chemotherapy drug obtained by the judgment module.

[0193] Comparative Example 1 A method for determining the homologous recombination repair defect state of a sample for non-diagnostic purposes

[0194] 1. Experimental Methods

[0195] Based on the 18 genes obtained in Example 1 that are correlated with the disease-free survival expectation of ovarian cancer patients (P-value < 0.05): AADAC, ADA, ANXA4, CD27, GJB1, GRB7, GSTZ1, HLA.DOA, SHMT2, TCF15, WARS, TNFSF11, UBD, GALNT6, SASH1, PHF20, ZFR, TMEM30B.

[0196] The 196 ovarian cancer patients in the sample set of Example 1 were used as ovarian cancer samples to be tested. According to the method shown in Example 2, the regularization parameters λ1 and λ2 were adjusted to obtain genes related to the responsiveness of ovarian cancer patients to platinum-based chemotherapy drugs and the relevant weight coefficients of the genes. The 196 ovarian cancer patients in Example 1 were used as the sample set to determine the responsiveness of ovarian cancer patients to platinum-based chemotherapy drugs and calculate ACC.

[0197] 2. Experimental Results

[0198] After adjusting the regularization parameters λ1 and λ2, the gene information related to the responsiveness of ovarian cancer patients to platinum chemotherapy drugs and the accuracy of judging the responsiveness to platinum chemotherapy drugs are shown in Table 4.

[0199] Table 4 Gene information and accuracy results

[0200]

[0201]

[0202]

[0203]

[0204]

[0205]

[0206]

[0207]

[0208]

[0209]

[0210] The results showed that ACC > 0.8 only when the responsiveness of ovarian cancer patients to platinum chemotherapy drugs was judged according to the gene combination shown in combination 1 (ie, the method shown in Example 2).

[0211] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention rather than to limit the protection scope of the present invention. For ordinary technicians in this field, other different forms of changes or modifications can be made based on the above descriptions and ideas. It is not necessary and impossible to list all the implementation methods here. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection scope of the claims of the present invention.

Claims

1. Use of a detection reagent in the preparation of a product for determining the responsiveness of patients with homologous recombination repair defect-positive ovarian cancer to platinum-based chemotherapy drugs, wherein the detection reagent is a reagent for detecting gene expression levels, and the genes are ANXA4, CD27, GRB7, GSTZ1, SHMT2, TCF15, WARS, GALNT6 and ZFR.

2. The use of a detection reagent in the preparation of a product for determining the responsiveness of patients with homologous recombination repair defect-negative ovarian cancer to platinum-based chemotherapy drugs, wherein the detection reagent is a reagent for detecting gene expression levels; the genes are AADAC, ADA, ANXA4, CD27, GJB1, GRB7, GSTZ1, SHMT2, TCF15, WARS, TNFSF11, UBD, GALNT6, PHF20, ZFR and TMEM30B.

3. Use of a detection reagent in the preparation of a product for determining the responsiveness of ovarian cancer patients to platinum-based chemotherapy drugs, wherein the detection reagent is a reagent for detecting gene expression levels; the genes are AADAC, ADA, ANXA4, CD27, GJB1, GRB7, GSTZ1, SHMT2, TCF15, WARS, TNFSF11, UBD, GALNT6, PHF20, ZFR and TMEM30B.

4. The use according to any one of claims 1 to 3, characterized in that: The platinum drugs are cisplatin, carboplatin, oxaliplatin, nedaplatin and / or ethplatin.

5. A product for judging the responsiveness of platinum chemotherapy drugs, characterized in that: Contains detection reagents for detecting the expression level of each gene in a gene combination, wherein the gene combination includes ANXA4, CD27, GRB7, GSTZ1, SHMT2, TCF15, WARS, GALNT6 and ZFR.

6. A model for determining the responsiveness of ovarian cancer patients with positive homologous recombination repair deficiency to platinum-based chemotherapy drugs, characterized in that: It includes a judgment module and a result output module; The judgment module judges the responsiveness of platinum chemotherapy drugs based on the expression levels of the following genes in homologous recombination repair defect-positive ovarian cancer patient samples; The genes include ANXA4, CD27, GRB7, GSTZ1, SHMT2, TCF15, WARS, GALNT6 and ZFR genes; The result output module is used to output the responsiveness result of the platinum chemotherapy drug obtained by the judgment module.

7. A model for determining the responsiveness of patients with homologous recombination repair-negative ovarian cancer to platinum-based chemotherapy drugs, characterized in that: It includes a judgment module and a result output module; The judgment module judges the responsiveness of platinum chemotherapy drugs based on the expression levels of the following genes in homologous recombination repair defect-negative ovarian cancer patients; The genes include AADAC, ADA, ANXA4, CD27, GJB1, GRB7, GSTZ1, SHMT2, TCF15, WARS, TNFSF11, UBD, GALNT6, PHF20, ZFR and TMEM30B genes; The result output module is used to output the responsiveness result of the platinum chemotherapy drug obtained by the judgment module.

8. A model for determining the responsiveness of platinum chemotherapy drugs, characterized in that: It includes a data acquisition module, a judgment module and a result output module; The data acquisition module is used to obtain the homologous recombination repair defect score of the ovarian cancer patient, and determine the homologous recombination repair defect status of the ovarian cancer patient based on the positive threshold of the homologous recombination repair defect score; The judgment module determines the responsiveness of ovarian cancer patients to platinum chemotherapy drugs based on the expression levels of ANXA4, CD27, GRB7, GSTZ1, SHMT2, TCF15, WARS, GALNT6 and ZFR genes in the samples of ovarian cancer patients with positive homologous recombination repair deficiency obtained by the data acquisition module; For ovarian cancer patient samples with negative homologous recombination repair deficiency obtained by the data acquisition module, the expression levels of AADAC, ADA, ANXA4, CD27, GJB1, GRB7, GSTZ1, SHMT2, TCF15, WARS, TNFSF11, UBD, GALNT6, PHF20, ZFR and TMEM30B genes in the samples were combined to judge the responsiveness of ovarian cancer patients to platinum chemotherapy drugs; The result output module is used to output the responsiveness result of the platinum chemotherapy drug obtained by the judgment module.

9. The model according to claim 8, characterized in that The positive threshold of homologous recombination repair defect score in the data acquisition module is 38-45.

10. The model according to claim 9, characterized in that The positive threshold of the homologous recombination repair deficiency score is 38, 39, 44 or 45.

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