Search

CN-121999856-A - Model for judging responsiveness of platinum chemotherapeutic drugs and application thereof

CN121999856ACN 121999856 ACN121999856 ACN 121999856ACN-121999856-A

Abstract

The invention discloses a model for judging responsiveness of a platinum chemotherapeutic drug of an ovarian cancer patient, which is characterized in that homologous recombination repair defect scores of samples are obtained firstly, homologous recombination repair defect states of the samples are judged based on positive threshold values of the homologous recombination repair defect scores, and then the responsiveness of the platinum chemotherapeutic drug of the ovarian cancer patient is judged by combining the expression level of a sample gene to be tested. When the model is used for judging the responsiveness of the platinum chemotherapeutic medicine of the ovarian cancer patient to be tested, the accuracy is higher than 80%, compared with the method for judging the homologous recombination repair defect state by only using the homologous recombination repair defect score, the accuracy is improved by about 11% when the responsiveness of the platinum chemotherapeutic medicine of the ovarian cancer patient is judged, and the model can be used for accurately judging the responsiveness of the platinum chemotherapeutic medicine of the ovarian cancer patient to be tested, so that guidance is provided for clinical use of the platinum medicine.

Inventors

  • ZHONG JIASHENG
  • CHEN SHIFU
  • LIU DANNI

Assignees

  • 深圳市海普洛斯生物科技有限公司

Dates

Publication Date
20260508
Application Date
20251022
Priority Date
20241025

Claims (10)

  1. 1. An application of a detection reagent in preparing a product for judging the responsiveness of a platinum chemotherapeutic medicament of a patient with homologous recombination repair deficiency positive ovarian cancer, wherein the detection reagent is a reagent for detecting the expression level of genes, and the genes are ANXA4, CD27, GRB7, GSTZ1, SHMT2, TCF15, WARS, GALNT6 and ZFR.
  2. 2. The application of a detection reagent in preparing a product for judging the responsiveness of a platinum chemotherapeutic drug of a patient with homologous recombination repair defect negative ovarian cancer is provided, wherein the detection reagent is a reagent for detecting the expression level of genes, and the genes are AADAC, ADA, ANXA4, CD27, GJB1, GRB7, GSTZ1, SHMT2, TCF15, WARS, TNFSF11, UBD, GALNT6, PHF20, ZFR and TMEM30B.
  3. 3. The application of the detection reagent in preparing a product for judging the responsiveness of platinum-based chemotherapeutic drugs of ovarian cancer patients is that the detection reagent is used for detecting the expression level of genes, wherein the genes are AADAC, ADA, ANXA4, CD27, GJB1, GRB7, GSTZ1, SHMT2, TCF15, WARS, TNFSF11, UBD, GALNT6, PHF20, ZFR and TMEM30B.
  4. 4. The use according to any one of claims 1 to 3, wherein the platinum-based drug is cisplatin, carboplatin, oxaliplatin, nedaplatin and/or ethylplatin.
  5. 5. A product for determining responsiveness of a platinum-based chemotherapeutic agent, comprising a test agent for testing the expression level of each gene in a gene set comprising ANXA4, CD27, GRB7, GSTZ1, SHMT2, TCF15, WARS, GALNT6 and ZFR.
  6. 6. A model for judging the responsiveness of a platinum chemotherapeutic drug of an ovarian cancer patient with positive homologous recombination repair defects is characterized by comprising a judging module and a result output module; The judging module judges the responsiveness of the platinum chemotherapeutic drugs based on the expression level of the following genes of the sample of the patient with the homologous recombination repair defect positive ovarian cancer; such genes include ANXA4, CD27, GRB7, GSTZ1, SHMT2, TCF15, WARS, GALNT6 and ZFR genes; The result output module is used for outputting the platinum chemotherapeutic drug responsiveness result obtained by the judging module.
  7. 7. The model for judging the responsiveness of the platinum-based chemotherapeutic drug of the patient with the homologous recombination repair defect-negative ovarian cancer is characterized by comprising a judging module and a result output module; The judging module judges the responsiveness of the platinum chemotherapeutic drugs based on the expression level of the genes below the patient with the homologous recombination repair defect negative ovarian cancer; Such 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 for outputting the platinum chemotherapeutic drug responsiveness result obtained by the judging module.
  8. 8. The model for judging the responsiveness of the platinum chemotherapeutic drugs is characterized by comprising a data acquisition module, a judging module and a result output module; The data acquisition module is used for acquiring homologous recombination repair defect scores of ovarian cancer patients and judging homologous recombination repair defect states of the ovarian cancer patients based on positive threshold values of the homologous recombination repair defect scores; the judging module is used for judging the responsiveness of the platinum-based chemotherapy drugs of the ovarian cancer patient according to the expression levels of ANXA4, CD27, GRB7, GSTZ1, SHMT2, TCF15, WARS, GALNT6 and ZFR genes of the ovarian cancer patient sample with positive homologous recombination repair defect state obtained by the data acquisition module; Judging the responsiveness of the ovarian cancer patient to the platinum chemotherapeutic drugs according to the sample of the ovarian cancer patient with the negative homologous recombination repair defect state obtained by the data acquisition module and the expression level of AADAC, ADA, ANXA, CD27, GJB1, GRB7, GSTZ1, SHMT2, TCF15, WARS, TNFSF11, UBD, GALNT6, PHF20, ZFR and TMEM30B genes of the sample; The result output module is used for outputting the platinum chemotherapeutic drug responsiveness result obtained by the judging module.
  9. 9. The model of claim 8, wherein the homologous recombination repair defect score positive threshold in the data acquisition module is 38-45.
  10. 10. The model of claim 9, wherein the homologous recombination repair deficiency score positive threshold is 38, 39, 44 or 45.

Description

Model for judging responsiveness of platinum chemotherapeutic drugs and application thereof Technical Field The invention relates to the technical field of molecular biology, in particular to a model for judging responsiveness of platinum chemotherapeutic drugs and application thereof. Background Ovarian cancer (Ovarian Cancer, OV) is a common malignancy of the female reproductive system, and there is no radical cure for ovarian cancer at present, classical treatment regimens are surgery combined with platinum-based chemotherapy, with an average 5-year survival rate of about 30%. The state of homologous recombination repair defects (Homologous Recombination Deficiency, HRD) is a classical biological index currently used to predict and evaluate the efficacy of platinum-based chemotherapeutics, and to a certain extent patients can be grouped, so that the proportion of the patients with ovarian cancer benefited from 20% to 50%. Homologous recombination repair (Homologous Recombination Repair, HRR) is a DNA double strand break (Double Strand Break, DSB) repair pathway based on complementary strand repair in cells, and is also a preferred repair method in cells due to its high fidelity. HRR is not normally used when HRD status occurs in cells, and DSBs rely on alternative Non-homologous end Joining (Non-Homologous End Joining, NHEJ), micro-homologous end repair (Miciohomology MEDIATED END Joining, MMEJ), and Single strand annealing pathway (Single-STRAND ANNEALING, SSA) for repair. These approaches do not rely entirely on template strands and are prone to new genetic mutations that ultimately lead to structural instability of the genome and cell death. Platinum-based chemotherapeutics 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 detrimental to cell transcription and replication. When ovarian cancer cells cannot be effectively repaired by HRR due to HRD, the drug-induced DSBs can enable the cancer cells to be repaired only by relying on a low-fidelity repair pathway, so that the instability of genome is further increased. Because these pathways are not accurate enough, errors in the repair process can lead to the accumulation of more mutations, activating intracellular stress responses and programmed death pathways (e.g., apoptosis), ultimately leading to cancer cell death. When the HRD state exists in tumor cells, the platinum chemotherapeutic drugs can effectively play a role in killing, so that judgment of the HRD state of patients is considered as an important biological marker for predicting the curative effect of the platinum chemotherapeutic drugs. Current decisions about HRD status are mainly assessed by calculating single or multiple, non-weighted or weighted evaluations of heterozygous deletions (Loss of heterozygosity, LOH), telomere genotypic irregularities (Telomeric allelic imbalance, TAI) and extensive structural transfer (LST) numbers (HRD score). For example, HRD positives are defined in FDA approved test product Myriad myChoice [ CDx (MYRIAD GENETIC Laboratories, inc.) as carrying BRCA1/2 somatic or germ line pathogenic mutations in tumor cells and/or HRD score of ≡42, the threshold being set based on the fifth position in BRCA-deficient ovarian and breast cancer samples. In another FDA obtained detection product Foundation Focus CDx BRCALOH (Foundation Medicine, inc.), HRD positive is defined as carrying BRCA1/2 somatic or germ line pathogenic mutation in tumor cells and/or LOH score is not less than 16%. The detection indexes are verified in large clinical researches, but can not fully reflect the platinum chemotherapy effect in the real world, so that the accuracy of judging the HRD state of an ovarian cancer patient sample is required to be improved, and the main reasons include that (1) the evaluation method only considers the HRD state, but does not consider other conditions such as tumor microenvironment, drug delivery and excretion, upstream and downstream supplementation or abnormal activation of a repair pathway and the like, and (2) the expression condition of genes related to the platinum chemotherapy effect is not fully considered, and the conditions of the genes are not necessarily reflected in the sequencing from an exome or the HRD state. Therefore, the method for judging the HRD state of the ovarian cancer patient sample more accurately is based at present, and further the use of platinum chemotherapeutic drugs is guided. Disclosure of Invention The invention aims to overcome the defects in the prior art and provides a model for judging responsiveness of platinum chemotherapeutic drugs of ovarian cancer patients and application thereof. The first object of the invention is to provide an application of a detection reagent in preparing a product for judging responsiveness of a platinum-based chemotherapeutic drug for a patient with homologous recombin