CN117587122A - Application of PRKN as marker for predicting tumor sensitivity to chemotherapy - Google Patents

Application of PRKN as marker for predicting tumor sensitivity to chemotherapy Download PDF

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CN117587122A
CN117587122A CN202210960260.8A CN202210960260A CN117587122A CN 117587122 A CN117587122 A CN 117587122A CN 202210960260 A CN202210960260 A CN 202210960260A CN 117587122 A CN117587122 A CN 117587122A
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prkn
tumor
microtubule
chemotherapeutic
gene
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尹东
陈恒星
李贇
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Sun Yat Sen Memorial Hospital Sun Yat Sen University
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Abstract

The invention discloses application of PRKN as a marker for predicting tumor sensitivity to chemotherapy. The invention is found by integrating and analyzing public database data and experiments: the lack or low expression of PRKN in tumors suggests that tumors respond poorly to anti-microtubule chemotherapeutics, suggesting that patients receive DNA damaging chemotherapeutics; and increasing the copy number amplification of the PRKN gene or the protein expression of PRKN in the tumor predicts that the tumor is sensitive to an anti-microtubule chemotherapeutic regimen, the patient is advised to receive a chemotherapeutic regimen containing an anti-microtubule chemotherapeutic agent. Therefore, the detection of the genetic variation and the expression level of PRKN in tumor tissues can be used as a marker for selecting a chemotherapy regimen of a tumor patient, and provides guidance for reasonably selecting the chemotherapy regimen clinically.

Description

Application of PRKN as marker for predicting tumor sensitivity to chemotherapy
Technical Field
The invention relates to the fields of biomedical technology and biological medicine, in particular to application of PRKN as a marker for predicting sensitivity of tumors to chemotherapy.
Background
Malignant tumors are one of the leading causes of threat to human health worldwide. Traditional treatments for malignant tumors include surgical excision, chemotherapy, and radiation therapy. Among them, chemotherapy belongs to systemic treatment means, and is one of the most effective methods for treating comprehensive malignant tumors. At present, chemotherapy is widely used in tumor treatment. Patients with tumors that are operable typically receive neoadjuvant or adjuvant chemotherapy for tumor shrinkage prior to surgery or for controlling tumor recurrence and metastasis after surgery. For non-operable tumor patients, the status of chemotherapy is more important, and is often used as a treatment means recommended by class I.
Chemotherapeutic agents currently in clinical use can be divided into six types according to their source: the first is an antitumor antibiotic drug whose mechanism of action is to inhibit synthesis of DNA and RNA, and the representative drug is anthracycline such as doxorubicin and the like. The second is antimetabolite whose mechanism of action is to inhibit the metabolic processes of folic acid, pyrimidine and purine, and the representative drugs are methotrexate, fluorouracil and cytarabine, etc. The third is topoisomerase inhibitor, which can inhibit DNA replication, and the representative drug is etoposide, etc. The fourth is alkylating agent, which can alkylate DNA, cause depurination and cleavage of DNA, and the representative drug is cyclophosphamide, etc. The fifth other chemotherapeutic drug, mainly including platinum chemotherapeutic drugs, can cause DNA cross-linking, and is represented by cisplatin, oxaliplatin, etc. The sixth is a plant antitumor drug, mainly comprising taxanes and vinblastine drugs, which can activate apoptosis by inhibiting polymerization and depolymerization of mitotic spindle microtubules, and the representative drugs are vincristine, paclitaxel, docetaxel, etc. In terms of action mechanism, the first five chemotherapeutic drugs belong to DNA damage type chemotherapeutic drugs, and all play roles by inhibiting DNA synthesis and causing DNA damage. The sixth belongs to the class of anti-microtubule chemotherapeutics, which by targeting microtubules, cause mitotic arrest and apoptosis. The DNA damage chemotherapeutics and the microtubule-resistant chemotherapeutics are widely applied clinically.
There are individual differences in the sensitivity of tumor patients to the above chemotherapeutic drugs. Since the clinical application of chemotherapeutic drugs, there is always a bottleneck in how to predict which chemotherapeutic drugs a tumor patient is sensitive to. Thus, there is a great clinical need for reliable biomarkers to guide the selection of tumor chemotherapeutic drugs.
Disclosure of Invention
The invention aims to overcome the defects and shortcomings of the prior art and provide application of a reagent for detecting the gene variation of PRKN and/or the expression level of PRKN protein in tumors in preparing a product for predicting the sensitivity and/or the reactivity of tumor patients to chemotherapeutic drugs.
The aim of the invention is achieved by the following technical scheme:
use of a reagent for detecting PRKN gene variation (condition) and/or PRKN protein expression level in a tumor in the preparation of a product for predicting sensitivity and/or responsiveness of a tumor patient to a chemotherapeutic agent.
The PRKN protein sequence is shown as SEQ ID NO. 1.
The PRKN gene has an accession number of 5071 in NCBI database.
The tumor is malignant tumor including breast cancer, etc.
The chemotherapeutic medicine is DNA damage chemotherapeutic medicine and/or microtubule resisting chemotherapeutic medicine.
The DNA damage chemotherapeutics comprise at least one of doxorubicin, methotrexate, fluorouracil, gemcitabine, cytarabine, etoposide, cyclophosphamide, cisplatin and oxaliplatin and derivatives of the above drugs.
The anti-microtubule chemotherapeutic medicine comprises docetaxel, paclitaxel, vinorelbine and vincristine, and at least one of derivatives of the above medicines.
The PRKN gene mutation comprises PRKN gene point mutation, increase of the copy number of the PRKN gene, deletion (low expression) of the copy number of the PRKN gene and the like; when the copy number of the PRKN gene is detected to be lost, the tumor is predicted to have low or no response to the anti-microtubule chemotherapeutic drug, and a tumor patient should be treated by the DNA damage chemotherapeutic drug during chemotherapy; when an increase in the copy number of the PRKN gene (PRKN gene amplification) is detected, the tumor is predicted to be sensitive to the anti-microtubule chemotherapeutic, and the tumor patient should receive a chemotherapeutic regimen containing the anti-microtubule chemotherapeutic during chemotherapy.
The PRKN gene copy number increase is preferably that the PRKN copy number is more than 2.
The deletion of the PRKN gene copy number is preferably that the PRKN copy number is less than 2.
The methods for detecting PRKN genetic variation in tumors include, but are not limited to, genomic hybridization chips and/or whole exon sequencing.
The sampling samples for detecting PRKN gene variation in the tumor comprise tumor related samples such as tumor subjected to surgical excision, tumor subjected to puncture biopsy sampling, and/or tumor DNA (deoxyribonucleic acid) of blood circulation.
The detection of PRKN protein expression level includes, but is not limited to, using immunohistochemical methods, detecting the percentage of PRKN protein staining positive tumor cells to total tumor cells in tumor tissue (Tumor cell proportion score, TPS); wherein, if TPS is less than or equal to 50% (preferably less than or equal to 10%), then the tumor is predicted to have low or no response to the anti-microtubule chemotherapeutic, and the tumor patient should receive the treatment of the DNA damage chemotherapeutic during chemotherapy; if TPS is greater than 50% (preferably greater than 75%), then the tumor is predicted to be sensitive to the anti-microtubule chemotherapeutic, and the tumor patient should receive a chemotherapeutic regimen containing the anti-microtubule chemotherapeutic at the time of chemotherapy.
The sampling sample for detecting the PRKN protein expression level comprises tumor excised by surgery and/or tumor sampled by puncture biopsy, etc.
The method for detecting the expression level of the PRKN protein is immunohistochemical staining.
The product comprises a kit, a chip, test paper, a high-throughput sequencing platform and the like.
Compared with the prior art, the invention has the following advantages and effects:
(1) The invention is found by integrating and analyzing public database data and experiments: the lack or low expression of PRKN in tumors suggests that tumors respond poorly to anti-microtubule chemotherapeutics, thus suggesting that patients are mainly treated with DNA damaging chemotherapeutics if chemotherapy is needed; the copy number amplification of the PRKN gene in the tumor or the increase of the protein expression of the PRKN can predict that the tumor is sensitive to the anti-microtubule chemotherapeutic regimen, so when the expression of the PRKN in the tumor tissue sample of a tumor patient is high, the chemotherapy is recommended to be considered, and the chemotherapeutic regimen containing the anti-microtubule chemotherapeutic drug is used. Therefore, the detection of the genetic variation and the expression level of PRKN in tumor tissues can be used as a marker for selecting a tumor patient chemotherapy regimen, so as to make up for the blank of the biomarker for guiding the selection of the tumor chemotherapy regimen in the prior art, and provide guidance for clinically and reasonably selecting the chemotherapy regimen.
(2) The biomarker which can be used for predicting the reactivity or the sensitivity of a tumor patient to a specific chemotherapeutic drug can predict the sensitivity of the tumor to the chemotherapeutic drug according to the genetic variation and the expression level of PRKN, and further can be used as a judgment standard for selecting a tumor chemotherapeutic scheme and used for developing a kit for guiding the selection of the chemotherapeutic scheme.
Drawings
FIG. 1 is a graph of the genetic variation of PRKN in breast cancer cells versus sensitivity to anti-microtubule chemotherapeutic drugs (docetaxel, paclitaxel, vinorelbine, vincristine); wherein, A is the half-inhibition concentration according to the anti-microtubule chemotherapeutic drugs (dividing tumor cells into sensitive and drug resistant groups, each point in the bar chart represents a tumor cell); b is the copy number of the PRKN gene in tumor cells sensitive to or resistant to the microtubule chemotherapeutic drug (the proportion of the amplification of the copy number of the PRKN gene in the tumor cells sensitive to the microtubule chemotherapeutic drug is higher, and the proportion of the deletion of the copy number of the PRKN gene in the tumor cells resistant to the microtubule chemotherapeutic drug is higher); c is the PRKN copy number amplified tumor cells against microtubule chemotherapy drug sensitivity (results have statistical significance, p < 0.05).
FIG. 2 is a graph of protein expression levels of PRKN in breast cancer versus the therapeutic effects of chemotherapeutic agents; wherein A is a graph of the expression level of PRKN protein in tumors of patients who do not receive chemotherapy and the survival time of the patients; b is the survival time of patients with high PRKN protein expression in tumors of patients receiving chemotherapy (the results show that the survival time of patients is longer, the results have statistical significance, and p < 0.05); c is the survival time of a patient with high PRKN protein expression in tumors of the patient receiving the anti-microtubule drug chemotherapy (the result shows that the survival time of the patient is longer, and the result has statistical significance, and p is less than 0.05); d is a graph of the expression level of PRKN protein in tumors of patients receiving DNA damage drug chemotherapy and the survival time of the patients (the result has statistical significance, and p is less than 0.05); e is the expression of PRKN protein in tumor cells sensitive or resistant to the microtubule chemotherapeutics (in tumors sensitive to the microtubule chemotherapeutics, PRKN protein is highly expressed, TPS >75%, in tumors resistant to the microtubule chemotherapeutics, PRKN protein is lowly expressed, TPS < 10%); f is the proportion of sensitivity of anti-microtubule chemotherapeutics in tumors with high proportion of PRKN protein staining positive cells; g is the condition of sensitivity of tumors with high PRKN protein expression to anti-microtubule chemotherapeutics (the result has statistical significance, and p is less than 0.05).
Detailed Description
The present invention will be described in further detail with reference to examples, but embodiments of the present invention are not limited thereto. Unless specifically stated otherwise, the reagents, methods and apparatus employed in the present invention are those conventional in the art. The test methods for specific experimental conditions are not noted in the examples below, and are generally performed under conventional experimental conditions or under experimental conditions recommended by the manufacturer. The reagents and starting materials used in the present invention are commercially available unless otherwise specified.
The chi-square test was used in the examples of the invention for the difference significance analysis (p values are all marked in the figures).
The PRKN gene related in the embodiment of the invention is positioned in human genome chr6:161,768,449-163,148,798, the amino acid sequence of the PRKN gene is shown as SEQ ID NO.1, and the accession number of the gene sequence at NCBI is: gene ID 5071.
EXAMPLE 1 study of the correlation of the genetic variation of PRKN with the sensitivity of tumor cells to anti-microtubule chemotherapeutic drugs
Semi-inhibitory concentration data for anti-microtubule chemotherapeutic drugs (docetaxel, paclitaxel, vinorelbine, vincristine) were from the Genomics of Drug Sensitivity in Cancer database (GDSC). The PRKN gene variation data for tumor cells were from the Cancer Cell Line Encyclopedia database (CCLE). Sensitive tumor cells and drug-resistant tumor cells are defined according to semi-inhibitory concentration data of anti-microtubule chemotherapeutic drugs. Tumor cells were then divided into two groups according to the genetic variation of PRKN: PRKN copy number amplification group, PRKN copy number deletion group. And analyzing the proportion of the sensitive tumor cells and the drug-resistant tumor cells in the PRKN copy number amplification group and the PRKN copy number deletion group respectively.
In this example, breast cancer cells are taken as an example, and the relationship between the genetic variation of PRKN in tumor cells and the sensitivity of anti-microtubule chemotherapeutics (docetaxel, paclitaxel, vinorelbine, vincristine) is shown. The method comprises the following steps:
(1) Semi-inhibition concentration data of anti-microtubule chemotherapeutic drugs docetaxel, paclitaxel, vinorelbine and vincristine on breast cancer cells of different breast cancer patients are obtained according to a GDSC database. Wherein 74 breast cancer cells recorded the half-inhibitory concentration of docetaxel, 44 breast cancer cells recorded the half-inhibitory concentration of paclitaxel, 32 breast cancer cells recorded the half-inhibitory concentration of vinorelbine, and 37 breast cancer cells recorded the half-inhibitory concentration of vinorelbine. Sensitive tumor cells and drug resistant tumor cells are defined according to the median of the semi-inhibitory concentration data. Tumor cells with half-inhibitory concentration data below (excluding) the median were defined as sensitive, and tumor cells with half-inhibitory concentration data above (including) the median were defined as drug resistant.
(2) And obtaining the copy number of the PRKN gene in the breast cancer cells according to a CCLE database. Tumor cells with a PRKN copy number greater than 2 were defined as PRKN copy number amplified groups and tumor cells with a PRKN copy number less than 2 were defined as PRKN copy number deleted groups (this experiment did not take into account the fact that the PRKN copy number was equal to 2).
(3) The proportion of sensitive tumor cells and drug resistant tumor cells was analyzed in the PRKN copy number amplified group and the PRKN copy number deleted group, respectively. The results of the chi-square test analysis are shown in FIG. 1 (the figure does not contain data with RKN gene copy number equal to 2): the results show that most of tumor cells amplified by PRKN copy number are sensitive to the microtubule chemotherapeutic drugs, and most of tumor cells deleted by PRKN copy number are resistant to the microtubule chemotherapeutic drugs.
EXAMPLE 2 study of correlation of PRKN expression levels with tumor sensitivity to anti-microtubule chemotherapeutic drugs
To verify the relationship between PRKN expression and tumor treatment effect of different chemotherapy regimens, the study was exemplified by breast cancer, incorporating 205 breast cancer patients, 62 of whom received no chemotherapy, and 143 of whom received chemotherapy; of 143 tumor patients receiving chemotherapy, 84 received an anti-microtubule drug chemotherapy regimen and 59 received a DNA damaging drug chemotherapy regimen. The specific treatment scheme is as follows:
(1) Of 84 patients receiving anti-microtubule drug-containing chemotherapy regimen:
(1) 57 patients received a docetaxel-containing chemotherapy regimen (docetaxel + capecitabine), with a docetaxel drug dose of 75mg/m 2 The drug dosage of capecitabine is 60mg/m 2 ("mg" refers to the mass of the drug, "m 2 "refers to the body surface area of a patient; body surface area = 0.010061 x height +0.010124 x weight-0.010099; the same applies below). 21 days is a period, and the medicine treatment is carried out on 1 st day of each period for 4 periods of chemotherapy.
(2) 24 patients received a docetaxel-containing chemotherapy regimen (docetaxel + doxorubicin) with a docetaxel drug dose of 75mg/m 2 The dosage of doxorubicin is 60mg/m 2 .21 days is a period, and the medicine treatment is carried out on 1 st day of each period for 4 periods of chemotherapy.
(3) 3 patients received a chemotherapeutic regimen containing vinorelbine (vinorelbine + capecitabine) at a drug dose of 60mg/m 2 Once daily on days 1 to 8 of each cycle; the drug dosage of capecitabine is 2000mg/m 2 Drug treatment was received once daily on days 9 to 16 of each cycle. 21 days is a period, and the total chemotherapy is 4 periods.
(2) Among 59 patients receiving a DNA damaging drug chemotherapy regimen:
(1) 26 patients received a chemotherapy regimen of cisplatin plus gemcitabine with a cisplatin drug dose of 75mg/m 2 Receive a medication on day 2 of each cycle; gemcitabine at a drug dose of 1000mg/m 2 Once daily, each cycle from day 1 to day 8 receives medication. 21 days as oneFor 4 to 6 cycles of co-chemotherapy.
(2) 14 patients received a chemotherapy regimen of fluorouracil + doxorubicin + cyclophosphamide with a fluorouracil drug dose of 600mg/m 2 Once daily on days 1 to 8 of each cycle; the dosage of doxorubicin is 75mg/m 2 Receive a medication once on day 1 of each cycle; the medicine dosage of cyclophosphamide is 600mg/m 2 Drug treatment was received once on day 1 of each cycle. 28 days is a period, and the total chemotherapy is 6 periods.
(3) 12 patients received a chemotherapy regimen of doxorubicin plus cyclophosphamide, wherein the dose of doxorubicin was 60mg/m 2 The medicine dosage of cyclophosphamide is 600mg/m 2 Drug treatment was received once on day 1 of each cycle. 21 days is a period, and the total chemotherapy is 4 periods.
(4) 7 patients received a chemotherapeutic regimen of cyclophosphamide + methotrexate + fluorouracil with a drug dose of cyclophosphamide of 100mg/m 2 Once daily on days 1 to 14 of each cycle; the medicine dosage of the methotrexate is 40mg/m 2 Once daily on days 1 to 8 of each cycle; the dosage of fluorouracil is 600mg/m 2 Once daily on days 1 to 8 of each cycle; 28 days is a period, and the total chemotherapy is 6 periods.
We used PRKN antibodies (ab 15494) to immunohistochemical staining of tumor tissues of these patients to detect expression of the PRKN protein. According to PRKN staining positive cell proportion (TPS), judging PRKN expression grading, wherein tumors with PRKN staining TPS less than or equal to 50% are defined as low-expression tumors, and tumors with PRKN staining TPS more than 50% are defined as high-expression tumors. The expression of PRKN in tumors was analyzed as a function of patient survival.
The results of the log-rank test analysis show that the expression level of the PRKN protein in the tumor is irrelevant to the survival time of patients who do not receive chemotherapy (FIG. 2A); in contrast, patients with high expression of PRKN protein in tumors survived significantly longer in patients receiving chemotherapy (fig. 2B).
Patients receiving chemotherapy are further divided into two categories: patients receiving anti-microtubule chemotherapy regimen and patients receiving DNA damage chemotherapy regimen. The results from the log-rank test analysis showed that the survival time of patients with high expression of PRKN protein in tumor was significantly longer in patients receiving anti-microtubule chemotherapy regimen (fig. 2C); in contrast, for patients treated with DNA-damaging chemotherapy regimens, the amount of PRKN protein expressed in the tumor was independent of patient survival (fig. 2D).
Further, we defined tumors that reached complete pathology remission after chemotherapy (pathological examination of specimens from breast cancer primary foci and axillary lymph node surgery without residual infiltrating tumor cells) as sensitive tumors, and tumors that did not reach complete pathology remission after chemotherapy as drug resistant tumors. PRKN expression classification was interpreted according to the proportion of PRKN staining positive cells (TPS), and was classified as 4: TPS less than or equal to 10%, 10% < TPS less than or equal to 50%, 50% < TPS less than or equal to 75%, TPS >75%. The proportion of sensitive and resistant tumors in group 4 was analyzed. Further, tumors with PRKN-stained TPS less than or equal to 50% are defined as low-expressing tumors, and tumors with PRKN-stained TPS >50% are defined as high-expressing tumors. The chemotherapeutic effect was compared between low-expressing and high-expressing tumors.
After chi-square test analysis, the result shows that: in tumors sensitive to anti-microtubule chemotherapeutics, PRKN protein is highly expressed, TPS >75%; in tumors resistant to microtubule chemotherapeutics, PRKN protein is expressed low, TPS is less than or equal to 10% (fig. 2E); in tumors with high proportion of PRKN protein-stained positive cells, the proportion of anti-microtubule chemotherapeutic drug sensitivity is high (fig. 2F); tumors with high expression of PRKN protein are sensitive to the anti-microtubule chemotherapeutic drugs (figure 2G), namely, the anti-microtubule chemotherapeutic drugs have good treatment effect on the high-expression PRKN tumors, and the anti-microtubule chemotherapeutic drugs have poor treatment effect on the low-expression PRKN tumors.
The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.

Claims (10)

1. Use of a reagent for detecting PRKN gene variation and/or PRKN protein expression levels in a tumor in the preparation of a product for predicting sensitivity and/or responsiveness of a tumor patient to a chemotherapeutic agent.
2. The use according to claim 1, characterized in that: the PRKN protein sequence is shown as SEQ ID NO. 1.
3. The use according to claim 1, characterized in that: the chemotherapeutic medicine is DNA damage chemotherapeutic medicine and/or microtubule resisting chemotherapeutic medicine.
4. A use according to claim 3, characterized in that:
the DNA damage chemotherapeutics comprise at least one of doxorubicin, methotrexate, fluorouracil, gemcitabine, cytarabine, etoposide, cyclophosphamide, cisplatin and oxaliplatin and derivatives of the above drugs;
the anti-microtubule chemotherapeutic medicine comprises docetaxel, paclitaxel, vinorelbine and vincristine, and at least one of derivatives of the above medicines.
5. The use according to claim 1, characterized in that: the tumor is malignant tumor.
6. The use according to claim 5, characterized in that: the tumor is breast cancer.
7. The use according to claim 1, characterized in that:
the PRKN gene mutation comprises PRKN gene point mutation, PRKN gene copy number increase and PRKN gene copy number deletion; when the copy number of the PRKN gene is detected to be lost, the tumor is predicted to have low or no response to the anti-microtubule chemotherapeutic drug, and a tumor patient should be treated by the DNA damage chemotherapeutic drug during chemotherapy; when the copy number of the PRKN gene is detected to be increased, predicting that the tumor is sensitive to the anti-microtubule chemotherapeutic drug, and the tumor patient should receive a chemotherapeutic regimen containing the anti-microtubule chemotherapeutic drug during chemotherapy;
the detection of the expression level of the PRKN protein is to detect the percentage of the tumor cells positive to the PRKN protein dyeing in the tumor tissue to the total number of the tumor cells by adopting an immunohistochemical method; if TPS is less than or equal to 50%, the tumor is predicted to have low or no response to the anti-microtubule chemotherapeutic drug, and the tumor patient should receive the treatment of the DNA damage chemotherapeutic drug during chemotherapy; if TPS is greater than 50%, the tumor is predicted to be sensitive to the anti-microtubule chemotherapeutic drug, and the tumor patient should receive a chemotherapeutic regimen containing the anti-microtubule chemotherapeutic drug during chemotherapy.
8. The use according to claim 7, characterized in that:
the copy number of the PRKN gene is increased to be more than 2;
the deletion of the PRKN gene copy number is that the PRKN copy number is less than 2.
9. The use according to claim 1, characterized in that:
the method for detecting the PRKN gene variation in the tumor is a genome hybridization chip and/or a whole exon sequencing;
the sampling sample for detecting PRKN gene variation in the tumor is a tumor subjected to surgical excision, a tumor subjected to puncture biopsy sampling and/or a blood circulation tumor DNA sample;
the method for detecting the expression level of the PRKN protein is immunohistochemical staining;
the sampling sample for detecting the PRKN protein expression level is a tumor subjected to surgical excision and/or a tumor subjected to puncture biopsy sampling, and the like.
10. The use according to claim 1, characterized in that: the product comprises a kit, a chip, test paper and a high-throughput sequencing platform.
CN202210960260.8A 2022-08-11 2022-08-11 Application of PRKN as marker for predicting tumor sensitivity to chemotherapy Pending CN117587122A (en)

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