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WO2024066941A1 - Composition pour détecter le cancer de la vessie, kit et son utilisation - Google Patents

Composition pour détecter le cancer de la vessie, kit et son utilisation Download PDF

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Publication number
WO2024066941A1
WO2024066941A1 PCT/CN2023/116826 CN2023116826W WO2024066941A1 WO 2024066941 A1 WO2024066941 A1 WO 2024066941A1 CN 2023116826 W CN2023116826 W CN 2023116826W WO 2024066941 A1 WO2024066941 A1 WO 2024066941A1
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WIPO (PCT)
Prior art keywords
methylation
detecting
bladder cancer
composition
kit
Prior art date
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Ceased
Application number
PCT/CN2023/116826
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English (en)
Chinese (zh)
Inventor
戴立忠
杨丽
彭磊
刘佳
洪梅
胡志红
陈明
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sansure Biotech Inc
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Sansure Biotech Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from CN202211212129.XA external-priority patent/CN117844921A/zh
Priority claimed from CN202211216837.0A external-priority patent/CN117844922A/zh
Priority claimed from CN202211216063.1A external-priority patent/CN117802225A/zh
Application filed by Sansure Biotech Inc filed Critical Sansure Biotech Inc
Publication of WO2024066941A1 publication Critical patent/WO2024066941A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer

Definitions

  • the present invention belongs to the field of molecular biological detection, specifically, to the field of bladder cancer detection, and more specifically, to the detection of the methylation level of bladder cancer gene markers.
  • Bladder cancer is the most common malignant tumor of the urinary system and one of the top ten common tumors in the body. It ranks first in the incidence of urogenital tumors in my country. There are about 550,000 new cases and 200,000 deaths each year in the world, and the incidence in China is increasing year by year. In my country, nearly 80% of bladder cancers are diagnosed as non-muscle-invasive bladder cancer (NMIBC). The prognosis is good after transurethral bladder tumor resection, but 70% of patients will experience tumor recurrence after surgery, and 15% of patients will progress in staging and grading; the remaining patients are diagnosed with muscle-invasive bladder cancer (MIBC), which is prone to distant metastasis and has a high risk of death.
  • MIBC muscle-invasive bladder cancer
  • bladder cancer patients usually need multiple follow-up examinations and bladder instillation treatment after surgery, which is expensive.
  • the preoperative diagnosis and postoperative recurrence monitoring of bladder cancer mainly rely on invasive cystoscopy, which not only causes pain to patients, but may also cause urinary tract damage and infection, etc., and patient compliance is poor.
  • Finding non-invasive, accurate, stable and effective molecular markers for bladder cancer is a key to the early diagnosis of bladder cancer.
  • Early screening, diagnosis and recurrence detection are of great significance.
  • Tumor marker detection is a method developed in recent years for detecting diseases, and finding accurate, stable and effective bladder cancer molecular markers is of great significance for early diagnosis and early treatment of bladder cancer.
  • DNA methylation, histone modification, and abnormal miRNA expression are all epigenetic changes, and the core link of tumor occurrence is also related to abnormal DNA methylation.
  • DNA methylation testing is stable, easy to detect, and its abnormality is often related to the progression of cancer. It is the marker with the greatest potential for early screening of tumors.
  • the present invention collected 413 cancer tissues, 231 adjacent tissues or normal control tissues and 656 healthy whole blood methylation data from the TCGA dataset (https://tcga.xenahubs.net) of the UCSC Xena website and the GEO database of the National Center for Biotechnology Information (NCBI).
  • the bladder cancer and control data were used for differential analysis. Through a large number of studies, the applicant found that the methylation levels of certain methylation sites are closely related to bladder cancer.
  • the present invention provides a composition for detecting bladder cancer, the composition comprising a detection reagent for detecting at least one of the following methylation sites: cg00206063, cg03278514, and cg13314394.
  • compositions of the present invention in tissue samples, all compositions can predict bladder cancer with a specificity of at least 0.8571, a sensitivity of 0.7203, and an area under the curve of 0.8585.
  • urine free DNA samples all compositions can predict bladder cancer with a specificity of at least 0.9048, a sensitivity of 0.6525, and an area under the curve of 0.8060.
  • the compositions of the present invention can detect bladder cancer with high sensitivity and good specificity in the clinic with fewer markers, saving both cost and time. In the clinic, it can effectively detect bladder cancer in the early stages of malignant transformation. Sensitive and specific detection.
  • the composition includes detection reagents for detecting at least two of the following methylation sites: cg00206063, cg03278514, and cg13314394.
  • the composition includes detection reagents for detecting the following methylation sites: cg00206063, cg03278514.
  • the composition includes detection reagents for detecting the following methylation sites: cg00206063, cg13314394.
  • the composition includes detection reagents for detecting the following methylation sites: cg03278514, cg13314394.
  • the composition includes detection reagents for detecting the following methylation sites: cg00206063, cg03278514, and cg13314394.
  • the composition further comprises a detection reagent for detecting the methylation level of at least one of the following: SPATS2, PARP4.
  • the composition includes detection reagents for detecting the following methylation sites: cg00206063, SPATS2, PARP4.
  • the composition includes detection reagents for detecting the following methylation sites: SPATS2, PARP4, cg03278514.
  • the composition includes detection reagents for detecting the following methylation sites: SPATS2, PARP4, cg13314394.
  • the composition further comprises a detection reagent for detecting the methylation level of: SPATS2, PARP4.
  • the methylation level detection reagent can be a detection reagent for detecting the average methylation level of the entire gene.
  • the methylation level detection reagent can also be a detection reagent for detecting the average methylation level of a gene fragment.
  • the methylation level detection reagent can also be a detection reagent for detecting the average methylation level of a gene promoter region or a fragment thereof.
  • the methylation level detection reagent can also be a detection reagent for detecting one or more methylation sites of a gene.
  • the composition further comprises a detection reagent for detecting the methylation level of the methylation site cg06712013 of the SPATS2 gene.
  • the composition further comprises a detection reagent for detecting the methylation level of the PARP4 gene methylation site cg20765408.
  • the composition includes detection reagents for detecting the methylation levels of cg13314394, cg00206063, cg06712013, cg20765408, and cg03278514.
  • composition of the above scheme can detect bladder cancer with higher sensitivity and better specificity; clinically, bladder cancer can be detected sensitively and specifically in the early stages of malignant transformation.
  • the detection reagent of the present invention can be used to detect the methylation level of the corresponding gene present in the sample.
  • sample is a biological sample selected from an individual. Specifically, for example, selected from cell lines, tissue sections, biopsy tissues, paraffin-embedded tissues, body fluids, feces, colon effluent, urine, plasma, serum, whole blood, separated blood cells, cells separated from blood, or a combination thereof.
  • the "sample” of the present invention is urine, ie, free DNA in urine.
  • Free DNA in urine can be used to detect tumors, with the characteristics of little harm to patients and good specificity. However, due to its extremely low content in urine, it generally has the problem of low sensitivity when used for cancer detection.
  • free DNA in urine can be used as a sample for detection, with high sensitivity and specificity.
  • detection reagent refers to a reagent for detecting the methylation level of a gene in a sample, wherein the methylation level is measured by amplification-sequencing, chip, methylation fluorescence quantitative PCR, etc.
  • the detection reagents include, but are not limited to, nucleic acid primers and sequencing Tag sequences, for measuring methylation levels by amplification-sequencing.
  • the amplification-sequencing is performed by treating the nucleic acid in the sample with bisulfite, then constructing a pre-library, then constructing a final library, and finally performing sequencing evaluation.
  • the detection reagent includes but is not limited to a chip, and the chip is a methylation chip, and the methylation chip has a probe that specifically binds to the methylation region.
  • the chip can be, for example, but is not limited to, Agilent's Human CpG Island Microarrays and Human DNA Methylation Microarrays, Illumina's Infinium Human Methylation 27 Bead Chip, Infinium Human Methylation 450 Bead Chip and Golden Gate Methylation Assay, and Roche NimbleGen's Human DNA Methylation 2.1M Deluxe Promoter Array, Human DNA Methylation Array, etc., for measuring the methylation level through the chip.
  • the detection reagents include, but are not limited to, nucleic acid primers and nucleic acid probes for measuring methylation levels by methylation fluorescence quantitative PCR.
  • the detection reagent also includes an internal standard primer and an internal standard probe.
  • the above composition may further include other reagents, specifically, for example, various reagents required for pre-treatment or pre-processing of the sample, such as a sample release agent for extracting sample nucleic acid, a purification agent for purifying sample nucleic acid, bisulfite or bisulfite used for conversion, etc.
  • reagents specifically, for example, various reagents required for pre-treatment or pre-processing of the sample, such as a sample release agent for extracting sample nucleic acid, a purification agent for purifying sample nucleic acid, bisulfite or bisulfite used for conversion, etc.
  • the above composition also includes a reagent for extracting free DNA in urine.
  • the present invention provides a kit for preparing a kit for detecting bladder cancer using the above composition. Uses in.
  • the above composition is used in the preparation of a kit for detecting bladder cancer, wherein the composition is a detection reagent for the following methylation site: cg13314394.
  • the present invention provides use of the above composition in preparing a kit for detecting bladder cancer using urine free DNA.
  • the present invention provides a kit for detecting bladder cancer, the kit comprising the composition as described above.
  • the kit also includes, but is not limited to, at least one of a reagent for extracting nucleic acid, a reagent for purifying nucleic acid, bisulfite, T4 polynucleotide kinase, and T4 ligase.
  • the reagents for extracting nucleic acid are reagents for extracting tissue DNA and reagents for extracting urine free DNA.
  • the reagent for extracting nucleic acid is a reagent for extracting free DNA in urine.
  • FIG1 is a ROC diagram of the methylation level of a single gene in distinguishing cancer from non-cancer in tissues
  • FIG2 is a ROC diagram of the methylation levels of two genes in differentiating cancer from non-cancer tissues
  • FIG3 is a ROC diagram of the methylation levels of five genes in differentiating cancer from non-cancerous tissues
  • FIG4 is a ROC diagram of the methylation level of a single gene in distinguishing cancer from non-cancer in urine;
  • FIG5 is a ROC diagram of the methylation levels of two genes in distinguishing cancer from non-cancer in urine
  • FIG. 6 is a ROC diagram of the methylation levels of five genes in distinguishing cancer from non-cancer in urine.
  • the present invention collected 413 cancer tissues, 231 paracancerous tissues or normal control tissues and 656 healthy whole blood methylation data from the TCGA data set (https://tcga.xenahubs.net) of the UCSC Xena website and the GEO database of the National Center for Biotechnology Information (NCBI).
  • the bladder cancer and control data were used for differential analysis, and the physical location and gene information of the differential sites were annotated.
  • the screening of methylated gene fragments needs to meet the following requirements at the same time: 1) The selected gene fragments are required to have no less than 2 adjacent sites with consistent methylation levels; 2) The bladder cancer and paracancerous tissues or normal control tissues were used for differential analysis, and the gene fragments with high consistency and high differential methylation in the bladder cancer samples were selected as candidate target genes; 3) The whole blood methylation detection data of bladder cancer and healthy samples were used for differential analysis, and the gene fragments with high differential methylation in bladder cancer were selected; 4) Finally, the methylation sites were analyzed one by one to obtain the candidate methylation sites.
  • the sample preparation of the present invention is to extract 4 ml of urine supernatant using VAHTS Free-Circulating DNA Maxi Kit and elute with 45 ⁇ L of elution buffer.
  • the extracted free nucleic acid must meet the following quality control conditions: the total amount of extracted nucleic acid is greater than 20 ng.
  • all free nucleic acids that have passed the quality control are treated with bisulfite using the EZ DNA Methylation-Lightning TM Kit. Subsequently, the sample DNA treated with bisulfite is used to construct a pre-library using a single-stranded library construction method. After the pre-library passes the quality inspection, the target region is captured and enriched by liquid chip hybridization to complete the construction of the final library.
  • Prelibrary construction steps 1) Phosphorylation: T4 polynucleotide kinase phosphorylates the 5 end of the bisulfite treated DNA; 2) SS1 ligation: T4 DNA Ligase (Rapid) ligates SS1 The adapter was connected to the 5 end of the phosphorylated DNA; 3) Nucleic acid purification: Use 2 volumes of Agencourt AMPure XP system to remove the remaining adapter; 4) SS2 connection: T4 DNA Ligase (Rapid) connected the SS2 adapter to the 3 end of the phosphorylated DNA; 5) Nucleic acid purification: Use 2 volumes of Agencourt AMPure XP system to remove the remaining adapter; 6) Amplification: Use NEBNext Q5U Master Mix, primer1.0 (universal primer) and Bacard sequence to amplify the nucleic acid in the previous step; 7) Nucleic acid purification: Use 1.2 volumes of Agencourt AMPure XP system to remove primer dimers and excess primers
  • Chip hybridization capture steps 1) Chip hybridization: vacuum concentrate 1.5ug of the qualified mixed library into powder in advance and then mix it with Panel, Hybridization Mix, Blocker Solution, Universal Blockers, and Hybridization Enhancer reagents, and place it in a PCR instrument and incubate it at 70 degrees for 16 hours overnight (the hot cover temperature is 85 degrees); 2) Magnetic bead capture: wash the captured magnetic beads 3 times with Streptavidin Binding Buffer in advance, add the hybridization product to the captured magnetic beads, incubate for 30 minutes, wash once with Wash Buffer I, wash 3 times with Wash Buffer 2, and finally elute with 42 ⁇ l ultrapure water; 3) Amplification: use KAPA HiFi HotStart ReadyMix and universal primers to amplify the captured library; 4) Purification: use 1 volume of Agencourt AMPure XP system to remove primer dimers and excess primers.
  • the purified library was used The dsDNA HS Assay Kit and LabChip GXII Touch were used to perform quality checks on the total nucleic acid content, fragment distribution, and primer dimer ratio in the library.
  • the libraries to be tested that have passed the quality inspection of the total amount of the library, the fragment size distribution of the amplified product, and the primer dimer ratio are mixed at a 1:1 ratio and used
  • the dsDNA HS Asay Kit was used to accurately quantify the mixed library, and the library was denatured and diluted before sequencing using the NextSeq500 desktop sequencer using PE75.
  • the original fastq data obtained by sequencing was filtered and then the methylation analysis of the chip captured fragments was performed using the bismark methylation analysis software to obtain the methylation level of the candidate gene.
  • the methylation level of the candidate gene fragment was used to perform differential analysis and model construction for bladder cancer and control samples.
  • Example 3 Test results of the test samples of the composition of the present invention
  • Tissue samples from 63 patients with primary bladder cancer, 23 patients with cystitis, 10 ml of urine from 118 patients with bladder cancer, and 10 ml of urine from 60 patients with bladder disease and healthy people were collected to detect and analyze the methylation levels of candidate gene fragment methylation markers in urine samples.
  • the test results are shown in Table 1 and Figures 1 to 6.
  • Table 1 1 is cg13314394, 2 is cg00206063, 3 is cg06712013, 4 is cg20765408 and 5 is cg03278514.
  • the compositions in tissue samples, all the compositions can predict bladder cancer with a specificity of at least 0.8571, a sensitivity of 0.7203, and an area under the curve of 0.8585.
  • all the compositions can predict bladder cancer with a specificity of at least 0.9048, a sensitivity of 0.6525, and an area under the curve of 0.8060. Therefore, the composition of the present invention has a good predictive effect on bladder cancer, especially, when urine free DNA is used as a sample, it has excellent specificity and sensitivity.
  • methylation sites upstream and downstream of these sites were selected. The detection was also performed according to the method of the above embodiment, and the detection results are shown in Tables 2 to 4 below.
  • the highest AUC of the upstream and downstream methylation sites of the cg13314394 site in tissue samples is 0.760, and the highest AUC in free DNA samples is 0.522, which is lower than the AUC of the cg13314394 site of the present invention.
  • the highest AUC of the upstream and downstream methylation sites of the cg03278514 site in tissue samples is 0.857, and the highest AUC in free DNA samples is 0.878, which are lower than the AUC of the cg03278514 site of the present invention.
  • the methylation sites cg16732616 and cg04974290 which are closely related to bladder cancer and are known in the art, were further selected.
  • the detection was also performed according to the method of the above embodiment, and the detection results are shown in Table 3 below.
  • the highest AUC of a single comparison site in tissue samples is 0.848, and the highest AUC of a single site in free DNA samples is 0.751; the highest AUC of the comparison site combination in tissue samples is 0.851, and the highest AUC of the combination in free DNA samples is 0.862, which are lower than the AUCs of the cg00206063, cg03278514, and cg13314394 sites of the present invention.

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Abstract

La présente invention concerne une composition pour détecter le cancer de la vessie. La composition comprend un réactif de détection pour détecter au moins un des sites de méthylation suivants : cg00206063, cg03278514 et cg13314394. L'invention concerne également l'utilisation de la composition, et un kit comprenant la composition. Dans un échantillon tissulaire, toutes les compositions peuvent prédire le cancer de la vessie avec une spécificité d'au moins 0,8571, une sensibilité de 0,7203 et une aire sous la courbe de 0,8585. Cependant, dans un échantillon d'ADN sans urine, toutes les compositions peuvent prédire le cancer de la vessie avec une spécificité d'au moins 0,9048, une sensibilité de 0,6525 et une aire sous la courbe de 0,8060. La composition peut détecter cliniquement le cancer de la vessie avec une sensibilité élevée et une bonne spécificité en utilisant moins de marqueurs, de manière à économiser du temps et de l'argent. Sur le plan clinique, la transformation maligne du cancer de la vessie peut être détectée de manière sensible et particulièrement précoce.
PCT/CN2023/116826 2022-09-30 2023-09-04 Composition pour détecter le cancer de la vessie, kit et son utilisation Ceased WO2024066941A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
CN202211216063.1 2022-09-30
CN202211212129.XA CN117844921A (zh) 2022-09-30 2022-09-30 一种用于检测膀胱癌的试剂组合、试剂盒及其用途
CN202211216837.0A CN117844922A (zh) 2022-09-30 2022-09-30 一种用于检测膀胱癌的试剂组合、试剂盒及其用途
CN202211216837.0 2022-09-30
CN202211216063.1A CN117802225A (zh) 2022-09-30 2022-09-30 一种用于检测膀胱癌的试剂组合、试剂盒及其用途
CN202211212129.X 2022-09-30

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Citations (7)

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Publication number Priority date Publication date Assignee Title
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CN105039523A (zh) * 2008-11-17 2015-11-11 威拉赛特公司 用于疾病诊断的分子表达谱的方法和组合物
WO2017180984A1 (fr) * 2016-04-14 2017-10-19 The Texas A&M University System Biomarqueurs épigénétiques et à micro-arn de premier trimestre pour la prééclampsie
US20190316202A1 (en) * 2016-12-19 2019-10-17 Indiana University Research And Technology Corporation Dna methylation in inflammatory disease
CN110343762A (zh) * 2019-06-06 2019-10-18 宽盈医疗科技(上海)有限公司 膀胱癌标志物组及其应用
CN112322736A (zh) * 2020-11-17 2021-02-05 圣湘生物科技股份有限公司 一种用于检测肝癌的试剂组合，试剂盒及其用途
US20220025466A1 (en) * 2018-11-29 2022-01-27 Ucl Business Ltd Differential methylation

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105039523A (zh) * 2008-11-17 2015-11-11 威拉赛特公司 用于疾病诊断的分子表达谱的方法和组合物
CN102424840A (zh) * 2011-12-20 2012-04-25 上海市肿瘤研究所 尿液诊断膀胱癌患者复发危险性的方法和试剂盒
WO2017180984A1 (fr) * 2016-04-14 2017-10-19 The Texas A&M University System Biomarqueurs épigénétiques et à micro-arn de premier trimestre pour la prééclampsie
US20190316202A1 (en) * 2016-12-19 2019-10-17 Indiana University Research And Technology Corporation Dna methylation in inflammatory disease
US20220025466A1 (en) * 2018-11-29 2022-01-27 Ucl Business Ltd Differential methylation
CN110343762A (zh) * 2019-06-06 2019-10-18 宽盈医疗科技(上海)有限公司 膀胱癌标志物组及其应用
CN112322736A (zh) * 2020-11-17 2021-02-05 圣湘生物科技股份有限公司 一种用于检测肝癌的试剂组合，试剂盒及其用途

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