WO2024001602A1 - Composition pour la détection du cancer gastrique, kit et son utilisation - Google Patents

Composition pour la détection du cancer gastrique, kit et son utilisation Download PDF

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Publication number
WO2024001602A1
WO2024001602A1 PCT/CN2023/095273 CN2023095273W WO2024001602A1 WO 2024001602 A1 WO2024001602 A1 WO 2024001602A1 CN 2023095273 W CN2023095273 W CN 2023095273W WO 2024001602 A1 WO2024001602 A1 WO 2024001602A1
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seq
region
gene
methylation
nucleic acid
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PCT/CN2023/095273
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English (en)
Chinese (zh)
Inventor
高堂杰
罗诗雅
陈明
戴宏霜
赵浩强
吴康
刘佳
戴立忠
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圣湘生物科技股份有限公司
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Priority claimed from CN202210775335.5A external-priority patent/CN116064786A/zh
Priority claimed from CN202211430609.3A external-priority patent/CN115961038A/zh
Application filed by 圣湘生物科技股份有限公司 filed Critical 圣湘生物科技股份有限公司
Publication of WO2024001602A1 publication Critical patent/WO2024001602A1/fr

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    • 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 biology detection, specifically to the field of gastric cancer detection, and more specifically to the detection of methylation levels of gastric cancer gene markers.
  • the 5-year survival rate can reach 90%.
  • early gastric cancer has no obvious symptoms and is easy to be ignored. Therefore, most gastric cancer cases are usually diagnosed in the middle and late stages, and 5 years after surgery
  • the annual survival rate is low, less than 30%.
  • the treatment costs for stage I, II, III and IV gastric cancer are approximately 50,000-20,000 yuan, 30,000-50,000 yuan, 100,000 yuan/year, and 150,000-200,000 yuan/year respectively.
  • Stomach cancer is difficult and expensive to treat. It can be seen that early screening and early diagnosis of gastric cancer can not only improve the survival rate of patients, but also reduce national and individual medical expenditures. out of burden. How to detect gastric cancer in its early stages and achieve true early screening and early intervention for gastric cancer is an urgent and arduous task.
  • Gastroscopy and endoscopic biopsy are the gold standard for gastric cancer diagnosis and can detect gastric cancer earlier.
  • it is an invasive examination with poor patient compliance and high professional requirements for endoscopists.
  • imaging examination methods such as X-ray or CT scan have a low diagnostic rate for early gastric cancer and usually carry risks such as radiation and contrast agent safety.
  • Serological screening methods are easy to operate and are non-invasive tests.
  • markers include PG, G-17, CEA, CA199, etc. However, the sensitivity and specificity of these markers for detecting gastric cancer are low, and their diagnostic value for early screening is low. limited.
  • ctDNA methylation is an ideal detection marker.
  • Research shows that increased methylation levels of tumor suppressor genes usually occur in the early stages of cancer and are a hallmark change in early tumor development; in the CpG islands of the human genome, 60-80% of cytosine residues are methylated Modification, DNA methylation has become a common and abundant source of signals in early cancer screening; in addition, different cancer types have their own unique DNA methylation patterns, which are highly organ-specific and can enable tissue traceability. Therefore, ctDNA methylation is a mainstream detection indicator used by early screening companies at home and abroad.
  • the present invention provides a composition for detecting gastric cancer, which composition includes a detection reagent for detecting the methylation level of the following region:
  • the region shown in SEQ ID NO:1 in the OTX1 gene, the region shown in SEQ ID NO:2 in the ZNF671 gene, and the region shown in SEQ ID NO:3 in the ELMO1 gene are the promoter regions of the respective genes.
  • SEQ ID NO:1 region of the OTX1 (Genbank accession number: NC_000002.12) gene is as follows:
  • the SEQ ID NO:2 region of the ZNF671 (Genbank accession number: NC_000019.10) gene is as follows:
  • the SEQ ID NO:3 region of the ELMO1 (Genbank accession number: NC_000007.14) gene is as follows:
  • composition for detecting gastric cancer comprising a detection reagent for detecting methylation levels in the following regions:
  • the region shown in SEQ ID NO:29 in the KCNA3 gene, the region shown in SEQ ID NO:30 in the FGF12 gene, and the region shown in SEQ ID NO:31 in the NPY gene are the promoter regions of the respective genes.
  • SEQ ID NO:29 region of the KCNA3 (Genbank accession number: NC_000001.11) gene is as follows:
  • the SEQ ID NO:30 region of the FGF12 (Genbank accession number: NG_051966.1) gene is as follows:
  • the SEQ ID NO:31 region of the NPY (Genbank accession number: NG_016148.1) gene is as follows:
  • gastric cancer tissue samples can be clinically detected with at least 97.97% sensitivity; clinically, gastric cancer can be detected sensitively and specifically in the early stages of malignant transformation.
  • CpG island is the abbreviation of cytosine (C)-phosphate (p)-guanine (G), which refers to the promoter and exon region of the gene and is rich in CpG dinucleosides. Some regions of acid are 300 to 3000 bp in length.
  • the methylation level of the CpG island on the corresponding gene present in the sample or a sequence on the CpG island can be detected.
  • a sample is a biological sample selected from an individual. Specifically, for example, selected from cell lines, histological sections, tissue biopsies/paraffin-embedded tissues, body fluids, feces, colonic effluent, urine, plasma, serum, whole blood, isolated blood cells, cells isolated from blood , or a combination thereof.
  • the "sample” of the present invention is plasma, that is, free DNA in plasma.
  • Free DNA in plasma can be used to detect tumors, which has the characteristics of less harm to patients and good specificity. However, due to its extremely low content in plasma, there is a problem of low sensitivity.
  • free DNA in plasma can be used as a sample, and clinical detection can be performed with a sensitivity of at least 88.33% and a specificity of 96.67%.
  • detection reagent refers to a reagent for detecting the methylation level of a gene in a sample.
  • the methylation level is measured by amplification-sequencing, chip, and methylation fluorescence quantitative PCR.
  • detection reagents include, but are not limited to, nucleic acid primers and sequencing Tag sequences for measuring methylation levels by amplification-sequencing.
  • detection reagents include, but are not limited to, chips that are methylation chips having probes that specifically bind to methylated regions.
  • the chip may include, but is not limited to, Agilent's Human CpG Island Microarrays and Human DNA Methylation Microarrays, Illumina's Infinium HumanMethylation27BeadChip, Infinium HumanMethylation450BeadChip and GoldenGate Methylation Assay, and Roche NimbleGen's Human DNA Methylation 2.1M Deluxe Promoter Array, Human DNA Methylation Array, etc., are used to measure methylation levels by chip.
  • 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 internal standard primers and internal standard probes.
  • the target of the internal standard primers and probes is the ⁇ -actin gene.
  • the target of the internal standard primers and probes is the region shown in SEQ ID NO:4 of the ⁇ -actin gene.
  • SEQ ID NO:4 region of the ⁇ -actin gene (Gene bank accession number: NC_007992.1) is as follows:
  • the detection reagent detects the methylation level of the nucleic acid in the sample through methylation fluorescence quantitative PCR.
  • methylation fluorescence quantitative PCR refers to converting the region to be detected by sulfite conversion or digesting it with a methylation-sensitive restriction endonuclease, and then using primers and probes specifically designed for the detection target. The needle performs fluorescent quantitative PCR detection to obtain the methylation level of the region to be detected.
  • composition may further include other reagents, specifically, for example, Various reagents required for pretreatment or pretreatment of samples.
  • reagents specifically, for example, nucleic acid releasing agents for extracting sample nucleic acid, bisulfite or bisulfite used for conversion, etc.
  • the detection reagents are as shown in Table 1 and Table 2:
  • the four fluorescence channels used in the present invention are FAM, HEX, CY5 and ROX channels, but the actual application is not limited to this, and can be any combination of other fluorescence channels; at the same time, different targets It can also correspond to different fluorescence channels, for example, any fluorescence channel can be used as the internal standard detection channel.
  • the detection sensitivity and specificity are improved by about 10% respectively compared to using the remaining primer and probe compositions. Therefore, using this preferred composition can be used clinically with higher accuracy. Sensitivity and better specificity in detecting early gastric cancer further improve the detection accuracy of early gastric cancer.
  • the present invention provides the use of the above composition in preparing a kit for detecting gastric cancer.
  • the present invention provides the use of the above reagent combination in preparing a kit for detecting gastric cancer using plasma free DNA.
  • the present invention provides a kit for detecting gastric cancer, which kit includes the composition as described above.
  • the kit also includes, but is not limited to, at least one of reagents for extracting nucleic acids, reagents for purifying nucleic acids, and bisulfite.
  • kit also includes negative samples.
  • negative samples are human genomic DNA that has been verified by sequencing to have no target gene methylation.
  • the reagents for extracting nucleic acids are reagents for extracting tissue DNA and reagents for extracting plasma free DNA.
  • the reagent for extracting nucleic acid is a reagent for extracting plasma free DNA.
  • the kit also includes at least one of dNTPs, Mg 2+ , methylation-sensitive restriction enzyme, PCR buffer, and hot-start enzyme.
  • kit also includes a GC enhancer.
  • the methylation-sensitive restriction endonuclease includes at least one of HpaII, HinP1I and HhaI.
  • the range of the final concentration of each component is as follows: Mg 2+ 1 ⁇ 6mM, dNTPs 1 ⁇ 40mM, methylation-sensitive restriction enzyme 0.01 ⁇ 30U, primer 0.1 ⁇ 40 ⁇ M, probe 0.1 ⁇ 20 ⁇ M.
  • the final concentration of Mg 2+ is 2-6mM.
  • Figure 1 is the detection of methylation of composition 1 of the present invention in 0.05ng/reaction
  • Figure 2 shows the detection of no non-specific amplification of composition 1 of the present invention in 20ng/reaction of unmethylated DNA
  • Figure 3 is the detection results of the composition 1 of the present invention for detecting gastric cancer tissue and paracancerous tissue;
  • Figure 4 shows the detection of target gene methylation in composition 2 of the present invention containing 0.5% in 1ng/ ⁇ L nucleic acid
  • Figure 5 shows the detection of no non-specific amplification of composition 2 of the present invention in 20ng/reaction of unmethylated DNA.
  • the present invention collects tumor methylation detection data from the TCGA data set of the UCSC Xena website (https://tcga.xenahubs.net) and the GEO database of the National Center for Biotechnology Information (NCBI).
  • Use gastric cancer and control data to perform differential analysis, and annotate the physical location and genetic information of the differential sites.
  • the screening of methylated gene fragments needs to meet the following requirements: 1) It is required that the selected gene fragments have no less than 2 sites with relatively consistent methylation levels; 2) Perform differential analysis on gastric cancer and para-cancerous tissues or normal control tissues, and select gastric cancer samples with high consistency and those with para-cancerous or normal control tissues.
  • CpG islands in the promoter regions of three genes, OTX1, ZNF671, and ELMO1, were determined.
  • the CpG island in the promoter region of the three genes KCNA3, FGF12, and NPY is the optimal combination of detection targets, and the ⁇ -actin gene is used as the internal standard for detection.
  • the compositions used in the present invention are shown in Table 1 and Table 2, and the compositions of comparative examples are shown in Table 8 and Table 10.
  • Positive sample a mixture of standard methylated human genomic DNA and target gene unmethylated human genomic DNA, with a concentration of 1ng/ ⁇ L containing 10% standard methylated human genomic DNA; a concentration of 1ng/ ⁇ L containing 1% standard Methylated human genomic DNA; concentration is 1ng/ ⁇ L containing 0.5% standard methylated human genomic DNA;
  • Negative sample human genomic DNA with no target gene methylation verified by sequencing, 2ng/ ⁇ L.
  • PCR system configuration Prepare the PCR reaction solution according to the reagent formulas in Table 3 and Table 4 below;
  • Methylation-sensitive restriction enzymes in Table 3 include HpaII, HinP1I, and HhaI;
  • Methylation-sensitive restriction enzymes in Table 4 include HpaII and HinP1I.
  • Fluorescence detection channel selection OTX1 and KCNA3 select ROX channel (Reportere:ROX,Quencher:None) for detection; ZNF671 and FGF12 select FAM channel (Reportere:FAM,Quencher:None) for detection; ELMO1 and NPY select HEX channel (Reportere: HEX,Quencher:None) detection; ⁇ -actin selects CY5 channel (Reportere:CY5,Quencher: None) as internal standard to detect housekeeping genes;
  • the instrument After the reaction is completed, the instrument automatically saves the results. You can use the software that comes with the instrument for automatic analysis (you can also manually adjust the starting value, end value and threshold line value of the baseline for analysis).
  • the intersection of the amplification curve and the threshold line is called Ct (cycle threshold, refers to the cycle value experienced when the fluorescence signal in the PCR reaction tube reaches the set threshold).
  • Ct cycle threshold, refers to the cycle value experienced when the fluorescence signal in the PCR reaction tube reaches the set threshold).
  • the sensitivity of the detection reagent provided by the invention can reach 0.05ng/reaction ( Figures 1 and 4), and there is no non-specific amplification in 20ng/reaction of unmethylated DNA ( Figures 2 and 5).
  • 150 clinical plasma samples were collected, including 60 plasma samples from gastric cancer patients, 60 plasma samples from healthy people, and 30 plasma samples from other cancer patients; 150 paraffin section samples of cancer tissue from gastric cancer patients were also collected.
  • the amplified Ct values of the three target genes in gastric cancer tissue were all less than 32, indicating positive methylation.
  • the amplified Ct values of the three target genes in gastric cancer tissue were significantly different from those of adjacent tissue, indicating that the target had good specificity (Figure 3).
  • the detection specificity and sensitivity of plasma samples of the composition of the present invention are 96.67% and 88.33% respectively, and the detection sensitivity of tissue samples is 100%.
  • the specific detection results are shown in Table 6 below. It can also be seen from the table that the specificity of the composition of the present invention is relatively good. Only two of the 30 patients with other cancers tested positive.
  • the negative samples are the combined samples of all non-gastric cancer patients.
  • the detection specificity and sensitivity of plasma samples of the composition of the present invention were 95.56% and 86.67% respectively, and the detection sensitivity of tissue samples was 97.97%.
  • the specific detection results are shown in Table 7 below. It can also be seen from the table that the specificity of the composition of the present invention is good, and only 1 of 30 patients with other cancers tested positive.
  • the negative samples are the combined samples of all non-gastric cancer patients.
  • 150 clinical plasma samples were collected, including 60 plasma samples from gastric cancer patients, 60 plasma samples from healthy people, and 30 plasma samples from other cancer patients; 150 paraffin section samples of cancer tissue from gastric cancer patients were also collected.
  • the detection specificity and sensitivity of plasma samples of the comparative composition of the present invention were 77.78% and 70.00% respectively, and the detection sensitivity of tissue samples was 80.67%.
  • the specific detection results are shown in Table 9 below.
  • the OTX1 detection sequence (SEQ ID NO:26) is as follows:
  • the ZNF671 detection sequence (SEQ ID NO:27) is as follows:
  • the ELMO1 detection sequence (SEQ ID NO:28) is as follows:
  • 150 clinical plasma samples were collected, including 60 plasma samples from gastric cancer patients, 60 plasma samples from healthy people, and 30 plasma samples from other cancer patients; 150 paraffin section samples of cancer tissue from gastric cancer patients were also collected.
  • the detection specificity and sensitivity of plasma samples of the composition of the present invention are 83.33% and 71.67% respectively, and the detection sensitivity of tissue samples is 81.08%.
  • the specific detection results are shown in Table 11 below.

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Abstract

La présente est une composition pour la détection du cancer gastrique, comprenant : un réactif de détection pour détecter le niveau de méthylation dans la région suivante : une région du gène OTX1 représentée dans SEQ ID NO : 1 ; une région du gène ZNF671 représentée dans SEQ ID NO : 2 ; et une région du gène ELMO1 représentée dans SEQ ID NO : 3 ; ou un réactif de détection pour la détection du niveau de méthylation dans la région suivante : une région du gène KCNA3 représentée dans SEQ ID NO : 29 ; une région du gène FGF12 représentée dans SEQ ID NO : 30 ; et une région du gène NPY représentée dans SEQ ID NO : 31. L'invention concerne également un kit comprenant la composition, et l'utilisation de la composition.
PCT/CN2023/095273 2022-07-01 2023-05-19 Composition pour la détection du cancer gastrique, kit et son utilisation WO2024001602A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN202210775335.5A CN116064786A (zh) 2022-07-01 2022-07-01 一种用于检测胃癌的组合物，试剂盒及其用途
CN202210775335.5 2022-07-01
CN202211430609.3A CN115961038A (zh) 2022-11-15 2022-11-15 一种用于检测胃癌的组合物，试剂盒及其用途
CN202211430609.3 2022-11-15

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110151443A1 (en) * 2009-12-23 2011-06-23 The Chinese University of Hong Kong Room 328, Pi Ch'iu Building Marker for gastric cancer
WO2012070861A2 (fr) * 2010-11-24 2012-05-31 (주)지노믹트리 Biomarqueur de méthylation spécifique du cancer de l'estomac pour le diagnostic du cancer de l'estomac
US20150240313A1 (en) * 2012-07-18 2015-08-27 National Cancer Center Use of adcy3 for diagnosis and treatment of gastric cancer
US20210222260A1 (en) * 2018-07-26 2021-07-22 Exellon Medical Technology Co., Ltd Method and kit for identifying gastric cancer status
CN115961038A (zh) * 2022-11-15 2023-04-14 圣湘生物科技股份有限公司 一种用于检测胃癌的组合物，试剂盒及其用途
CN116064786A (zh) * 2022-07-01 2023-05-05 圣湘生物科技股份有限公司 一种用于检测胃癌的组合物，试剂盒及其用途

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110151443A1 (en) * 2009-12-23 2011-06-23 The Chinese University of Hong Kong Room 328, Pi Ch'iu Building Marker for gastric cancer
WO2012070861A2 (fr) * 2010-11-24 2012-05-31 (주)지노믹트리 Biomarqueur de méthylation spécifique du cancer de l'estomac pour le diagnostic du cancer de l'estomac
US20150240313A1 (en) * 2012-07-18 2015-08-27 National Cancer Center Use of adcy3 for diagnosis and treatment of gastric cancer
US20210222260A1 (en) * 2018-07-26 2021-07-22 Exellon Medical Technology Co., Ltd Method and kit for identifying gastric cancer status
CN116064786A (zh) * 2022-07-01 2023-05-05 圣湘生物科技股份有限公司 一种用于检测胃癌的组合物，试剂盒及其用途
CN115961038A (zh) * 2022-11-15 2023-04-14 圣湘生物科技股份有限公司 一种用于检测胃癌的组合物，试剂盒及其用途

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