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WO2018124619A1 - Procédé de diagnostic du cancer de la vessie par analyse métagénomique microbienne - Google Patents

Procédé de diagnostic du cancer de la vessie par analyse métagénomique microbienne Download PDF

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Publication number
WO2018124619A1
WO2018124619A1 PCT/KR2017/015177 KR2017015177W WO2018124619A1 WO 2018124619 A1 WO2018124619 A1 WO 2018124619A1 KR 2017015177 W KR2017015177 W KR 2017015177W WO 2018124619 A1 WO2018124619 A1 WO 2018124619A1
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bladder cancer
derived
bacteria
extracellular vesicles
decrease
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PCT/KR2017/015177
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English (en)
Korean (ko)
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김윤근
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주식회사 엠디헬스케어
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Priority claimed from KR1020170175822A external-priority patent/KR101936006B1/ko
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Publication of WO2018124619A1 publication Critical patent/WO2018124619A1/fr

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    • 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

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  • the present invention relates to a method for diagnosing bladder cancer through a microbial metagenome analysis, and more specifically, the content of specific bacteria and archaea-derived extracellular vesicles by performing microbial metagenomic analysis of bacteria, archaea, etc. using a sample derived from a subject.
  • the present invention relates to a method for diagnosing bladder cancer by analyzing the increase and decrease.
  • Bladder cancer is a malignant tumor of the bladder, which accounts for 90% of the transitional epithelial cell carcinoma derived from the transitional epithelial cell in direct contact with urine, and other squamous cell carcinoma, adenocarcinoma and sarcoma.
  • Bladder cancers can be divided into superficial bladder cancers limited to the bladder mucosa or submucosa, invasive bladder cancers involving the muscle layer, and metastatic bladder cancers that have spread to other organs.
  • the symbiosis of the human body reaches 100 trillion times 10 times more than human cells, the number of genes of the microorganism is known to be more than 100 times the number of human genes.
  • a microbiota is a microbial community, including bacteria, archaea, and eukarya that exist in a given settlement.
  • the intestinal microbiota plays an important role in human physiology.
  • it is known to have a great effect on human health and disease through interaction with human cells.
  • the symbiotic bacteria secrete nanometer-sized vesicles to exchange information about genes and proteins in other cells.
  • the mucous membrane forms a physical protective film that particles larger than 200 nanometers (nm) in size can't pass through, so that the symbiotic bacteria cannot pass through the mucosa, but bacterial-derived vesicles are usually less than 100 nanometers in size. It freely speaks to the mucous membrane and is absorbed by our body.
  • Metagenomics also called environmental genomics, is an analysis of metagenomic data obtained from samples taken from the environment. Recently, it has become possible to list the bacterial composition of the human microflora by a method based on 16s ribosomal RNA (16s rRNA) sequencing. Next generation sequencing of 16s rDNA sequencing gene of 16s ribosomal RNA is performed. , NGS) platform (Nature. 2007 Oct 18; 449 (7164): 804-810).
  • NGS NGS
  • the present inventors In order to diagnose bladder cancer, the present inventors extracted a gene from bacteria and archaea-derived extracellular vesicles using blood and urine, a sample derived from a subject, and performed a metagenome analysis on the result, which may act as a causative factor of bladder cancer. Bacterial-derived extracellular vesicles were identified, which completed the present invention.
  • an object of the present invention is to provide a method for providing information for diagnosing bladder cancer through metagenomic analysis of bacteria and archaea-derived extracellular vesicles.
  • an object of the present invention is to provide a method for diagnosing bladder cancer and predicting the risk of developing bladder cancer through metagenomic analysis of the extracellular vesicles.
  • the present invention provides a method for providing information for diagnosing bladder cancer, comprising the following steps:
  • the present invention also provides a bladder cancer diagnostic method comprising the following steps:
  • the present invention also provides a method for predicting the risk of developing bladder cancer, comprising the following steps:
  • the subject sample may be blood or urine.
  • Rubrobacterales, Erysipelotrichales, Burkholderiales, Enterobacteria isolated from the subject blood sample in step (c) It may be to compare the increase or decrease in the content of one or more order bacteria-derived extracellular vesicles selected from the group consisting of Enterobacteriales, Lactobacillales, Neisseriales, RF32.
  • Oxalobacteraceae isolated from the subject blood sample in step (c) (Oxalobacteraceae), Rikenellaaceae (Erysipelotrichaceae), Basil Bacillaceae, Rhizobiaceae, Fusobacteriaceae, Pseudomonadaceae, Comamonadaceae, Planococcaceae, Enterobacteriaceci Enterobacteriaceae, Lachnospiraceae, Corynebacteriaceae, Deinococcaceae, Porphyromonadaceae, Neisseriaceae, Enterero Extracellular vesicles derived from one or more family bacteria selected from the group consisting of Enterococcaceae, Lactobacillaceae, Tissierellaceae, and Peptocacaaceae Of It may be to compare the amount of increase or decrease.
  • the cyanobacteria, Gemmatimonadetes, Planctomycetes, Acidobacteria isolated from the urine sample of the subject in step (c) It may be to compare the increase and decrease of the content of one or more phylum bacteria-derived extracellular vesicles selected from the group consisting of, and Euryarchaeota.
  • Bactobacteriia acidobacteriia
  • Pedosphaerae Pedosphaerae
  • Stramenopiles, Streptophyta, Pseudomonadales, Turicibacterales isolated from the subject urine sample in step (c) Increase or decrease in the amount of extracellular vesicles derived from one or more order bacteria selected from the group consisting of Turicibacterales, Methanobacteriales, Gemmatales, Acidobacteriales, and Ellin329 It may be to compare the.
  • Flavobacteriaceae Lactobacillaceae, Pseudomonadaceae, Luminosity isolated from the subject urine sample in the step (c) Ruminococcaceae, Comamonadaceae, Turicibacteraceae, Clostridiaceae, Gordoniaaceae, Rikennellaceae, Pres 1 selected from the group consisting of Prevotellaceae, Methanobacteriaceae, Barnesiellaceae, Peptostreptococcaceae, and Koribacteraceae. It may be to compare the increase or decrease in the content of extracellular vesicles derived from species or more family (bacteria).
  • the blood may be whole blood, serum, plasma, or blood monocytes.
  • Extracellular vesicles secreted by bacteria and archaea present in the environment can be absorbed directly into the body and directly affect cancer development, and since bladder cancer is difficult to diagnose early due to difficult early diagnosis, the human body according to the present invention Metagenome analysis of extracellular vesicles derived from bacteria using the derived samples predicts the risk of bladder cancer in advance, and diagnoses and predicts the risk group of bladder cancer early, so that it can be delayed or prevented by proper management. Early diagnosis can reduce the incidence of bladder cancer and increase the therapeutic effect.
  • metagenome analysis in patients diagnosed with bladder cancer can be used to avoid the causative agent to improve the course of the cancer or prevent recurrence.
  • Figure 1a is a photograph of the distribution of bacteria and vesicles by time after the oral administration of enteric bacteria and bacterial derived vesicles (EV) to the mouse
  • Figure 1b is 12 hours after oral administration, blood And several organs were extracted to evaluate the distribution of bacteria and vesicles in the body.
  • Figure 2 shows the distribution of bacterial derived vesicles from bladder cancer patients and normal blood, and performing a metagenome analysis to show the distribution of bacterial derived vesicles (EVs) of significant diagnostic performance at the class level.
  • EVs bacterial derived vesicles
  • FIG. 3 is a result showing the distribution of bacteria-derived vesicles (EVs) with significant diagnostic performance at the order (neck) level after separating the bacteria-derived vesicles from bladder cancer patients and normal blood.
  • EVs bacteria-derived vesicles
  • Figure 4 shows the distribution of bacteria-derived vesicles (EVs) with significant diagnostic performance at the family level by separating the bacteria-derived vesicles in bladder cancer patients and normal blood, and performing a metagenome analysis.
  • EVs bacteria-derived vesicles
  • FIG. 5 is a result showing the distribution of bacteria-derived vesicles (EVs) with significant diagnostic performance at the genus level after separating the bacteria-derived vesicles from bladder cancer patients and normal blood.
  • EVs bacteria-derived vesicles
  • FIG. 6 is a result showing the distribution of bacteria-derived vesicles (EVs) of significant diagnostic performance at the phylum level by separating the bacteria-derived vesicles in bladder cancer patients and normal urine.
  • EVs bacteria-derived vesicles
  • FIG. 7 is a result showing the distribution of bacteria-derived vesicles (EVs) with significant diagnostic performance at the class level by separating the bacteria-derived vesicles from bladder cancer patients and normal urine.
  • EVs bacteria-derived vesicles
  • FIG. 8 shows the distribution of bacteria-derived vesicles (EVs) with significant diagnostic performance at the neck level after separation of bacteria-derived vesicles from bladder cancer patients and normal urine.
  • EVs bacteria-derived vesicles
  • FIG. 9 is a result showing the distribution of bacteria-derived vesicles (EVs) with significant diagnostic performance at the family level by separating the bacteria-derived vesicles from bladder cancer patients and normal urine.
  • EVs bacteria-derived vesicles
  • FIG. 10 is a result showing the distribution of bacteria-derived vesicles (EVs) with significant diagnostic performance at the genus level after separating the bacteria-derived vesicles in bladder cancer patients and normal urine.
  • EVs bacteria-derived vesicles
  • the present invention relates to a method for diagnosing bladder cancer through bacterial and archaea metagenomic analysis, and the present inventors extracted genes from bacterial and archaea-derived extracellular vesicles using a sample derived from a subject, and performed a metagenomic analysis on them. Bacterial-derived extracellular vesicles that could act as causative agents of bladder cancer were identified.
  • the present invention comprises the steps of (a) extracting DNA from the extracellular vesicles isolated from the subject sample;
  • (C) provides an information providing method for diagnosing bladder cancer comprising the step of comparing the increase and decrease of the content of bacteria and archaea-derived extracellular vesicles and the normal-derived sample through the sequencing of the PCR product.
  • the term "diagnosis of bladder cancer” refers to determining whether bladder cancer is likely to develop, whether bladder cancer is relatively high, or whether bladder cancer has already occurred.
  • the method of the present invention can be used to prevent or delay the onset of the disease through special and appropriate management as a patient at high risk of developing bladder cancer for any particular patient.
  • the methods of the present invention can be used clinically to determine treatment by early diagnosis of bladder cancer and selection of the most appropriate treatment regimen.
  • metagenome used in the present invention, also referred to as “metagenome”, refers to the total of the genome including all viruses, bacteria, fungi, etc. in an isolated area such as soil, animal intestine, It is mainly used as a concept of genome explaining the identification of many microorganisms at once using sequencer to analyze microorganisms which are not cultured.
  • metagenome does not refer to one species of genome or genome, but refers to a kind of mixed dielectric as the genome of all species of one environmental unit. This is a term from the point of view of defining a species in the course of the evolution of biology in terms of functional species as well as various species that interact with each other to create a complete species.
  • metagenome analysis was preferably performed using bacteria-derived extracellular vesicles isolated from blood and urine.
  • the subject sample may be blood or urine, and the blood may preferably be whole blood, serum, plasma, or blood monocytes, but is not limited thereto.
  • the metagenome analysis of the extracellular vesicles derived from bacteria and archaea was performed, and at the level of phylum, class, order, family, and genus, Each analysis identified bacterial vesicles that could actually cause bladder cancer.
  • the contents of the extracellular vesicles derived from Rubrobacteria and Erysipelotrichi bacteria are found in bladder cancer patients and normal people. There was a significant difference between them (see Example 4).
  • bacterial metagenomes were analyzed at the neck level for vesicles present in a blood sample derived from a subject, and Rubrobacterales, Erysipelotrichales, Burkholderiales, Enterobacteriales, Lactobacillales, Neisseriales, and RF32 neck bacterial derived cells. There was a significant difference in the content of external vesicles between bladder cancer patients and normal individuals (see Example 4).
  • the bacterial metagenome of the vesicles present in the blood samples from the subject at the level of analysis Oxalobacteraceae, Rikenellaceae, Erysipelotrichaceae, Bacillaceae, Rhizobiaceae, Fusobacteriaceae, Pseudomonadaceae, Comamonadaceae, Planococcaceae, There were significant differences between Enterobacteriaceae, Lachnospiraceae, Corynebacteriaceae, Deinococcaceae, Porphyromonadaceae, Neisseriaceae, Enterococcaceae, Lactobacillaceae, Tissierellaceae, and Peptococcaceae and bacterial extracellular vesicles between normal and bladder cancer patients (see Example 4).
  • Cupriavidus Eubacterium, Blautia, Catenibacterium, Collinsella, Geobacillus, Roseburia, Coprococcus, Faecalibacterium, Pseudomonas, Corynebacterium, Mucispirillum, Deinococcus, Anaerococcus, Dorea, Enterococcus, Adlercreutzia, Parabacteroides, Lactobacillus, rc4-4, Peptoniphilus, and Finegoldia were found to be significantly different between bladder cancer patients and normal individuals. See Example 4).
  • the results of analyzing the bacterial metagenome at the gate level for the vesicles present in the urine sample derived from the subject the content of extracellular vesicles derived from Cyanobacteria, Gemmatimonadetes, Planctomycetes, Acidobacteria, and Euryarchaeota door bacteria
  • the results of analysis of bacterial metagenome at the river level for vesicles present in the urine sample derived from the subject the content of extracellular vesicles derived from Chloroplast, Methanobacteria, Planctomycetia, Acidobacteriia, and Pedosphaerae river bacteria
  • the bacterial metagenome was analyzed at the neck level for vesicles present in a urine sample derived from a subject, and Stramenopiles, Streptophyta, Pseudomonadales, Turicibacterales, Methanobacteriales, Gemmatales, Acidobacteriales, and Ellin329 throat bacteria
  • the content of derived extracellular vesicles was significantly different between bladder cancer patients and normal subjects (see Example 5).
  • the bacterial metagenome of the vesicles present in the subject-derived urine sample at the genus level Rhizobium, Proteus, Pseudomonas, Lactobacillus, Turicibacter, Ruminococcus, Klebsiella, Faecalibacterium, Brevundimonas
  • the contents of extracellular vesicles derived from bacteria of the genus Clostridium, Jeotgalicoccus, Megasphaera, Gordonia, Prevotella, Actinobacillus, Thermoanaerobacterium, and Methanobrevibacter were significantly different between bladder cancer patients and normal individuals (see Example 5).
  • the present invention through the results of the above Example, by identifying the bacteria-derived extracellular vesicles isolated from blood and urine by metagenomic analysis of bacteria-derived vesicles significantly changed in bladder cancer patients compared to normal people was identified , Metagenomic analysis confirmed that bladder cancer can be diagnosed by analyzing the increase and decrease of the contents of the bacteria-derived vesicles at each level.
  • Example 1 Analysis of absorption, distribution, and excretion of intestinal bacteria and bacterial-derived vesicles
  • the fluorescently labeled 50 ⁇ g of bacteria and bacteria-derived vesicles were administered in the same manner as above 12 hours.
  • Blood, Heart, Lung, Liver, Kidney, Spleen, Adipose tissue, and Muscle were extracted from mice.
  • the intestinal bacteria (Bacteria) were not absorbed into each organ, whereas the intestinal bacteria-derived extracellular vesicles (EV) were detected in the tissues, as shown in FIG. And distribution in liver, kidney, spleen, adipose tissue, and muscle.
  • PCR was performed using the 16S rDNA primer shown in Table 1 to amplify the gene and perform sequencing (Illumina MiSeq sequencer). Output the result as a Standard Flowgram Format (SFF) file, convert the SFF file into a sequence file (.fasta) and a nucleotide quality score file using GS FLX software (v2.9), check the credit rating of the lead, and window (20 bps) The part with the average base call accuracy of less than 99% (Phred score ⁇ 20) was removed.
  • SFF Standard Flowgram Format
  • the Operational Taxonomy Unit performed UCLUST and USEARCH for clustering according to sequence similarity. Specifically, the clustering is based on 94% genus, 90% family, 85% order, 80% class, and 75% sequence similarity. OTU's door, river, neck, family and genus level classifications were performed, and bacteria with greater than 97% sequence similarity were analyzed using BLASTN and GreenGenes' 16S DNA sequence database (108,453 sequences) (QIIME).
  • Example 3 By the method of Example 3, the vesicles were isolated from the blood of 91 patients with bladder cancer and 176 normal people of age and sex matched with metagenome sequencing. In the development of the diagnostic model, the strains whose p-value between the two groups is 0.05 or less and more than two times different between the two groups are selected in the t-test. under curve), sensitivity, and specificity.
  • Example 3 By the method of Example 3, vesicles were isolated from urine of 42 patients with bladder cancer and 107 normal subjects matched with age and sex, followed by metagenome sequencing. In the development of the diagnostic model, the strains whose p-value between the two groups is 0.05 or less and more than two times different between the two groups are selected in the t-test. under curve), sensitivity, and specificity.

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Abstract

La présente invention concerne un procédé de diagnostic du cancer de la vessie par analyse métagénomique microbienne et, plus particulièrement, un procédé de diagnostic du cancer de la vessie par la réalisation d'une analyse métagénomique d'un microbe, tel qu'une bactérie et une archée, à l'aide d'un échantillon dérivé d'un sujet et par l'analyse d'une augmentation ou d'une diminution de la teneur en une vésicule extracellulaire dérivée d'un microbe spécifique. Une vésicule extracellulaire sécrétée par un microbe, tel qu'une bactérie, présente dans l'environnement peut être absorbée dans le corps et influencer directement l'apparition d'un cancer et le diagnostic précoce d'un cancer de la vessie est difficile avant l'apparition d'un quelconque symptôme, ce qui complique un traitement efficace. Ainsi, par l'intermédiaire de l'analyse métagénomique d'un microbe, tel qu'une bactérie et une archée, à l'aide d'un échantillon dérivé du corps humain selon la présente invention, le risque d'apparition d'un cancer de la vessie peut être prédit à l'avance, ce qui permet un diagnostic précoce et la prédiction d'un groupe à risque du cancer de la vessie et de retarder le moment d'apparition ou de prévenir l'apparition par des soins appropriés et un diagnostic précoce est encore possible même après l'apparition, ce qui peut abaisser le taux d'incidence du cancer de la vessie et améliorer l'effet de traitement.
PCT/KR2017/015177 2016-12-26 2017-12-21 Procédé de diagnostic du cancer de la vessie par analyse métagénomique microbienne WO2018124619A1 (fr)

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KR10-2016-0179240 2016-12-26
KR20160179240 2016-12-26
KR10-2017-0175822 2017-12-20
KR1020170175822A KR101936006B1 (ko) 2016-12-26 2017-12-20 미생물 메타게놈 분석을 통한 방광암 진단방법

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CN113286897A (zh) * 2019-01-09 2021-08-20 Md保健株式会社 来源于红球菌属细菌的纳米囊泡及其用途
CN114686607A (zh) * 2020-12-31 2022-07-01 深圳华大生命科学研究院 棒状杆菌作为尿液微生物标志物在制备用于检测膀胱癌的相关检测产品中的应用

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113286897A (zh) * 2019-01-09 2021-08-20 Md保健株式会社 来源于红球菌属细菌的纳米囊泡及其用途
CN114686607A (zh) * 2020-12-31 2022-07-01 深圳华大生命科学研究院 棒状杆菌作为尿液微生物标志物在制备用于检测膀胱癌的相关检测产品中的应用
CN114686607B (zh) * 2020-12-31 2023-09-26 深圳华大生命科学研究院 棒状杆菌作为尿液微生物标志物在制备用于检测膀胱癌的相关检测产品中的应用

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