WO2019078432A1 - Procédé de diagnostic du lymphome par l'intermédiaire de l'analyse métagénomique bactérienne - Google Patents

Procédé de diagnostic du lymphome par l'intermédiaire de l'analyse métagénomique bactérienne Download PDF

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Publication number
WO2019078432A1
WO2019078432A1 PCT/KR2018/004798 KR2018004798W WO2019078432A1 WO 2019078432 A1 WO2019078432 A1 WO 2019078432A1 KR 2018004798 W KR2018004798 W KR 2018004798W WO 2019078432 A1 WO2019078432 A1 WO 2019078432A1
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group
derived
extracellular vesicles
bacterial
lymphoma
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PCT/KR2018/004798
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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 KR1020180047607A external-priority patent/KR102007783B1/ko
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Priority to JP2020521551A priority Critical patent/JP7112125B2/ja
Priority to US16/757,231 priority patent/US11708615B2/en
Priority to CN201880067789.9A priority patent/CN111373058A/zh
Priority to EP18867803.1A priority patent/EP3690065A4/fr
Publication of WO2019078432A1 publication Critical patent/WO2019078432A1/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
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6888—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for detection or identification of organisms
    • C12Q1/6895—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for detection or identification of organisms for plants, fungi or algae

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  • the present invention relates to a method for diagnosing lymphoma through the analysis of a bacterial metagenome, and more specifically, by analyzing a bacterial metagenome using a sample derived from a normal person and an examinee to analyze a change in the content of a specific bacterium-derived extracellular vesicle, And the like.
  • Lymphoma is a kind of blood cancer originating from lymphatic cells, mainly originating from the lymph node, but can occur anywhere in the lymphoid tissue. Typical symptoms include lymphadenopathy, night sweats, fever, weight loss, and tiredness. The enlarged lymph nodes are painless, which distinguishes them from inflated lymph node enlargement. Surgical treatment is usually not expected because it is basically a cancer of the blood. Instead, chemotherapy or radiotherapy is heard well. According to the data released by the Korean Central Cancer Registry in 2011, 192,561 cases of cancer occurred annually in Korea. Among them, malignant lymphomas accounted for 2.13% of the total cancer incidence, 4,093 cases per year.
  • the number of male and female cases was 2,313 cases per year for men and 1,780 cases for women. By age group, males and females showed the greatest number of males in their 60s (22.1%), fifties and seventies (19.3%) and fifties (15.4%).
  • lymphoma associated with acquired immune deficiency virus lymphoma associated with acquired immune deficiency virus
  • chronic hepatitis C-associated lymphoma chronic hepatitis C-associated lymphoma
  • Burkitt lymphoma and NK / T lymphoma associated with EB virus lymphoma associated with Helicobacter pylori
  • lymphoma associated with Helicobacter pylori lymphoma may occur even in the condition of decreased immunity, and the incidence is higher in organ transplantation, acquired immunodeficiency syndrome, congenital immunodeficiency syndrome, and autoimmune disease.
  • Lymphomas are usually diagnosed by lymph node biopsy. When pathological tissues are obtained, immunohistochemical staining is carried out in addition to basic staining. Other long-term involvement can be found through PET-CT.
  • microorganisms that are symbiotic to the human body is 10 times more than that of human cells, and the number of microorganisms is known to be over 100 times that of human genes.
  • Microbiota refers to microbial communities that include bacteria, archaea, and eukarya in a given settlement. Intestinal microbial guns play an important role in human physiology , And it is known to have a great influence on human health and disease through interaction with human cells. Bacteria that coexist in our body secrete nanometer-sized vesicles to exchange information such as genes, proteins, and low molecular compounds into other cells.
  • the mucous membrane forms a physical barrier that can not pass through particles of 200 nanometers (nm) or larger and can not pass through the mucous membrane when the bacteria are symbiotic to the mucous membrane.
  • the bacterial-derived vesicles are usually 100 nanometers or less in size, It is freely absorbed into our body through the mucosa.
  • Metagenomics also called environmental genomics, can be said to be an analysis of metagenomic data obtained from samples taken in the environment (Korean Patent Laid-Open Patent No. 2011-073049).
  • 16s ribosomal RNA (16s rRNA) base sequence-based method has been able to catalog the bacterial composition of human microbial genome.
  • the 16s rDNA nucleotide sequence of 16s ribosomal RNA can be sequenced by next generation sequencing , NGS) platform.
  • the present inventors extracted genes from bacterial-derived extracellular vesicles present in blood, which is a sample derived from normal persons and subjects, and conducted metagenome analysis to diagnose the causative factors and risk of developing lymphoma. As a result, Derived vesicles capable of acting as a factor were identified. Based on this finding, the present invention was completed.
  • the present invention provides a method for providing information for lymphoma diagnosis, comprising the following steps.
  • the present invention also provides a method of diagnosing a lymphoma, comprising the steps of:
  • the present invention also provides a method for predicting the risk of developing lymphoma, comprising the following steps.
  • step (c) one or more phylum bacterial-derived extracellular vesicles selected from the group consisting of Cyanobacteria, Thermi, and Euryarchaeota, Of lymphomas by comparing the increase or decrease in the amount of lymphoma.
  • the normal person and the subject sample may be blood.
  • step (c) in step (c), at least one class bacterium selected from the group consisting of Deinococci, Chloroplast, and Betaproteobacteria And to diagnose lymphoma by comparing the increase or decrease in the content of the extracellular vesicles.
  • step (c) at least one of Deinococcales, Rickettsiales, Streptophyta, Rhizobiales, Oceanospirillales, , Pasteurellales, and Neisseriales in order to diagnose lymphoma by comparing the increase or decrease in the content of at least one out of the bacterium-derived extracellular vesicles selected from the group consisting of Pseudomonas aeruginosa, Pasteurellales, and Neisseriales.
  • step (c) Erythrobacteraceae, Rhodospirillaceae, Deinococcaceae, Nocardioidaceae, ), Oxalobacteraceae, mitochondria, Lactobacillaceae, Ruminococcaceae, Halomonadaceae, Micrococcaceae, and the like. But are not limited to, Corynebacteriaceae, Propionibacteriaceae, Prevotellaceae, Burkholderiaceae, Actinomycetaceae, Tissierella spp. Tissierellaceae, Pasteurellaceae, Carnobacteriaceae, Neisseriaceae, and Alcanivoracaceae.
  • the term " familial " y) may be to diagnose lymphoma by comparing the increase or decrease in the content of extracellular vesicles derived from bacteria.
  • Extracellular vesicles derived from one or more classes of bacteria selected from the group consisting of Deinococci, Chloroplast, and Betaproteobacteria,
  • One or more order bacterial-derived extracellular vesicles selected from the group consisting of:
  • Prevotellaceae Prevotellaceae, Burkholderiaceae, Actinomycetaceae, Tissierellaceae, Pasteurellaceae, Carnobacteriaceae, One or more family bacterial-derived extracellular vesicles selected from the group consisting of Carnobacteriaceae, Neisseriaceae, and Alcanivoraceae, or
  • Rothia Actinomyces, Haemophilus, Peptoniphilus, Capnocytophaga, Lautropia, Granulicatella
  • step (c) as compared with a sample derived from a normal person,
  • Betaproteobacteria Bacteria-derived extracellular vesicles from the class
  • One or more order bacterial-derived extracellular vesicles selected from the group consisting of Oceanospirillales, Pasteurellales, and Neisseriales,
  • Micrococcaceae Corynebacteriaceae, Propionibacteriaceae, Prevotellaceae, Burkholderiaceae, Actinomycetaceae, Actinomycetaceae, Bacillus thuringiensis, Selected from the group consisting of Tissierellaceae, Pasteurellaceae, Carnobacteriaceae, Neisseriaceae, and Alcanivoraceae.
  • Micrococcus Such as Micrococcus, Corynebacterium, Propionibacterium, Anaerococcus, Porphyromonas, Prevotella, Veillonella, but are not limited to, Rothia, Actinomyces, Haemophilus, Peptoniphilus, Capnocytophaga, Lautropia, Granulicatella, The amount of one or more genus bacterial extracellular vesicles selected from the group consisting of Finegoldia, Neisseria, Selenomonas, and Alcanivorax is increased Lymphomas can be diagnosed.
  • step (c) as compared with a sample derived from a normal person,
  • One or more phylum bacterial-derived extracellular vesicles selected from the group consisting of Cyanobacteria, Thermi, and Euryarchaeota,
  • One or more order bacterial extracellular vesicles selected from the group consisting of Deinococcales, Rickettsiales, Streptophyta, and Rhizobiales,
  • Extracellular vesicles derived from one or more family members selected from the group consisting of Lactobacillaceae, Ruminococcaceae, and Halomonadaceae, or
  • Lymphocytes can be diagnosed when the content of one or more genus bacterial-derived extracellular vesicles selected from the group consisting of the cells is decreased.
  • the blood may be whole blood, serum, plasma, or blood mononuclear cells.
  • the extracellular vesicles secreted by bacteria present in the environment are absorbed into the body and can directly affect cancer development, and lymphoma is difficult to treat effectively because it is difficult to diagnose early before symptoms occur.
  • the metagenome analysis of the extracellular vesicles derived from the bacterium using the human-derived sample according to the present invention can diagnose the risk factor of the lymphoma and diagnose the risk of the disease early, thereby diagnosing the early stage of the lymphoma, Or prevent the onset. In addition to this, early diagnosis can be performed after the onset of the disease, so that the incidence of lymphoma can be lowered and the therapeutic effect can be enhanced.
  • metagenome analysis can be used to diagnose the causative agent, , There is an advantage to prevent recurrence.
  • FIG. 1A is a photograph of distribution patterns of bacteria and vesicles after oral administration of intestinal bacteria and bacterial-derived vesicles (EV) to a mouse
  • FIG. 1B is a photograph of blood And various organs were extracted to evaluate the distribution patterns of bacteria and vesicles in the body.
  • FIG. 2 shows the distribution of bacterial-derived vesicles (EVs), which have significant diagnostic performance at the phylum level, by performing a metagenome analysis after separating bacterial-derived vesicles from lymphoma patients and normal blood.
  • EVs bacterial-derived vesicles
  • FIG. 3 shows the distribution of bacterial-derived vesicles (EVs) with diagnostic performance at the class level by performing a metagenome analysis after separating bacterial-derived vesicles from lymphoma patients and normal blood.
  • EVs bacterial-derived vesicles
  • Figure 4 shows the distribution of bacterial-derived vesicles (EVs) with diagnostic performance at the order level by performing a metagenome analysis after separating bacterial-derived vesicles from lymphoma and normal human blood.
  • EVs bacterial-derived vesicles
  • FIG. 5 is a graph showing the distribution of bacterial-derived vesicles (EVs) having a diagnostic performance at the family level by performing a metagenome analysis after separating bacterial-derived vesicles from lymphoma patients and normal blood.
  • EVs bacterial-derived vesicles
  • FIG. 6 shows the distribution of bacterial-derived vesicles (EVs), which have a diagnostic performance at the genus level by performing a metagenome analysis after separating bacterial-derived vesicles from lymphoma patients and normal blood.
  • EVs bacterial-derived vesicles
  • the present invention relates to a method for diagnosing lymphoma through the analysis of a bacterial metagenome.
  • the present inventors extracted a gene from a bacterial-derived extracellular vesicle using a sample derived from a normal person and an examinee, conducted a metagenome analysis thereof, The extracellular vesicles derived from bacteria that could act as factors were identified.
  • the present invention provides a method for detecting abnormalities in a sample, comprising the steps of: (a) extracting DNA from extracellular vesicles present in a normal person and a sample of a subject;
  • diagnosis of lymphoma means to determine whether the patient is likely to develop lymphoma, whether the likelihood of developing lymphoma is relatively high, or whether the lymphoma has already developed.
  • the method of the present invention can be used to slow the onset or prevent the onset of disease through special and appropriate management as a patient with a high risk of developing lymphoma in any particular patient.
  • the method of the present invention can be used clinically to determine treatment by early diagnosis of lymphoma and by selecting the most appropriate treatment regime.
  • metagenome refers to the total of genomes including all viruses, bacteria, fungi, etc. in an isolated area such as soil, It is used as a concept of a genome to explain the identification of many microorganisms at once by using a sequencer to analyze microorganisms that are not cultured mainly.
  • a metagenome is not a genome or a genome of a species, but a kind of mixed genome as a dielectric of all species of an environmental unit. This is a term derived from the viewpoint that when defining a species in the course of omics biology development, it functions not only as an existing species but also as a species that interacts with various species to form a complete species.
  • metagenomic analysis was carried out preferably using extracellular vesicles derived from bacteria isolated from blood.
  • the normal person and the subject sample may be blood or urine, and the blood may be preferably whole blood, serum, plasma, or blood mononuclear cells, but is not limited thereto.
  • the metagenomic analysis of the extracellular vesicles derived from the bacterium was performed and analyzed at the level of phylum, class, order, family, and genus, respectively To identify bacterial - derived vesicles that could actually act as a cause of lymphoma development.
  • the analysis of the bacterial metagenomes on vesicles present in blood samples from the subject revealed that the content of extracellular vesicles derived from Cyanobacteria, Thermi, and Euryarchaeota germs was significantly higher in patients with lymphoma There was a significant difference between normal subjects (see Example 4).
  • the bacterial metagenomes were analyzed at the river level for vesicles present in blood samples from the subject, and the results showed that the content of extracellular vesicles derived from Deinococci, Chloroplast, and Betaproteobacteria strong bacteria was significantly higher in patients with lymphoma There was a significant difference between normal subjects (see Example 4).
  • the bacterial metagenomes were analyzed at the neck level for vesicles present in a blood sample from the subject, and as a result, Deinococcales, Rickettsiales, Streptophyta, Rhizobiales, Oceanospirillales, Pasteurellales, and Neisseriales There was a significant difference in the content of outer vesicles between lymphoma patients and normal subjects (see Example 4).
  • the bacterial metagenomes were analyzed at a high level against vesicles present in a blood sample from a subject, and as a result, it was found that the bacteria metagenomes were identified as Erythrobacteraceae, Rhodospirillaceae, Deinococcaceae, Nocardioidaceae, Oxalobacteraceae, Mitochondria, Lactobacillaceae, Ruminococcaceae, Halomonadaceae, The contents of micrococcaceae, Corynebacteriaceae, Propionibacteriaceae, Prevotellaceae, Burkholderiaceae, Actinomycetaceae, Tissierellaceae, Pasteurellaceae, Carnobacteriaceae, Neisseriaceae, and Alcanivoraceae and bacterial-derived extracellular vesicles were significantly different between lymphoma patients and normal subjects (see Example 4).
  • the bacterial metagenomes were analyzed at a low level against the vesicles present in blood samples from the subject.
  • the bacterial metagenomes were found to be in the order of Cupriavidus, Deinococcus, Clostridium, Dialister, Faecalibacterium, Lactobacillus, Citrobacter, Micrococcus, Corynebacterium, The contents of extracellular vesicles derived from bacteria belonging to the genus of Propionibacterium, Anaerococcus, Porphyromonas, Prevotella, Veillonella, Rothia, Actinomyces, Haemophilus, Peptoniphilus, Capnocytophaga, Lautropia, Granulicatella, Finegoldia, Neisseria, Selenomonas and Alcanivorax were significantly (See Example 4).
  • Example 1 Analysis of intestinal absorption, distribution, and excretion of intestinal bacteria and bacterial-derived vesicles
  • blood was first added to a 10 ml tube and centrifuged (3,500 xg, 10 min, 4 ° C) to resuspend the supernatant and recover the supernatant. I moved.
  • Bacteria and foreign substances were removed from the recovered supernatant using a 0.22 mu m filter, transferred to centripreigugal filters 50 kD, centrifuged at 1500 xg for 15 minutes at 4 DEG C to discard substances smaller than 50 kD, ≪ / RTI > After removing bacteria and debris using a 0.22 ⁇ m filter, the supernatant was discarded using a Type 90 rotator at 150,000 x g for 3 hours at 4 ° C, and the supernatant was discarded. The pellet was dissolved in physiological saline (PBS) A vesicle was obtained.
  • PBS physiological saline
  • PCR was performed using the 16S rDNA primer shown in Table 1 to amplify the gene and perform sequencing (Illumina MiSeq sequencer).
  • the result is output to the Standard Flowgram Format (SFF) file and the SFF file is converted into the sequence file (.fasta) and the nucleotide quality score file using the GS FLX software (v2.9) (20 bps) and less than 99% of the average base call accuracy (Phred score ⁇ 20).
  • SFF Standard Flowgram Format
  • GS FLX software v2.9
  • clustering is performed based on sequence similarity of 94% for the genus, 90% for the family, 85% for the order, 80% for the class, and 75% for the phylum Bacteria with a sequence similarity of 97% or more were analyzed using the 16S DNA sequence database (108,453 sequence) of BLASTN and GreenGenes (QIIME).
  • Example 4 Isolated from blood Bacterial origin parcel Meta genome Analysis-based lymphoma diagnosis model
  • metagenomic sequencing was performed after separating vesicles from blood of 53 normal persons who matched 63 lymphoma patients with age and sex.
  • the diagnostic model first the p value between the two groups was less than 0.05 and the difference between the two groups was more than 2 times, and the logistic regression analysis was used to determine the diagnostic performance index AUC under curve, sensitivity, and specificity.
  • Bacterial-derived vesicles in the blood were analyzed at the family level and found to be in the order of Erythrobacteraceae, Rhodospirillaceae, Deinococcaceae, Nocardioidaceae, Oxalobacteraceae, Mitochondria, Lactobacillaceae, Ruminococcaceae, Halomonadaceae, Micrococcaceae, Corynebacteriaceae, Propionibacteriaceae, Prevotellaceae, Burkholderiaceae, Actinomycetaceae, Tissierellaceae, Pasteurellaceae, When diagnostic models were developed with Carnobacteriaceae, Neisseriaceae, and Alcanivoracaceae and bacterial biomarkers, the diagnostic performance of lymphomas was significant (see Table 5 and Figure 5).
  • Bacterial-derived vesicles in the blood were analyzed at the genus level and found to be in the order of Cupriavidus, Deinococcus, Clostridium, Dialister, Faecalibacterium, Lactobacillus, Citrobacter, Micrococcus, Corynebacterium, Propionibacterium, Anaerococcus, Porphyromonas, Prevotella, Veillonella, Rothia, Actinomyces, Haemophilus, When diagnostic models were developed with bacterial biomarkers from genus Peptoniphilus, Capnocytophaga, Lautropia, Granulicatella, Finegoldia, Neisseria, Selenomonas, and Alcanivorax, diagnostic performance for lymphoma was significant (see Table 6 and Figure 6).
  • the method of providing information on the diagnosis of lymphoma through the analysis of the bacterial metagenome according to the present invention is carried out by analyzing the bacterial metagenomes using samples derived from normal persons and the subject to analyze the increase and decrease of the content of the extracellular vesicles derived from a specific bacterium, And can be used to diagnose lymphoma.

Abstract

La présente invention concerne un procédé de diagnostic du lymphome par l'intermédiaire de l'analyse métagénomique bactérienne et, plus particulièrement, un procédé de diagnostic d'un lymphome en effectuant l'analyse métagénomique bactérienne à l'aide de prélèvements provenant d'une personne normale et d'un sujet et l'analyse des variations dans les contenus des vésicules extracellulaires dérivées de certaines bactéries. Les vésicules extracellulaires sécrétées des bactéries qui sont présentes dans l'environnement peuvent être absorbés dans un corps et présenter une influence directe sur l'apparition des cellules cancéreuses, et le lymphome est difficile à diagnostiquer à un stade précoce avant l'apparition de ses symptômes et ainsi rend difficile l'atteinte d'un traitement efficace. L'analyse métagénomique des vésicules extracellulaires, dérivées de bactéries, en utilisant des prélèvements dérivés de corps humains, selon la présente invention, permet la prédiction du risque d'incidence du lymphome, permettant ainsi le diagnostic précoce et la prédiction d'un groupe à risque de présenter un lymphome et peut retarder le moment d'apparition ou empêcher l'apparition de la maladie par une gestion appropriée, et également peut réduire le taux d'incidence du lymphome et accroître l'effet du traitement en permettant le diagnostic précoce après l'apparition.
PCT/KR2018/004798 2017-10-18 2018-04-25 Procédé de diagnostic du lymphome par l'intermédiaire de l'analyse métagénomique bactérienne WO2019078432A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP2020521551A JP7112125B2 (ja) 2017-10-18 2018-04-25 細菌メタゲノム分析を通したリンパ腫の診断方法
US16/757,231 US11708615B2 (en) 2017-10-18 2018-04-25 Method for diagnosing lymphoma via bacterial metagenomic analysis
CN201880067789.9A CN111373058A (zh) 2017-10-18 2018-04-25 通过细菌宏基因组分析来诊断淋巴瘤的方法
EP18867803.1A EP3690065A4 (fr) 2017-10-18 2018-04-25 Procédé de diagnostic du lymphome par l'intermédiaire de l'analyse métagénomique bactérienne

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KR1020180047607A KR102007783B1 (ko) 2017-10-18 2018-04-24 세균 메타게놈 분석을 통한 림프종 진단방법

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