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WO2019078434A1 - Procédé de diagnostic du cancer de la tête et du cou par l'intermédiaire de l'analyse métagénomique bactérienne - Google Patents

Procédé de diagnostic du cancer de la tête et du cou par l'intermédiaire de l'analyse métagénomique bactérienne Download PDF

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Publication number
WO2019078434A1
WO2019078434A1 PCT/KR2018/004837 KR2018004837W WO2019078434A1 WO 2019078434 A1 WO2019078434 A1 WO 2019078434A1 KR 2018004837 W KR2018004837 W KR 2018004837W WO 2019078434 A1 WO2019078434 A1 WO 2019078434A1
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derived
group
bacterial
extracellular vesicles
neck cancer
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PCT/KR2018/004837
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English (en)
Korean (ko)
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김윤근
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MD Healthcare Inc
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MD Healthcare Inc
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Priority claimed from KR1020180047952A external-priority patent/KR102007786B1/ko
Application filed by MD Healthcare Inc filed Critical MD Healthcare Inc
Priority to US16/757,260 priority Critical patent/US20210189464A1/en
Priority to CN201880067793.5A priority patent/CN111406116A/zh
Publication of WO2019078434A1 publication Critical patent/WO2019078434A1/fr
Anticipated expiration legal-status Critical
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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

Definitions

  • the present invention relates to a method for diagnosing head and neck cancer through bacterial metagenomic analysis, and more specifically, by analyzing bacterial metagenomes using normal and subject-derived samples to analyze changes in the content of extracellular vesicles derived from a specific bacterium, And a method for diagnosing cervical cancer.
  • head and neck cancer Under the brain, the upper part of the chest is called the head and neck. It includes the oral cavity, larynx, pharynx, nasal cavity, etc. These tumors are called head and neck cancer.
  • Oral cancer is a cancer that occurs in the oral cavity, and most of the cancer is originated from the squamous cells that constitute the mucous membranes surrounding the oral cavity. Risk factors include smoking and unclean oral hygiene, and chronic chronic irritation.
  • Pharyngeal cancer is a malignant tumor that occurs in the mucous membrane of the pharynx, and smoking, drinking, and viral infection are known to be risk factors.
  • head and neck cancer occurs every year in 3,000 patients, and the incidence among cancer is 8th. The diagnosis of head and neck cancer is confirmed by biopsy if the cancer is suspected and the tissue is removed from the tumor.
  • CT scans, MRI scans, and proton scans are performed to determine the extent of cancer.
  • 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 about genes, proteins, etc., 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.
  • NGS next generation sequencing
  • the present inventors extracted genes from bacterial-derived extracellular vesicles present in saliva, which is a sample derived from healthy persons and subjects, and conducted metagenome analysis in order to diagnose causative factors and risk of head cancer of head and neck. As a result, Derived vesicles capable of acting as a causative factor of the present invention. Based on these findings, the present invention has been completed.
  • the present invention provides a method for providing information for the diagnosis of head and neck cancer, comprising the following steps.
  • the present invention also provides a diagnostic method of head and neck cancer, comprising the following steps.
  • the present invention also provides a method for predicting the risk of head and neck cancer, comprising the steps of:
  • the sample may be saliva.
  • step (c) the content of at least one phylum bacterial-derived extracellular vesicle selected from the group consisting of Cyanobacteria and Fusobacteria is compared, It may be to diagnose head and neck cancer.
  • step (c) at least one river selected from the group consisting of Halobacteria, Chloroplast, Fusobacterias, and Epsilonproteobacteria and to diagnose head and neck cancer by comparing the increase or decrease in the content of extracellular vesicles derived from a class of bacteria.
  • step (c) Halobacterials, Bifidobacteriales, Streptophyta, Pseudomonadales, Oceanospirillales
  • the present invention relates to a method for diagnosing head and neck cancer by comparing the increase or decrease in the content of at least one out of cell extracellular vesicles selected from the group consisting of Oceanospirillales, Fusobacteriales, and Campylobacterales have.
  • step (c) at least one selected from the group consisting of Pseudomonadaceae, Halobacteriaceae, Oxalobacteraceae, Halomonadaceae, One species selected from the group consisting of Comamonadaceae, Lactobacillaceae, Paraprevotellaceae, Fusobacteriaceae, and Campylobacteraceae.
  • the diagnosis of head and neck cancers can be made by comparing the increase or decrease in the content of extracellular vesicles derived from the above-mentioned family.
  • At least one selected from the group consisting of Cupriavidus, Chromohalobacter, Pseudomonas, Acinetobacter, Enhydrobacter, Lactobacillus, Veillonella, Fusobacterium, Actinomyces, Prevotella, Megasphaera, Campylobacter, Lactobacillus, , And Drosophila (Oribacterium) may be used to diagnose head and neck cancer by comparing the increase or decrease in the content of one or more genus bacterial-derived extracellular vesicles.
  • step (c) in step (c), one or more phylum bacterial-derived extracellular vesicles selected from the group consisting of Cyanobacteria and Fusobacteria,
  • Extracellular vesicles derived from one or more classes of bacteria selected from the group consisting of Halobacteria, Chloroplast, Fusobacterias, and Epsilonproteobacteria,
  • halobacterials Bifidobacteriales, Streptophyta, Pseudomonadales, Oceanospirillales, Fusobacteriales, and Campylobacteria
  • At least one order bacterial-derived extracellular vesicles selected from the group consisting of Campylobacterales,
  • Pseudomonadaceae Halobacteriaceae, Oxalobacteraceae, Halomonadaceae, Comamonadaceae, Lactobacillaceae, Lactobacillus, Lactobacillus, Lactobacillus, One or more family bacterial extracellular vesicles selected from the group consisting of Paraprevotellaceae, Fusobacteriaceae, and Campylobacteraceae, or
  • Cupriavidus Chromohalobacter, Pseudomonas, Acinetobacter, Enhydrobacter, Lactobacillus, Veillonella, (1) selected from the group consisting of Fusobacterium, Actinomyces, Prevotella, Megasphaera, Campylobacter, and Oribacterium. And to compare the increase or decrease in the content of extracellular vesicles derived from genus or more bacteria.
  • step (c) as compared with a sample derived from a normal person,
  • One or more order bacterial extracellular vesicles selected from the group consisting of Fusobacteriales and Campylobacterales,
  • One or more family bacterial strains selected from the group consisting of Lactobacillaceae, Paraprevotellaceae, Fusobacteriaceae, and Campylobacteraceae. Extracellular vesicles, or
  • the amount of extracellular vesicles derived from at least one genus of bacteria can be diagnosed as head and neck cancer.
  • step (c) as compared with a sample derived from a normal person,
  • One or more genus bacteria selected from the group consisting of Cupriavidus, Chromohalobacter, Pseudomonas, Acinetobacter, and Enhydrobacter. If the content of extracellular vesicles is decreased, it can be diagnosed as head and neck cancer.
  • the extracellular vesicles secreted from bacteria in the environment can be absorbed into the body and directly affect the cancer development.
  • early diagnosis is difficult before the symptoms appear, so it is difficult to effectively treat it.
  • 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 factors of head and neck cancer early and diagnose the risk of head and neck cancer, Can be delayed or prevented.
  • early diagnosis after head and neck cancer can be performed to lower the incidence of head and neck cancer and improve the therapeutic effect. In the case of head and neck cancer, Or to prevent recurrence.
  • FIG. 1A is a photograph of distribution patterns of bacteria and feces in the mouth after oral intestinal bacteria and bacterial-derived vesicles (EV) are administered to the mouse.
  • FIG. 1B is a photograph of the saliva 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) with diagnostic performance at the phylum level by performing a metagenome analysis after separating bacterial-derived vesicles from head and neck cancer patients and normal saliva.
  • EVs bacterial-derived vesicles
  • FIG. 3 is a graph showing 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 head and neck cancer patients and normal saliva.
  • EVs bacterial-derived vesicles
  • FIG. 4 is a graph showing 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 head and neck cancer patients and normal saliva.
  • EVs bacterial-derived vesicles
  • FIG. 5 is a graph showing the distribution of bacterial-derived vesicles (EVs) with diagnostic performance at the family level by performing a metagenome analysis after separating bacterial-derived vesicles from head and neck cancer patients and normal saliva.
  • EVs bacterial-derived vesicles
  • FIG. 6 shows the distribution of bacterial-derived vesicles (EVs) with diagnostic performance at the genus level by performing a metagenome analysis after separating bacterial-derived vesicles from head and neck cancer patients and normal saliva.
  • EVs bacterial-derived vesicles
  • the present invention relates to a method for diagnosing head and neck cancer through bacterial metagenomic analysis.
  • the present inventors extracted genes from bacterial-derived extracellular vesicles using normal and subject-derived samples and conducted metagenome analysis thereon. Derived vesicles that could act as a causative factor for the bacterial outgrowth.
  • head and neck cancer refers to cancer of the organs such as oral cavity, larynx, pharynx, nasal cavity and the like, and includes oral cancer, salivary cancer, pharyngeal cancer and nasal cancer.
  • diagnosis of head and neck cancer means to determine whether head and neck cancer is likely to occur, whether the likelihood of head and neck cancer is relatively high, or whether head and neck cancer 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 head and neck cancer for any particular patient.
  • the method of the present invention can also be clinically used to determine treatment by early diagnosis of head and neck cancer and by selecting the most appropriate treatment regimen.
  • 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 serum.
  • the normal person and the subject sample may be saliva, but are 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 And the bacterial - derived vesicles which could actually cause the development of head and neck cancer were identified.
  • the analysis of the bacterial metagenomes on the vesicles present in the saliva samples from the subject revealed that the content of extracellular vesicles derived from Cyanobacteria and Fusobacteria germs was significantly higher than that of patients with head and neck cancer (See Example 4).
  • the analysis of the bacterial metagenomes on vesicles present in the saliva samples from the subject revealed that the content of extracellular vesicles derived from Halobacteria, Chloroplast, Fusobacterias, and Epsilonproteobacteria There was a significant difference between patients with head and neck cancer and normal (see Example 4).
  • the analysis of the bacterial metagenomes against the parasites present in the saliva samples from the subject revealed that the cells of Halobacteriales, Bifidobacteriales, Streptophyta, Pseudomonadales, Oceanospirillales, Fusobacteriales, and Campylobacterales There was a significant difference between the contents of the outer vesicle and the head and neck cancer patients (see Example 4).
  • the bacterial metagenomes were analyzed at a high level against the vesicles present in the saliva samples from the subject, and as a result, the bacterial metagenomes were analyzed at the level of Pseudomonadaceae, Halobacteriaceae, Oxalobacteraceae, Halomonadaceae, Comamonadaceae, Lactobacillaceae, Paraprevotelaceae, Fusobacteriaceae and Campylobacteraceae And bacterial-derived extracellular vesicles were significantly different between head and neck cancer patients and normal subjects (see Example 4).
  • the bacterial metagenomes were analyzed at the genus level against the vesicles present in the saliva samples from the subject. As a result, it was confirmed that the bacterial metagenomes were found to be in the order of Cupriavidus, Chromohalobacter, Pseudomonas, Acinetobacter, Enhydrobacter, Lactobacillus, Veillonella, Fusobacterium, Actinomyces, The content of extracellular vesicles derived from Prevotella, Megasphaera, Campylobacter, and Oribacterium bacteria was significantly different between head and neck cancer patients (see Example 4).
  • Example 1 Analysis of absorption, distribution, and excretion of bacteria and bacterial-derived vesicles
  • the fluorescence-labeled bacteria and the bacterial-derived vesicles were administered in the same manner as described above to evaluate the pattern of invasion into various organs.
  • the blood, heart, lung, liver, kidney, spleen, adipose tissue, and muscle were excised.
  • the extracellular vesicles (EV) derived from the bacteria were saliva, heart, lung, liver , Kidney, spleen, adipose tissue, and muscle.
  • Example 2 Separation of vesicles from saliva and DNA extraction
  • saliva was first added to a 10 ml tube and centrifuged (3,500 x g, 10 min, 4 ° C) to resuspend the supernatant and transfer it to a new 10 ml tube.
  • 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).
  • META genome sequencing was performed by separating vesicles from saliva of 215 healthy persons who matched 50 male and 25 female patients with age and gender by the method of Example 3 above.
  • 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, accuracy, sensitivity, and specificity.
  • the method for providing information on the diagnosis of head and neck cancer through the analysis of the bacterial metagenomes according to the present invention can be carried out by analyzing the bacterial metagenomes using samples derived from healthy persons and the subject, It can be used to predict the risk of onset and to diagnose head and neck cancer.

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Abstract

La présente invention concerne un procédé de diagnostic du cancer de la tête et du cou par l'intermédiaire de l'analyse métagénomique bactérienne et, plus particulièrement, un procédé de diagnostic du cancer de la tête et du cou 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 par des bactéries qui sont présentes dans l'environnement peuvent entraîner l'inflammation chronique localement, ou être absorbées dans un corps et avoir une influence directe sur la carcinogenèse, et le cancer de la tête et du cou est difficile à diagnostiquer à un stade précoce avant l'apparition de ses symptômes et ainsi rend difficile le traitement efficace. L'analyse métagénomique des vésicules extracellulaires, dérivées de bactéries, en utilisant des prélèvements provenant de corps humains, selon la présente invention, permet la prédiction du risque d'incidence du cancer de la tête et du cou, permettant ainsi le diagnostic précoce et la prédiction d'un groupe à risque de développer le cancer de la tête et du cou et peut retarder le temps d'apparition ou empêcher l'apparition de la maladie par la gestion appropriée, et peut également réduire le niveau d'incidence du cancer de la tête et du cou et accroître l'effet du traitement en permettant le diagnostic précoce après l'apparition.
PCT/KR2018/004837 2017-10-18 2018-04-26 Procédé de diagnostic du cancer de la tête et du cou par l'intermédiaire de l'analyse métagénomique bactérienne Ceased WO2019078434A1 (fr)

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Application Number Priority Date Filing Date Title
US16/757,260 US20210189464A1 (en) 2017-10-18 2018-04-26 Method for diagnosing head and neck cancer via bacterial metagenomic analysis
CN201880067793.5A CN111406116A (zh) 2017-10-18 2018-04-26 通过细菌宏基因组分析来诊断头颈癌的方法

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KR20170135467 2017-10-18
KR10-2017-0135467 2017-10-18
KR1020180047952A KR102007786B1 (ko) 2017-10-18 2018-04-25 세균 메타게놈 분석을 통한 두경부암 진단방법
KR10-2018-0047952 2018-04-25

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011027990A2 (fr) * 2009-09-04 2011-03-10 주식회사이언메딕스 Vésicules extracellulaires issues de bactéries à gram positif et leur utilisation
WO2017009693A1 (fr) * 2015-07-10 2017-01-19 Uniwersytet Jagielloński Amorces universelles d'arn ribosomique 16s et leur utilisation pour les analyses microbiologiques et les diagnostics
WO2018008895A1 (fr) * 2016-07-08 2018-01-11 주식회사 엠디헬스케어 Nanovésicules dérivées de bactéries du genre propionibacterium et leur utilisation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011027990A2 (fr) * 2009-09-04 2011-03-10 주식회사이언메딕스 Vésicules extracellulaires issues de bactéries à gram positif et leur utilisation
WO2017009693A1 (fr) * 2015-07-10 2017-01-19 Uniwersytet Jagielloński Amorces universelles d'arn ribosomique 16s et leur utilisation pour les analyses microbiologiques et les diagnostics
WO2018008895A1 (fr) * 2016-07-08 2018-01-11 주식회사 엠디헬스케어 Nanovésicules dérivées de bactéries du genre propionibacterium et leur utilisation

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
AL-HEBSHI, NEZAR NOOR O: "Inflammatory bacteriome featuring Fusobacterium nucleatum and Pseudomonas aeruginosa identified in association with oral squamous cell carcinoma", SCIENTIFIC REPORTS, vol. 7, no. 1, 1834, 12 May 2017 (2017-05-12), pages 1 - 10, XP055598192, DOI: 10.1038/s41598-017-02079-3 *
PRINCIPE, SIMONA O: "Tumor-derived exosomes and microvesicles in head and neck cancer: Implications for tumor biology and biomarker discovery", PROTEOMICS, vol. 13, no. 10-11, 2013, pages 1608 - 1623, XP055598190 *
SHIN, JAE M. O: "Microbial communities associated with primary and metastatic head and neck squamous cell carcinoma-a high Fusobacterial and low Streptococcal signature", SCIENTIFIC REPORTS, vol. 7, no. 1, 9934, 30 August 2017 (2017-08-30), pages 1 - 11, XP055598193 *

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