CN110982902A - Intestinal cancer biomarker and application thereof - Google Patents
Intestinal cancer biomarker and application thereof Download PDFInfo
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- CN110982902A CN110982902A CN201911392211.3A CN201911392211A CN110982902A CN 110982902 A CN110982902 A CN 110982902A CN 201911392211 A CN201911392211 A CN 201911392211A CN 110982902 A CN110982902 A CN 110982902A
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- 239000000107 tumor biomarker Substances 0.000 title claims abstract description 7
- 208000005016 Intestinal Neoplasms Diseases 0.000 title abstract description 6
- 201000002313 intestinal cancer Diseases 0.000 title abstract description 6
- 206010009944 Colon cancer Diseases 0.000 claims abstract description 35
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims abstract description 35
- 239000000090 biomarker Substances 0.000 claims abstract description 35
- 241000193403 Clostridium Species 0.000 claims abstract description 12
- 238000001514 detection method Methods 0.000 claims description 19
- 201000002758 colorectal adenoma Diseases 0.000 claims description 15
- 239000012634 fragment Substances 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 12
- 238000012165 high-throughput sequencing Methods 0.000 claims description 9
- 238000003753 real-time PCR Methods 0.000 claims description 8
- 210000003608 fece Anatomy 0.000 claims description 7
- 238000012163 sequencing technique Methods 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 238000000018 DNA microarray Methods 0.000 claims description 2
- 238000002844 melting Methods 0.000 claims description 2
- 230000008018 melting Effects 0.000 claims description 2
- 210000003296 saliva Anatomy 0.000 claims description 2
- 239000002689 soil Substances 0.000 claims description 2
- 210000002700 urine Anatomy 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims 1
- 238000010998 test method Methods 0.000 claims 1
- 229940124597 therapeutic agent Drugs 0.000 claims 1
- 229940126585 therapeutic drug Drugs 0.000 claims 1
- 238000013399 early diagnosis Methods 0.000 abstract description 6
- 244000005700 microbiome Species 0.000 abstract description 4
- 238000004393 prognosis Methods 0.000 abstract description 4
- 230000035945 sensitivity Effects 0.000 abstract description 4
- 230000003902 lesion Effects 0.000 abstract description 3
- 238000012544 monitoring process Methods 0.000 abstract description 3
- 241000894006 Bacteria Species 0.000 description 5
- 238000011529 RT qPCR Methods 0.000 description 5
- 230000002550 fecal effect Effects 0.000 description 5
- 238000003908 quality control method Methods 0.000 description 4
- 230000003321 amplification Effects 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000003199 nucleic acid amplification method Methods 0.000 description 3
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
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- 238000000137 annealing Methods 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 238000010835 comparative analysis Methods 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
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- 230000000968 intestinal effect Effects 0.000 description 2
- 230000000813 microbial effect Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000012795 verification Methods 0.000 description 2
- 108020004465 16S ribosomal RNA Proteins 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- 208000003200 Adenoma Diseases 0.000 description 1
- 238000007400 DNA extraction Methods 0.000 description 1
- 241000605986 Fusobacterium nucleatum Species 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 108010054147 Hemoglobins Proteins 0.000 description 1
- 238000012408 PCR amplification Methods 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 238000009534 blood test Methods 0.000 description 1
- 238000002052 colonoscopy Methods 0.000 description 1
- 238000012136 culture method Methods 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
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- 238000001839 endoscopy Methods 0.000 description 1
- 230000001815 facial effect Effects 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 235000012631 food intake Nutrition 0.000 description 1
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- 238000012986 modification Methods 0.000 description 1
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- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
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- 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
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- 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
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/158—Expression markers
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Abstract
The invention provides an intestinal cancer biomarker and application thereof, wherein the intestinal cancer biomarker is clostridium family XI; the microorganism determined by the invention is used as a biomarker for early diagnosis and prognosis monitoring of colorectal cancer and precancerous lesions, and has the advantages of high accuracy, good specificity, strong sensitivity, wide application prospect and great market value.
Description
Technical Field
The invention belongs to the technical field of microorganisms, relates to an intestinal cancer biomarker and application thereof, and mainly relates to application of the biomarker in colorectal cancer diagnosis and colorectal cancer early screening.
Background
Colorectal cancer is the third most common cancer in the world, 120 thousands of patients are diagnosed with CRC every year, 60 thousands of people die every year, the incidence rate of colorectal cancer in 2015 accounts for 24.3% of the world, the number of deaths accounts for 22.9% of the world, at least 80% of colorectal cancers are considered to have colorectal adenomas evolved by research, the colorectal cancer is about 10-15 years old, the active diagnosis and treatment of colorectal adenomas is an important way to control and reduce colorectal cancer, and early discovery and treatment are reported to enable the 5-year survival rate of colorectal cancer to be as high as 90%. However, in China, more than 80% of patients actually have been diagnosed and developed to the middle and late stage, and the early diagnosis rate is only 10%. Therefore, it is important to note that early detection of colorectal cancer is extremely important for improvement of prognosis.
The current colorectal cancer detection methods commonly used at home and abroad mainly comprise colonoscopy, occult blood test (FOB) and fecal immunochemical examination (FIT). The most widely and reliably available examination is colorectal endoscopy, however, this examination is invasive and has certain discomfort and complications and poor patient experience. FOB is generally used for screening colorectal cancer and adenoma of asymptomatic people, needs to be detected for many times, and has low detection rate. FIT utilizes monoclonal or polyclonal antibody to directly detect hemoglobin in human fecal samples, which is not influenced by food intake, but FIT detects 80% of cancer sensitivity in one detection and only 20% -30% of sensitivity in detecting highly atypical adenomas, and needs to be repeatedly carried out in order to improve the detection rate.
Therefore, a non-invasive detection method is urgently needed, which can efficiently and accurately evaluate the risk of suffering from colorectal cancer and improve the early diagnosis rate of colorectal cancer.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a colorectal cancer biomarker and application thereof, wherein the biomarker is intestinal microorganisms, is used for evaluating the risk of an individual suffering from colorectal cancer by detecting the content of the biomarker in a stool sample, and provides a non-invasive detection method for early diagnosis of colorectal cancer.
The technical scheme adopted by the invention is as follows:
in a first aspect, the invention provides a biomarker of intestinal cancer, said biomarker being clostridium perfamily XI.
In the invention, the inventor utilizes methods such as high-throughput sequencing, real-time fluorescence quantitative PCR, a culture method and a chip method to perform difference comparative analysis and verification on the abundance and relative content of intestinal microorganisms clostridium family XI in feces samples of a large number of colorectal cancer and precancerous lesion (colorectal adenoma) individuals and a large number of healthy control individuals, and determines that clostridium family XI is related to colorectal cancer and colorectal adenoma, and clostridium family XI has high accuracy, good specificity and strong sensitivity for evaluating colorectal cancer and colorectal adenoma, and can be used for early diagnosis and prognosis monitoring of colorectal cancer.
In a second aspect, the present invention provides a method of detecting a biomarker as described in the first aspect, the method comprising the steps of:
(1) extracting sample DNA;
(2) designing a primer of the biomarker;
(3) and (3) detecting the abundance of the biomarker in the sample by using the primer in the step (2).
Preferably, the sample of step (1) is derived from any one or a combination of at least two of feces, soil, urine or saliva, preferably from feces.
Preferably, the primer of step (2) is designed against 16S rRNA of the biomarker.
Preferably, the detection method in step (3) comprises any one or a combination of at least two of high-throughput sequencing, real-time fluorescence quantitative PCR, high-resolution melting curve method or biochip, preferably high-throughput sequencing or real-time fluorescence quantitative PCR.
Preferably, the detection method of high throughput sequencing comprises the following steps:
(1') carrying out library building and sequencing on sample DNA by using a designed primer, and assembling a sequencing result;
(2') comparing the assembly fragment with a reference sequence of the biomarker, wherein the identity of the assembly fragment and the reference sequence of the biomarker is not less than 90%, determining that the assembly fragment is derived from the biomarker, and obtaining the abundance of the assembly fragment;
(3') determining the abundance of the biomarker in the sample from the average of the abundance of the assembled fragments.
Preferably, in real-time fluorescent quantitative PCR, the primer comprises random bases, and the number of the random bases is 3-5, such as 3, 4 or 5.
In the invention, random bases are added into the primer, and the number of the random bases is regulated and controlled, thereby being beneficial to improving the detection specificity.
In a third aspect, the invention provides a kit comprising Clostridium family XI related primers.
Preferably, the kit further comprises qPCR SYBRGreen Mix, ddH2O and PCR reaction solution.
Preferably, the PCR reaction solution comprises 10-75mmol/L Tris-HCl, 10-40mmol/L ammonium sulfate, 1-5.0mmol/L MgCl2 and 100-500. mu. mol/L dNTPs.
Preferably, the kit further comprises a negative quality control substance and a positive quality control substance;
preferably, the negative quality control comprises sterile water;
preferably, the positive quality control comprises fusobacterium nucleatum genomic DNA.
Preferably, the determination of the PCR result is as follows:
A) experimental validity:
(1') negative control: no canonical sigmoid amplification curve;
(2') Positive control: a typical S-shaped amplification curve is formed, and the Ct value is less than or equal to 30;
(3') Ct value of the detection sample is less than 40;
B) and (4) interpretation of results:
relative bacterial content = 2-Ct; where Ct = Ct bacteria-total Ct bacteria.
Compared with the prior art, the invention has the following beneficial effects:
(1) according to the invention, the microbial abundance and relative content difference of a large number of colorectal cancer and colorectal adenoma patients and healthy individual stool samples are compared, analyzed and verified, and the fact that clostridium family XI is related to colorectal cancer and colorectal adenoma is determined, and the clostridium family XI can be used as a microbial marker of colorectal cancer and adenoma;
(2) the primer group provided by the invention has good specificity and high accuracy; the detection system prepared by the primer group provided by the invention has good performance, the amplification efficiency of the curve reaches 90-105%, the linear correlation coefficient R2 is greater than 0.98, and the Ct value of each gradient repeated sample is close; the prepared kit is simple and convenient to operate and easy to popularize when used for detection.
Detailed Description
To further illustrate the technical means and effects of the present invention, the following further describes the technical solution of the present invention with reference to the preferred embodiments of the present invention, but the specific embodiments described herein are only used for explaining the present invention and are not limited within the scope of the embodiments.
Example 1 real-time fluorescent quantitative PCR detection of biomarker abundance in a sample
Primer design software Primer 5 is utilized to design primers and total bacteria primers of the biomarkers, and the design requirements of the primers are as follows: the primer length is 18-25 bp, secondary structure is avoided, GC content is 50-60%, Tm value is 60-65 ℃, and the product length is 100-250 bp; the designed specific primers (such as SEQ ID NO: 1-26) comprise random bases, and the number of the random bases is 3-5;
the relative content of clostridium family familyXI is calculated by taking fecal flora genome DNA as a template and taking the total number of bacteria in feces as an internal reference.
The qPCR reaction system and conditions were as follows:
(1) qPCR experimental system: 20 μ L system, qPCR SYBRGreen Mix (2X) 10 μ L, forward and reverse primers 0.5 μ L each, DNA 1 μ L, ddH2O 8 μ L;
(2) qPCR experimental conditions: pre-denaturation at 95 ℃ for 3 min; denaturation at 95 ℃ for 15s, annealing at the optimum annealing temperature for 60 ℃ for 1min, and 45 cycles.
Ct values for biomarkers were obtained by 2-△CtAnd (△ Ct = Ct bacteria-Ct total bacteria), and obtaining the relative content of the biomarker in the sample in the total bacteria.
Example 2 high throughput sequencing to detect the abundance of biomarkers in a sample
In this embodiment, after a disposable sample collector (prosheny) is used to collect a stool sample, a DNA extraction kit is used to extract sample DNA, and a 16S universal primer is used to perform PCR amplification and sequencing on V3 and V4 variable regions, specifically including the following steps:
(1) carrying out library building and sequencing on the extracted sample DNA to obtain off-line data;
(2) assembling the reading sections by utilizing SOAPdenovo software to obtain an assembled section;
(3) comparing the assembly fragment with a reference sequence of the biomarker, determining that the assembly fragment is derived from the biomarker, and obtaining the abundance of the assembly fragment, wherein the identity of the assembly fragment and the reference sequence of the biomarker is not less than 90%;
(4) determining the abundance of the biomarker in the sample from the average of the abundance of the assembled fragments.
Example 3 detection of colorectal cancer, colorectal adenoma, and colorectal tumorous polyps
245 colorectal cancer high-risk volunteers are screened out through a questionnaire form, feces samples of the volunteers are collected, the abundance of clostridium family similarity XI in the feces samples is detected through a high-throughput sequencing method, and the risk of suffering colorectal cancer and colorectal adenoma of a patient is predicted. After sampling, patients were advised to perform enteroscopy, and 96 of the high-risk colorectal cancer volunteers received the enteroscopy. Comparing the enteroscopy results, the accuracy of prediction of colorectal cancer/colorectal adenoma by the biomarker clonidilevfamily XI was analyzed.
TABLE 1 test results
It can be seen that the accuracy of colorectal cancer occurrence prediction by using the biomarkers in the stool sample reaches 98%, and the accuracy of colorectal adenoma reaches 97.6%.
The examples do not specify particular techniques or conditions, according to techniques or conditions described in the literature in the field or according to the product specifications. The reagents and apparatus used are conventional products commercially available from normal sources, without reference to the manufacturer.
In conclusion, the invention collects the fecal samples of patients with colorectal cancer and precancerous lesions and healthy individuals, carries out comparative analysis and verification on the abundance and relative content difference of clostridium family facial XI in the fecal samples, is used for detecting colorectal cancer and colorectal adenoma, has the highest accuracy respectively reaching 98 percent and 97.6 percent, and has important significance in early diagnosis and prognosis monitoring of colorectal cancer.
The applicant states that the present invention is illustrated in detail by the above examples, but the present invention is not limited to the above detailed methods, i.e. it is not meant that the present invention must rely on the above detailed methods for its implementation. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.
Claims (7)
1. A colorectal cancer biomarker, wherein the biomarker is clostridium family XI.
2. A method of detecting a biomarker according to claim 1, comprising the steps of:
(1) extracting sample DNA;
(2) designing a primer of the biomarker;
(3) and (3) detecting the abundance of the biomarker in the sample by using the primer in the step (2).
3. The test method according to claim 2, wherein the sample is derived from any one of or a combination of at least two of feces, soil, urine, or saliva.
4. The detection method according to claim 2, wherein the detection method comprises any one or a combination of at least two of high-throughput sequencing, real-time fluorescence quantitative PCR, high-resolution melting curve method or biochip, preferably high-throughput sequencing or real-time fluorescence quantitative PCR.
5. The detection method according to claim 2 or 4, wherein the detection method of high throughput sequencing comprises the following steps:
(1') carrying out library building and sequencing on sample DNA by using a designed primer, and assembling a sequencing result;
(2') comparing the assembly fragment with a reference sequence of the biomarker, wherein the identity of the assembly fragment and the reference sequence of the biomarker is not less than 90%, determining that the assembly fragment is derived from the biomarker, and obtaining the abundance of the assembly fragment;
(3') determining the abundance of the biomarker in the sample from the average of the abundance of the assembled fragments;
preferably, in the real-time fluorescent quantitative PCR, the primer comprises random bases, and the number of the random bases is 3-5;
preferably, the length of the primer is 18-25 bp;
preferably, the GC content of the primer is 50-60%;
preferably, the Tm value of the primer is 60-65 ℃.
6. Use of the biomarker according to any claim 1 and primers thereof in the preparation of a diagnostic reagent and/or a therapeutic agent for colorectal cancer.
7. Use of the biomarker according to any claim 1 and the primer set thereof in the preparation of a diagnostic reagent and/or a therapeutic drug for colorectal adenoma.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110512015A (en) * | 2019-09-11 | 2019-11-29 | 苏州普瑞森基因科技有限公司 | A kind of intestinal cancer biomarker combinations object and its application |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110512015A (en) * | 2019-09-11 | 2019-11-29 | 苏州普瑞森基因科技有限公司 | A kind of intestinal cancer biomarker combinations object and its application |
Non-Patent Citations (3)
| Title |
|---|
| JAKOB WIRBEL 等: "Meta-analysis of fecal metagenomes reveals global microbial signatures that are specific for colorectal cancer" * |
| PRICE, LANCE B.等: "Community Analysis of Chronic Wound Bacteria Using 16S rRNA Gene-Based Pyrosequencing: Impact of Diabetes and Antibiotics on Chronic Wound Microbiota" * |
| SEVERIN,WEIS 等: "Effect of Parkinson\'s disease and related medications on the composition of the fecal bacterial microbiota" * |
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