KR102133432B1 - A marker for diagnosis of lung cancer - Google Patents

Abstract

The present invention relates to a marker for diagnosis of lung cancer disease, and more specifically, the S100P gene consisting of the nucleotide sequence represented by SEQ ID NO: 1, the MMP11 gene consisting of the nucleotide sequence represented by SEQ ID NO: 2, the nucleotide sequence represented by SEQ ID NO: 3 CDCA7 gene consisting of, S100A2 gene consisting of the nucleotide sequence represented by SEQ ID NO: 4, ETV4 gene consisting of the nucleotide sequence represented by SEQ ID NO: 5, TOP2A gene consisting of the nucleotide sequence represented by SEQ ID NO: 6 and represented by SEQ ID NO: 7 Lung cancer diagnostic composition and kit comprising lung cancer diagnostic marker composition comprising any one or more genes selected from the group consisting of nucleotide sequences consisting of UBE2C gene, mRNA for the gene or protein expressed therefrom, and lung cancer The present invention relates to a method for providing information for diagnosis of a disease and a method for screening for treatment for lung cancer disease.
According to the composition, kit for diagnosing lung cancer according to the present invention, a method for diagnosing lung cancer using the same, and a method for obtaining information necessary for diagnosing lung cancer, it can be used to accurately and sensitively diagnose histological subtypes of lung cancer of an individual, for example, lung cancer.

Description

A marker for diagnosis of lung cancer

The present invention relates to a marker for diagnosis of lung cancer disease, and more specifically, the S100P gene consisting of the nucleotide sequence represented by SEQ ID NO: 1, the MMP11 gene consisting of the nucleotide sequence represented by SEQ ID NO: 2, the nucleotide sequence represented by SEQ ID NO: 3 CDCA7 gene consisting of, S100A2 gene consisting of the nucleotide sequence represented by SEQ ID NO: 4, ETV4 gene consisting of the nucleotide sequence represented by SEQ ID NO: 5, TOP2A gene consisting of the nucleotide sequence represented by SEQ ID NO: 6 and represented by SEQ ID NO: 7 Lung cancer diagnostic composition and kit comprising lung cancer diagnostic marker composition comprising any one or more genes selected from the group consisting of nucleotide sequences consisting of UBE2C gene, mRNA for the gene or protein expressed therefrom, and lung cancer The present invention relates to a method for providing information for diagnosis of a disease and a method for screening for treatment for lung cancer disease.

According to the Korea Central Cancer Registration Headquarters data released in 2008, among the average cancer outbreaks in Korea in 2003-2005, lung cancer ranked second with 12.1% of all cancers. The crude incidence rate per 100,000 population is 33.2 cases. The gender ratio of males and females was 3.83:1, which was more frequent among men, and the number of cases was the second among male cancers and the fifth among female cancers. According to the age group of men and women, 34.3% were the most in their 60s, followed by 31.0% in the 70s and 14.6% in the 50s (Data released on October 15, 2008 by the Central Cancer Registry of the Ministry of Health and Welfare). Moreover, it is a rapidly increasing tumor in Korea due to the increase in the smoking population and air pollution, and the mortality rate for each type of cancer is 1st at 21.4%, 24.9% for men and 15.1% for women, respectively (2006) Yearly Cause of Death Statistics, Statistics Korea).

Lung cancer usually causes symptoms such as invasion of surrounding tissues due to the growth of cancer cells, airway obstruction, and lymph node metastasis, but about 10-15% of patients are diagnosed at regular checkups without any symptoms. In addition, most lung cancers are diagnosed in a fairly advanced state at the time of diagnosis. Therefore, it is an urgent problem to diagnose lung cancer early and reduce the mortality rate from lung cancer.

Various methods have been used to diagnose lung cancer. To date, the size of a tumor is measured, the presence or absence of metastasis to a lymph node is analyzed, or biopsy of lung tumor tissue or lymph nodes is analyzed by immunohistochemical methods or chest computed tomography. , Bronchoscope, etc. are used. However, in the case of chest tomography, the lung cancer should be about 0.1 cm or more in size, and it is likely that the cancer has already metastasized to other tissues, and the endoscope is inserted into the bronchus and the bronchoscopy can be directly observed. The method has limitations that make it difficult to observe the tumor at the end of the lung.

Accordingly, attempts have been made to diagnose cancer using markers of lung cancer, and studies of excavating lung cancer diagnostic markers by examining the expression of multiple target genes or proteins have already been reported, and lung cancer marker genes using microarray technology There were also reports of excavating and diagnosing cancer. In addition, lung cancer is diagnosed by measuring the concentration of aspartate aminotransferase (AST), alanine transaminase (ALT), total bilirubin or creatinine in the patient's blood. There was an attempt to However, despite studies on these tumor markers, there are no lung cancer blood markers and compositions for diagnosing lung cancer using the same, which are still limitedly used.

Meanwhile, a method for diagnosing lung cancer through gene expression analysis based on next-generation sequencing is currently being actively studied. In particular, it is possible to predict or diagnose general lung cancer or non-small cell lung cancer by measuring mRNA expression of a gene that specifically increases the expression level in lung cancer tissue. In particular, in the case of non-small cell lung cancer, the survival rate is very low. The main reason for this is that the probability of accurately diagnosing early-stage lung cancer is remarkably low. Methods for improving the success rate of diagnosis of lung cancer have been continuously studied, and among these, the lung cancer tissue is specifically diagnosed in lung cancer by observing the mRNA expression pattern of a gene whose expression pattern is specifically changed to diagnose lung cancer. It can be dramatically improved. However, despite such continuous research, there is a problem in that it is difficult to effectively diagnose lung cancer because genes that specifically change expression patterns in lung cancer tissue are very limited.

Prior art documents related to the present invention include Korean Registered Patent No. 0846354 (hereinafter referred to as'patent document 1') for'a marker for diagnosing lung cancer separated from a blood sugar protein','a marker for diagnosing lung cancer comprising ＨPFα as an active ingredient' The Republic of Korea Patent Registration No. 131464 (hereinafter referred to as'patent document 2') is only disclosed.

Accordingly, the present inventors have discovered a gene that increases expression in lung cancer tissue or lung cancer cells, and completed the present invention by confirming that it is possible to diagnose lung cancer or determine lung cancer in a lung cancer patient using a composition for diagnosing lung cancer including them.

Patent Document 1: Republic of Korea Registered Patent No. 0846354 Patent Document 2: Republic of Korea Registered Patent No. 1331464

One object of the present invention is the S100P gene consisting of the nucleotide sequence represented by SEQ ID NO: 1, the MMP11 gene consisting of the nucleotide sequence represented by SEQ ID NO: 2, the CDCA7 gene consisting of the nucleotide sequence represented by SEQ ID NO: 3, SEQ ID NO: 4 A group consisting of the S100A2 gene consisting of the nucleotide sequence represented, the ETV4 gene consisting of the nucleotide sequence represented by SEQ ID NO: 5, the TOP2A gene consisting of the nucleotide sequence represented by SEQ ID NO: 6, and the UBE2C gene consisting of the nucleotide sequence represented by SEQ ID NO: 7 It provides a marker composition for diagnosing lung cancer comprising any one or more genes selected from.

Another object of the present invention is S100P gene consisting of the nucleotide sequence represented by SEQ ID NO: 1, MMP11 gene consisting of the nucleotide sequence represented by SEQ ID NO: 2, CDCA7 gene consisting of the nucleotide sequence represented by SEQ ID NO: 3, represented by SEQ ID NO: 4 From the group consisting of the S100A2 gene consisting of the nucleotide sequence, the ETV4 gene consisting of the nucleotide sequence shown in SEQ ID NO: 5, the TOP2A gene consisting of the nucleotide sequence shown in SEQ ID NO: 6, and the UBE2C gene consisting of the nucleotide sequence shown in SEQ ID NO: 7 It is to provide a composition for diagnosing lung cancer comprising an agent for measuring the level of mRNA or protein expressed from any one or more genes selected.

Another object of the present invention is to provide a lung cancer diagnostic kit comprising the composition for diagnosing lung cancer.

Another object of the present invention is composed of the S100P gene consisting of the nucleotide sequence represented by SEQ ID NO: 1 from the biological sample isolated from the individual, the MMP11 gene consisting of the nucleotide sequence represented by SEQ ID NO: 2, and the nucleotide sequence represented by SEQ ID NO: 3 CDCA7 gene, S100A2 gene consisting of nucleotide sequence represented by SEQ ID NO: 4, ETV4 gene consisting of nucleotide sequence represented by SEQ ID NO: 5, TOP2A gene consisting of nucleotide sequence represented by SEQ ID NO: 6 and nucleotide sequence represented by SEQ ID NO: 7 Measuring the expression level of the mRNA of any one or more genes selected from the group consisting of UBE2C gene consisting of or the expression level of the protein expressed therefrom (step 1); And it provides a method for providing information for the diagnosis of lung cancer disease in an individual comprising the step of comparing the measured value with a value measured from a sample of a normal control.

Another object of the present invention is to treat a lung cancer disease candidate material by treating a biological sample isolated from an individual who has the disease, consisting of the S100P gene consisting of the sequential sequence represented by SEQ ID NO: 1, and the nucleotide sequence represented by SEQ ID NO: 2 MMP11 gene, CDCA7 gene consisting of nucleotide sequence represented by SEQ ID NO: 3, S100A2 gene consisting of nucleotide sequence represented by SEQ ID NO: 4, ETV4 gene consisting of nucleotide sequence represented by SEQ ID NO: 5, nucleotide sequence represented by SEQ ID NO: 6 Measuring the expression level of mRNA of any one or more genes selected from the group consisting of the TOP2A gene consisting of and the UBE2C gene consisting of the nucleotide sequence represented by SEQ ID NO: 7 or the expression level of the protein expressed therefrom (step 1); And comparing the measured expression level with the expression level of a control group not treated with the candidate substance (second step), to provide a screening method for treating lung cancer disease.

The present inventors carried out various studies to develop a biomarker that can effectively diagnose lung cancer by mobilizing molecular biological techniques, while the mRNA expression level of the gene of S100P, MMP11, CDCA7, S100A2, ETV4, TOP2A or UBE2C in lung cancer tissue By discovering this increase, the present invention was completed by discovering that the gene can be used as a biomarker for diagnosing lung cancer. In particular, when provided as a composition for diagnosing lung cancer or a kit for diagnosing lung cancer by including the biomarker gene, it is possible to effectively diagnose whether lung cancer has occurred.

Thus, the fact that it is possible to diagnose lung cancer using the gene has not been known at all, and was first identified by the present inventors.

As one embodiment for achieving the above object, the present invention is a S100P gene consisting of the nucleotide sequence represented by SEQ ID NO: 1, the MMP11 gene consisting of the nucleotide sequence represented by SEQ ID NO: 2, the nucleotide sequence represented by SEQ ID NO: 3 CDCA7 gene consisting of, S100A2 gene consisting of the nucleotide sequence shown in SEQ ID NO: 4, ETV4 gene consisting of the nucleotide sequence shown in SEQ ID NO: 5, TOP2A gene consisting of the nucleotide sequence shown in SEQ ID NO: 6 and the base shown in SEQ ID NO: 7 Provided is a marker composition for diagnosing lung cancer comprising any one or more genes selected from the group consisting of UBE2C gene consisting of a sequence.

In the present invention, the term “gene” indicates homology with the base sequence of the S100P gene, MMP11 gene, CDCA7 gene, S100A2 gene, ETV4 gene, TOP2A gene or UBE2C gene consisting of the nucleotide sequence represented by SEQ ID NOs: 1 to 7 The polynucleotide comprising the base sequence may also be included in the category of the gene provided by the present invention, specifically, may be a polynucleotide containing the base sequence showing 80% or more homology, and more specifically 90% or more. It may be a polynucleotide including a nucleotide sequence showing homology, and most specifically, a polynucleotide including a nucleotide sequence showing 95% or more homology.

Meanwhile, in the polynucleotide, one or more bases may be changed by substitution, deletion, insertion, or a combination thereof. When nucleotide sequences are prepared by chemical synthesis, synthetic methods well known in the art can be used, for example, the methods described in Engels and Uhlmann, Angew Chem IntEd Engl., 37:73-127, 1988. , Triester, phosphite, phosphoramidite and H-phosphate methods, PCR and other autoprimer methods, oligonucleotide synthesis method on solid support, and the like.

In another aspect, the present invention comprises the S100P gene consisting of the nucleotide sequence represented by SEQ ID NO: 1, the MMP11 gene consisting of the nucleotide sequence represented by SEQ ID NO: 2, the CDCA7 gene consisting of the nucleotide sequence represented by SEQ ID NO: 3, SEQ ID NO: 4 A group consisting of the S100A2 gene consisting of the nucleotide sequence represented, the ETV4 gene consisting of the nucleotide sequence represented by SEQ ID NO: 5, the TOP2A gene consisting of the nucleotide sequence represented by SEQ ID NO: 6, and the UBE2C gene consisting of the nucleotide sequence represented by SEQ ID NO: 7 It provides a composition for diagnosing lung cancer comprising an agent for measuring the level of mRNA or protein expressed from any one or more genes selected from.

The composition in the present invention can diagnose lung cancer by confirming that the expression level of the mRNA of the gene or the protein expressed therefrom increases, including the agent.

The term "an agent for measuring the mRNA level of a gene" of the present invention means an agent used in a method for measuring the level of mRNA transcribed from the target gene in order to confirm whether the target gene contained in the sample is expressed or not. , Preferably RT-PCR, quantitative real-time PCR (PCR), competitive RT-PCR (RT-PCR), real-time quantitative RT-PCR (RT-PCR), RNase protection assay (RPA) assay), Northern blotting (Northern blotting), may include a primer or probe that can specifically bind to the target gene used in methods such as DNA chip analysis, but is not particularly limited thereto.

In the present invention, an agent for measuring the mRNA level of the gene may include a primer or probe that specifically binds the gene.

The term "primer" of the present invention is a nucleic acid sequence having a short free 3'hydroxyl group that can form a complementary template and a base pair and a starting point for template strand copying. Means a short nucleic acid sequence that functions as The primer can be initiated by DNA synthesis in the presence of a reagent for polymerization (ie, DNA polymerase or reverse transcriptase) at a suitable buffer and temperature and four different nucleoside triphosphates.

In the present invention, the primer may be a primer that can be used for amplification of the gene, and as long as it can be amplified by PCR by complementarily binding to the gene, the nucleotide sequence of the primer is not limited.

In the present invention, the probe may be a probe capable of complementarily binding to the gene, and as long as it is capable of complementarily binding to each gene, the nucleotide sequence of the probe is not limited.

In the present invention, the agent for measuring the level of the protein may include an antibody or aptamer specific to the protein.

The term "agent for measuring the level of protein" of the present invention means a agent used in a method for measuring the level of a target protein contained in a sample, preferably Western blotting, ELISA (enzyme linked immunosorbent) assay), radioimmunoassay (RIA), radioimmunodiffusion, Ouchterlony immune diffusion method, rocket immunoelectrophoresis, immunohistochemical staining, immunoprecipitation analysis method Used in methods such as (Immunoprecipitation Assay), Complement Fixation Assay, immunofluorescence, immunochromatography, FACS (fluorescence activated cell sorter analysis) and protein chip technology assay It may include an antibody, but is not limited thereto.

The term "antibody" of the present invention refers to a proteinaceous molecule capable of specifically binding to an antigenic site of a protein or peptide molecule. Such antibodies are cloned into an expression vector by cloning each gene according to a conventional method. The protein encoded by the marker gene is obtained and can be prepared by conventional methods from the obtained protein. The form of the antibody is not particularly limited, and polyclonal antibodies, monoclonal antibodies, fragments of antibodies, or recombinant antibodies, etc., as long as they have antigen binding properties, are also included in the antibodies of the present invention and all immunoglobulin antibodies may be included. In addition, it may contain special antibodies such as humanized antibodies. In addition, the antibody includes a complete form having two full-length light chains and two full-length heavy chains, as well as functional fragments of the antibody molecule. A functional fragment of an antibody molecule means a fragment having at least an antigen-binding function, and may be Fab, F(ab'), F(ab') 2, and Fv.

The term "aptamer" of the present invention refers to a single-stranded oligonucleotide, and refers to a nucleic acid molecule having a binding activity to a specific target molecule. The aptamer may have various three-dimensional structures according to its base sequence, and may have a high affinity for a specific substance, such as an antigen-antibody reaction. Aptamers can inhibit the activity of a given target molecule by binding to a given target molecule.

The aptamer of the present invention may be RNA, DNA, a modified nucleic acid or a mixture thereof, and the form may be linear or cyclic, but is not limited thereto. The aptamer of the present invention can be used for PDK 4. The aptamer having a binding activity to PDK 4 can be easily prepared according to a method known to those skilled in the art by referring to each base sequence.

In the present invention, the S100P gene, MMP11 gene, CDCA7 gene, S100A2 gene, ETV4 gene, TOP2A gene, or UBE2C gene are all specifically diagnosed for lung cancer, including agents that measure the level of mRNA or a protein expressed therefrom. In more detail, in the case of S100P or CDCA7 gene, it may be possible to more specifically diagnose lung cancer.

The term "lung cancer" of the present invention refers to a malignant tumor originating from the lung, and the lung cancer to be diagnosed by the present invention is not particularly limited, but is small cell lung cancer (SCLC) or non-small cell lung cancer; NSCLC), specifically, non-small cell lung cancer. The non-small cell lung cancer includes adenocarcinoma, squamous cell carcinoma, large cell cancer, or adenosquamous cell carcinoma.

The term "diagnosis" in the present invention means to identify the presence or characteristics of a pathological condition. For the purposes of the present invention, the diagnosis is to determine whether or not lung cancer has occurred.

In another aspect, the present invention provides a lung cancer diagnostic kit comprising the composition for diagnosing lung cancer. The kit may be an RT-PCR kit, a DNA chip kit or a protein chip kit.

As a specific example, the kit for measuring the mRNA expression level of the gene of the present invention may be a kit including essential elements necessary for performing RT-PCR. RT-PCR kits include test tubes or other suitable containers, reaction buffers (pH and magnesium concentrations vary), deoxynucleotides (dNTPs), Taq-polymerases and reverse transcriptases, in addition to each primer pair specific for the gene. Enzymes such as, DNase, RNAse inhibitors, DEPC-water (DEPC-water), sterile water, and the like. In addition, a primer pair specific to a gene used as a quantitative control may be included.

As another example, the kit of the present invention may include essential elements necessary for performing a DNA chip assay. The kit for DNA chip analysis may include a substrate to which a cDNA corresponding to a gene or a fragment thereof is attached as a probe, and reagents, agents, enzymes, and the like for preparing a fluorescently labeled probe. In addition, the substrate may include cDNA corresponding to a quantitative control gene or a fragment thereof.

As another example, the kit of the present invention may be a kit for protein chip analysis for measuring the level of a protein expressed from the gene. The kit is not particularly limited, but is described for immunological detection of antibodies, It may include a suitable buffer solution, a secondary antibody labeled with a coloring enzyme or a fluorescent substance, a coloring substrate, and the like. The substrate is not particularly limited, but a nitrocellulose membrane, a 96-well plate synthesized with polyvinyl resin, a 96-well plate synthesized with polystyrene resin, and glass slide glass may be used, and the chromogenic enzyme is not particularly limited thereto. However, peroxidase and alkaline phosphatase may be used, and the fluorescent substance is not particularly limited, but may be FITC, RITC, etc., and the chromogenic substrate solution is not particularly limited, but ABTS(2, 2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)) or OPD (o-phenylenediamine), TMB (tetramethyl benzidine).

The kit may further include a reagent for use in diagnosing lung cancer in an individual. The reagents can include buffers, indicators, or combinations thereof.

In another aspect, the present invention is composed of the S100P gene consisting of the nucleotide sequence represented by SEQ ID NO: 1 from the biological sample isolated from the individual, the MMP11 gene consisting of the nucleotide sequence represented by SEQ ID NO: 2, and the nucleotide sequence represented by SEQ ID NO: 3 CDCA7 gene, S100A2 gene consisting of nucleotide sequence represented by SEQ ID NO: 4, ETV4 gene consisting of nucleotide sequence represented by SEQ ID NO: 5, TOP2A gene consisting of nucleotide sequence represented by SEQ ID NO: 6 and nucleotide sequence represented by SEQ ID NO: 7 Measuring the expression level of the mRNA of any one or more genes selected from the group consisting of UBE2C gene consisting of or the expression level of the protein expressed therefrom (step 1); And it provides a method for providing information for the diagnosis of lung cancer disease in an individual comprising the step of comparing the measured value with a value measured from a sample of a normal control.

The first step refers to a step of measuring the expression level of the mRNA of the gene or the expression level of the protein expressed therefrom in a biological sample isolated from the individual.

Meanwhile, the step of measuring the expression level of the mRNA of the gene may include contacting the sample with a primer or probe that specifically binds the gene. The primer or probe is as described above.

In addition, the step of measuring the expression level of the protein may include contacting an antibody or aptamer specifically binding to the protein with a sample. The antibody and aptamer are as described above.

The term "individual" of the present invention can mean any animal, including humans, who have or are at risk of developing lung cancer disease. The animal may be a mammal, such as a cow, a horse, a sheep, a pig, a goat, a camel, an antelope, a dog, a cat, etc., which need treatment for similar symptoms, but are not limited thereto.

The second step refers to a step of comparing the value measured in the first step with a value measured from a normal control sample.

The term "normal control" of the present invention means an individual who does not develop or suspects of developing lung cancer disease.

The term "sample" of the present invention refers to a direct target for measuring the expression level of the gene isolated from a patient with lung cancer disease, and specifically, the biological sample is composed of lung cells, lung tissue, lung cancer tissue, and sputum. It may be any one or more selected from the group.

The method for providing information may further include a step of determining a lung cancer disease (a third step) when the value measured in the biological sample is higher than the value of the normal control sample.

In another aspect, the present invention is made of a sequential sequence represented by SEQ ID NO: 2, a S100P gene consisting of a nucleotide sequence represented by SEQ ID NO: 1 by treating a lung cancer disease candidate candidate with a biological sample isolated from the individual affected by the disease MMP11 gene, CDCA7 gene consisting of nucleotide sequence represented by SEQ ID NO: 3, S100A2 gene consisting of nucleotide sequence represented by SEQ ID NO: 4, ETV4 gene consisting of nucleotide sequence represented by SEQ ID NO: 5, nucleotide sequence represented by SEQ ID NO: 6 Measuring the expression level of mRNA of any one or more genes selected from the group consisting of the TOP2A gene consisting of and the UBE2C gene consisting of the nucleotide sequence represented by SEQ ID NO: 7 or the expression level of the protein expressed therefrom (step 1); And comparing the measured expression level with the expression level of a control group not treated with the candidate substance (second step).

The first step refers to a step of measuring the expression level of the mRNA of the gene or the expression level of the protein expressed therefrom by treating a candidate for treatment of lung cancer disease with a biological sample isolated from the individual who has the disease.

The biological sample may be any one or more selected from the group consisting of lung cells, lung tissue, lung cancer tissue, and tear fluid, but is not limited thereto.

The term "therapeutic candidate substance" of the present invention is a substance capable of treating lung cancer disease by reducing the expression or activity of the gene mRNA or protein, and includes, without limitation, oligonucleotides, proteins, compounds, and the like.

The term “oligonucleotide” used in the present invention means a polymer formed by polymerizing several to several tens of nucleotides into phosphodiester bonds. Examples of oligonucleotides that inhibit the expression of the mRNA or protein of the gene, preferably include antisense oligonucleotides specific to the nucleic acid of PDK 4, or small interfering RNA (siRNA). It is not.

The term "antisense oligonucleotide" used in the present invention refers to DNA or RNA or a derivative thereof containing a nucleic acid sequence complementary to a sequence of a specific mRNA, and binds to a complementary sequence in the mRNA to convert the mRNA into a protein. It acts to inhibit translation. In the present invention, the oligonucleotide that inhibits the expression of mRNA of the gene is DNA or RNA having a sequence complementary to the mRNA, or a derivative thereof, binding to the mRNA, translation of the mRNA, translocation into the cytoplasm, It may interfere with maturation, etc., or inhibit all other biological functions or activities of mRNA.

The length of the antisense oligonucleotide is not particularly limited, but may be specifically 6 to 100 bases, more specifically 8 to 60 bases, and most specifically 10 to 40 bases. The antisense oligonucleotide may be synthesized in vivo or synthesized in vitro according to a conventional method used in the art, and administered in vivo. A non-limiting example of a method for synthesizing an antisense RNA in vivo is a method in which an antisense RNA is transcribed using a vector in which the origin of a multi-cloning site (MCS) is opposite. . Non-limiting examples of methods for synthesizing antisense RNA in vitro include RNA polymerase I.

Antisense oligonucleotides that suppress the expression of mRNA or protein of the gene of the present invention can be easily produced by a person of ordinary skill in the art by referring to the nucleotide sequence of the gene.

The second step refers to a step of comparing the expression level of the mRNA or protein of the gene measured in the first step with the expression level of the control group not treated with the candidate substance.

Through the comparison of the second step, when the expression level of mRNA or protein of the gene is significantly decreased in the group treated with a candidate for treatment of lung cancer disease, the candidate is likely to be a therapeutic agent for lung cancer disease. Indicates.

According to the composition, kit for diagnosing lung cancer according to the present invention, a method for diagnosing lung cancer using the same, and a method for obtaining information necessary for diagnosing lung cancer, it can be used to accurately and sensitively diagnose histological subtypes of lung cancer of an individual, for example, lung cancer.

1 is a schematic diagram of a process for analyzing differences in mRNA expression according to Example 1.
2 is a result of visualizing after classifying the expression pattern of increased genes between normal and lung cancer tissues of lung cancer patients based on the P value value.
3 is a graph expressing the diagnostic ability through the AUC value, visualizing through the ROC curve based on the expression value of 10 genes quantified through NGS.
4 is a ROC curve and expression distribution of TOP2A.
5 is a distribution diagram of the ROC curve and expression of CDCA7.
6 is an ETV4 ROC curve and expression distribution.
7 is a ROC curve and expression distribution of MMP11.
8 is a ROC curve and expression distribution of UBE2C.
9 is a ROC curve and expression distribution of S100A2.
10 is a ROC curve and expression distribution of S100P.
11 is an ROC curve comparing the expression values of the top 7 genes in lung cancer and breast cancer.
12 is a result of comparing the distribution of expression and ROC curve in lung cancer and breast cancer with CDCA7.
13 is a comparison result of ROC curve and expression distribution in lung cancer and breast cancer with ETV4.
14 is a comparison result of ROC curve and expression distribution in lung cancer and breast cancer with S100A2.
15 is an ROC curve comparing the expression values of the top 7 genes in lung cancer and colon cancer.
16 is a ROC curve comparing the expression values of the top 7 genes in lung cancer and hepatocellular carcinoma.
17 is an ROC curve comparing the expression values of the top 7 genes in lung cancer and prostate cancer.
18 is a result of comparing ROC curve and expression distribution in lung cancer and prostate cancer with TOP2A.
19 is a result of comparing the distribution of expression and ROC curve in lung cancer and prostate cancer with CDCA7.
20 is a comparison result of ROC curve and expression distribution in lung cancer and prostate cancer with ETV4.
21 is a comparison result of ROC curve and expression distribution in lung cancer and prostate cancer with MMP11.
22 is a comparison result of ROC curve and expression distribution in lung cancer and prostate cancer with UBE2C.
23 is a result of comparing the ROC curve and expression distribution in lung cancer and prostate cancer with S100A2.
24 is a result of comparing the ROC curve and expression distribution in lung cancer and prostate cancer with S100P.

Hereinafter, the present invention will be described in detail by examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited by the following examples.

Example 1: Identification of differences in gene expression patterns in lung cancer tissue and normal tissue

After receiving the normal tissue and lung cancer tissue from six human lung cancer patients from the Human Resource Bank, NGS (Next Generation Sequecing) was used to obtain raw data (FASTQ) files through sequencing of mRNA (6 pairs) and NCEO's GEO ( Gene Expression Omnibus) secured raw data from a total of 77 normal/lung cancer tissues by additionally securing NGS data from normal and lung cancer tissues of 71 Koreans.

And after trimming data with QC value of 20 or less, mapping was performed based on the human reference genome of hg 19 version. Through the Cufflink package, mRNA expression levels in normal and lung cancer tissues were quantified. The expression level of the quantified mRNA was compared between normal tissue and lung cancer tissue to analyze the difference in mRNA expression. 1 is a schematic diagram of a process of analyzing differences in mRNA expression according to Example 1. In addition, Table 1 compares the differences in the expression patterns of the last 7 genes selected in this way.

division gene More information Fold change
(log2 base) FPKM mean expression value
(log2 base) p value Normal tissue
Average expression value Cancer tissue
Average expression value Normal and cancerous tissue
Average expression value One S100P S100 calcium binding protein P
(SEQ ID NO: 1) 4.51 5.41 0.000089 3.56 81.23 42.40 2 MMP11 matrix metallopeptidase 11 (stromelysin 3)
(SEQ ID NO: 2) 3.94 4.62 0.000000 3.01 46.29 24.65 3 CDCA7 cell division cycle associated 7
(SEQ ID NO: 3) 3.90 3.09 0.000001 1.07 15.97 8.52 4 S100A2 S100 calcium binding protein A2
(SEQ ID NO: 4) 3.82 5.00 0.008678 4.24 59.71 31.98 5 ETV4 ets variant 4
(SEQ ID NO: 5) 3.67 3.49 0.000000 1.64 20.84 11.24 6 TOP2A topoisomerase (DNA) II alpha 170 kDa
(SEQ ID NO: 6) 3.46 3.53 0.000000 1.93 21.19 11.56 7 UBE2C ubiquitin-conjugating enzyme E2C
(SEQ ID NO: 7) 3.42 3.53 0.000000 1.97 21.11 11.54

As can be seen in Table 1, the top 7 genes whose expression is specifically increased in lung cancer tissue were selected. In particular, it can be seen that the expression level of all of the top 7 genes increased more than 8-fold, and the average expression value in lung cancer tissues increased rapidly compared to the average expression value in normal tissues.

On the other hand, Figure 2 is a result of visualizing after classifying the expression pattern of genes increased between normal and lung cancer tissues of 77 lung cancer patients based on the P value value. In particular, in FIG. 2, it was confirmed that the expression levels in lung cancer tissues of CDCA7, MMP11, and S100P were significantly higher.

In addition, based on the expression values of the top 7 genes, the ability to classify with normal tissues was confirmed by the ROC curve. The results of this can be represented by a graph as shown in FIG. 3, FIG. 3 shows the ROC curve to confirm the usefulness of lung cancer diagnosis based on the expression values of 10 genes quantified by including the top 7 genes through NGS. It is a graph that visualizes through and expresses diagnostic ability through AUC value. In addition, Table 2 below shows this quantitatively, and it can be confirmed that all the top 7 genes show a value of 0.7 or more, and 5 of them show a high diagnostic value of 0.9 or more.

division Area Under the Curve Test Result Variable(s) Area One S100P 0.765 2 MMP11 0.951 3 CDCA7 0.968 4 S100A2 0.855 5 ETV4 0.955 6 TOP2A 0.980 7 UBE2C 0.944

On the other hand, Figure 4 is a ROC curve and expression distribution of only TOP2A, Figure 5 is a ROC curve and expression distribution only of CDCA7, Figure 6 is a ROC curve and expression distribution only of ETV4, Figure 7 is a ROC curve and expression distribution only of MMP11, FIG. 8 is a ROC curve and expression distribution diagram of UBE2C only, FIG. 9 is a ROC curve and expression distribution diagram of S100A2 only, and FIG. 10 is a ROC curve and expression distribution diagram of S100P only.

Example 2: Confirmation of lung cancer specificity of the top 7 genes in relation to other cancers

As can be seen in Example 1, after confirming the effectiveness of the top 7 genes in None small lung cancer / Adenocarcinoma lung cancer, the top 7 genes in 4 types of cancer (Breast, Colon, Hepatocellular, Prostate) The results were compared with those in lung cancer to determine whether lung cancer was specific.

< Example 2-1: Confirmation of specificity of lung cancer compared to breast cancer>

11 is an ROC curve comparing the expression values of the top 7 genes in lung cancer and breast cancer. In addition, Table 3 below is a quantitative measurement.

division Area Under the Curve Test Result Variable(s) Lung Breast Remark One S100P 0.765 0.910 2 MMP11 0.951 0.964 3 CDCA7 0.968 0.603 singularity 4 S100A2 0.855 0.577 singularity 5 ETV4 0.955 0.657 singularity 6 TOP2A 0.980 0.910 7 UBE2C 0.944 0.913

In the case of CDCA7, ETV4, and S100A2, as shown in Table 3, it can be confirmed that it is specific for lung cancer compared to the results of breast cancer, and it can be confirmed that the remaining 4 genes can be used for lung cancer as well. On the other hand, FIG. 12 is a result of comparing the ROC curve and expression distribution in lung cancer and breast cancer for CDCA7, FIG. 13 is a result of comparing the ROC curve and expression distribution in lung cancer and breast cancer for ETV4, and FIG. 14 is S100A2 This is the result of comparing the ROC curve and expression distribution in lung cancer and breast cancer.

< Example 2-2: Colon Cancer (Colon cacner Confirmation of lung cancer specificity compared to )>

15 is an ROC curve comparing the expression values of the top 7 genes in lung cancer and colon cancer. In addition, Table 4 below is a quantitative measurement.

division Area Under the Curve Test Result Variable(s) Lung Colon Remark One S100P 0.765 0.793 2 MMP11 0.951 0.836 3 CDCA7 0.968 0.799 4 S100A2 0.855 0.846 5 ETV4 0.955 0.932 6 TOP2A 0.980 0.750 7 UBE2C 0.944 0.824

As shown in Table 4, it was confirmed that the expression level for lung cancer was higher than that for colon cancer.

< Example 2-3: hepatocellular carcinoma ( Hepatocellular cacner Confirmation of lung cancer specificity compared to )>

16 is an ROC curve comparing the expression values of the top 7 genes in lung cancer and hepatocellular carcinoma. In addition, Table 5 below is a quantitative measurement.

division Area Under the Curve Test Result Variable(s) Lung Hepatocellular Remark One S100P 0.765 0.855 2 MMP11 0.951 0.851 3 CDCA7 0.968 0.923 4 S100A2 0.855 0.815 5 ETV4 0.955 0.813 6 TOP2A 0.980 0.957 7 UBE2C 0.944 0.957

As shown in Table 5, it was confirmed that the expression level for lung cancer was higher than that for hepatocellular carcinoma.

< Example 2-4: Confirmation of lung cancer specificity compared to prostate cancer>

17 is an ROC curve comparing the expression values of the top 7 genes in lung cancer and prostate cancer. In addition, Table 6 below is a quantitative measurement.

division Area Under the Curve Test Result Variable(s) Lung Prostate Remark One S100P 0.765 0.600 singularity 2 MMP11 0.951 0.550 singularity 3 CDCA7 0.968 0.550 singularity 4 S100A2 0.855 0.670 singularity 5 ETV4 0.955 0.770 singularity 6 TOP2A 0.980 0.260 singularity 7 UBE2C 0.944 0.350 singularity

As can be seen in Table 6, all of the top 7 genes were confirmed to be lung cancer-specific compared to prostate cancer. Meanwhile, FIG. 18 is a result of comparing ROC curve and expression distribution in lung cancer and prostate cancer with TOP2A, FIG. 19 is a result of comparing ROC curve and expression distribution in lung cancer and prostate cancer with CDCA7, and FIG. 20 is Results of comparing ROC curve and expression distribution in lung cancer and prostate cancer with ETV4, FIG. 21 is a result of comparing ROC curve and expression distribution in lung cancer and prostate cancer with MMP11, and FIG. 22 is lung cancer with UBE2C Results of comparing ROC curve and expression distribution in prostate cancer, FIG. 23 is a result of comparing ROC curve and expression distribution in lung cancer and prostate cancer with S100A2, and FIG. 24 in lung cancer and prostate cancer with S100P It is a result of comparing the ROC curve and expression distribution of.

When providing a composition for diagnosing lung cancer or a kit for diagnosing lung cancer by including the seven genes in the present invention through these experimental results, it is possible to diagnose lung cancer by comparing the expression pattern with a control group, so that lung cancer can be compared to other cancers. It was confirmed that the diagnostic ability (specificity) was high.

From the above description, those skilled in the art to which the present invention pertains will understand that the present invention may be implemented in other specific forms without changing its technical spirit or essential features. In this regard, the embodiments described above should be understood as illustrative in all respects and not restrictive. The scope of the present invention should be construed as including the meaning and scope of the claims, which are described later, rather than the above detailed description, and all modified or modified forms derived from equivalent concepts thereof.

<110> Dankook University Cheonan Campus Industry Academic Cooperation Foundation <120> A marker for diagnosis of lung cancer <130> KPA161168-KR-D1 <160> 7 <170> KoPatentIn 3.0 <210> 1 <211> 510 <212> DNA <213> Unknown <220> <223> S100P <400> 1 tgaggctgcc ttataaagca ccaagaggct gccagtggga cattttctcg gccctgccag 60 cccccaggag gaaggtgggt ctgaatctag caccatgacg gaactagaga cagccatggg 120 catgatcata gacgtctttt cccgatattc gggcagcgag ggcagcacgc agaccctgac 180 caagggggag ctcaaggtgc tgatggagaa ggagctacca ggcttcctgc agagtggaaa 240 agacaaggat gccgtggata aattgctcaa ggacctggac gccaatggag atgcccaggt 300 ggacttcagt gagttcatcg tgttcgtggc tgcaatcacg tctgcctgtc acaagtactt 360 tgagaaggca ggactcaaat gatgccctgg agatgtcaca gattcctggc agagccatgg 420 tcccaggctt cccaaaagtg tttgttggca attattcccc taggctgagc ctgctcatgt 480 acctctgatt aataaatgct tatgaaatga 510 <210> 2 <211> 2306 <212> DNA <213> Unknown <220> <223> MMP11 <400> 2 ataaggggcg gcggcccgga gcggcccagc aagcccagca gccccggggc ggatggctcc 60 ggccgcctgg ctccgcagcg cggccgcgcg cgccctcctg cccccgatgc tgctgctgct 120 gctccagccg ccgccgctgc tggcccgggc tctgccgccg gacgcccacc acctccatgc 180 cgagaggagg gggccacagc cctggcatgc agccctgccc agtagcccgg cacctgcccc 240 tgccacgcag gaagcccccc ggcctgccag cagcctcagg cctccccgct gtggcgtgcc 300 cgacccatct gatgggctga gtgcccgcaa ccgacagaag aggttcgtgc tttctggcgg 360 gcgctgggag aagacggacc tcacctacag gatccttcgg ttcccatggc agttggtgca 420 ggagcaggtg cggcagacga tggcagaggc cctaaaggta tggagcgatg tgacgccact 480 cacctttact gaggtgcacg agggccgtgc tgacatcatg atcgacttcg ccaggtactg 540 gcatggggac gacctgccgt ttgatgggcc tgggggcatc ctggcccatg ccttcttccc 600 caagactcac cgagaagggg atgtccactt cgactatgat gagacctgga ctatcgggga 660 tgaccagggc acagacctgc tgcaggtggc agcccatgaa tttggccacg tgctggggct 720 gcagcacaca acagcagcca aggccctgat gtccgccttc tacacctttc gctacccact 780 gagtctcagc ccagatgact gcaggggcgt tcaacaccta tatggccagc cctggcccac 840 tgtcacctcc aggaccccag ccctgggccc ccaggctggg atagacacca atgagattgc 900 accgctggag ccagacgccc cgccagatgc ctgtgaggcc tcctttgacg cggtctccac 960 catccgaggc gagctctttt tcttcaaagc gggctttgtg tggcgcctcc gtgggggcca 1020 gctgcagccc ggctacccag cattggcctc tcgccactgg cagggactgc ccagccctgt 1080 ggacgctgcc ttcgaggatg cccagggcca catttggttc ttccaaggtg ctcagtactg 1140 ggtgtacgac ggtgaaaagc cagtcctggg ccccgcaccc ctcaccgagc tgggcctggt 1200 gaggttcccg gtccatgctg ccttggtctg gggtcccgag aagaacaaga tctacttctt 1260 ccgaggcagg gactactggc gtttccaccc cagcacccgg cgtgtagaca gtcccgtgcc 1320 ccgcagggcc actgactgga gaggggtgcc ctctgagatc gacgctgcct tccaggatgc 1380 tgatggctat gcctacttcc tgcgcggccg cctctactgg aagtttgacc ctgtgaaggt 1440 gaaggctctg gaaggcttcc cccgtctcgt gggtcctgac ttctttggct gtgccgagcc 1500 tgccaacact ttcctctgac catggcttgg atgccctcag gggtgctgac ccctgccagg 1560 ccacgaatat caggctagag acccatggcc atctttgtgg ctgtgggcac caggcatggg 1620 actgagccca tgtctcctca gggggatggg gtggggtaca accaccatga caactgccgg 1680 gagggccacg caggtcgtgg tcacctgcca gcgactgtct cagactgggc agggaggctt 1740 tggcatgact taagaggaag ggcagtcttg ggcccgctat gcaggtcctg gcaaacctgg 1800 ctgccctgtc tccatccctg tccctcaggg tagcaccatg gcaggactgg gggaactgga 1860 gtgtccttgc tgtatccctg ttgtgaggtt ccttccaggg gctggcactg aagcaagggt 1920 gctggggccc catggccttc agccctggct gagcaactgg gctgtagggc agggccactt 1980 cctgaggtca ggtcttggta ggtgcctgca tctgtctgcc ttctggctga caatcctgga 2040 aatctgttct ccagaatcca ggccaaaaag ttcacagtca aatggggagg ggtattcttc 2100 atgcaggaga ccccaggccc tggaggctgc aacatacctc aatcctgtcc caggccggat 2160 cctcctgaag cccttttcgc agcactgcta tcctccaaag ccattgtaaa tgtgtgtaca 2220 gtgtgtataa accttcttct tctttttttt tttttaaact gaggattgtc attaaacaca 2280 gttgttttct aaaaaaaaaa aaaaaa 2306 <210> 3 <211> 2839 <212> DNA <213> Unknown <220> <223> CDCA7 <400> 3 cctccgggcc cgggtcggcg cgcccagcct gccagccgcg ctgctgctgc tcctcctgct 60 gtgggaccgc tgaccgcgcg gctgctccgc tctccccgct ccaagcgccg atctgggcac 120 ccgccaccag catggacgct cgccgcgtgc cgcagaaaga tctcagagta aagaagaact 180 taaagaaatt cagatatgtg aagttgattt ccatggaaac ctcgtcatcc tctgatgaca 240 gttgtgacag ctttgcttct gataattttg caaacacgaa acctaaattc aggtcagata 300 tcagtgaaga actggcaaat gttttttatg aggactctga taatgaatct ttctgcggct 360 tttcagaaag tgaggtgcaa gatgtattag accattgtgg atttttacag aaaccaaggc 420 cagatgtcac taacgaactg gccggtattt ttcatgccga ctctgacgat gaatcatttt 480 gcggtttctc agagagtgag atacaagatg gaatgaggct gcagtcagtt cgggaaggct 540 gtaggacccg cagccagtgc aggcactctg gacctctcag ggtggcgatg aagtttccag 600 cgcggagtac caggggagca accaacaaaa aagcagagtc ccgccagccc tcagagaatt 660 ctgtgactga ttccaactcc gattcagaag atgaaagtgg aatgaatttt ttggagaaaa 720 gggctttaaa tataaagcaa aacaaagcaa tgcttgcaaa actcatgtct gaattagaaa 780 gcttccctgg ctcgttccgt ggaagacatc ccctcccagg ctccgactca caatcaagga 840 gaccgcgaag gcgtacattc ccgggtgttg cttccaggag aaaccctgaa cggagagctc 900 gtcctcttac caggtcaagg tcccggatcc tcgggtccct tgacgctcta cccatggagg 960 aggaggagga agaggataag tacatgttgg tgagaaagag gaagaccgtg gatggctaca 1020 tgaatgaaga tgacctgccc agaagccgtc gctccagatc atccgtgacc cttccgcata 1080 taattcgccc agtggaagaa attacagagg aggagttgga gaacgtctgc agcaattctc 1140 gagagaagat atataaccgt tcactgggct ctacttgtca tcaatgccgt cagaagacta 1200 ttgataccaa aacaaactgc agaaacccag actgctgggg cgttcgaggc cagttctgtg 1260 gcccctgcct tcgaaaccgt tatggtgaag aggtcaggga tgctctgctg gatccgaact 1320 ggcattgccc gccttgtcga ggaatctgca actgcagttt ctgccggcag cgagatggac 1380 ggtgtgcgac tggggtcctt gtgtatttag ccaaatatca tggctttggg aatgtgcatg 1440 cctacttgaa aagcctgaaa caggaatttg aaatgcaagc ataatatctg gaaaatttgc 1500 tgcctgcctt ctacttctca aatctttctt gtaaaagttt ccaatttttt cactgaaacc 1560 tgagttaaaa atcttgatga tcagcctgtt tcataagaaa ctccaatcaa gttaatctta 1620 gcagacatgt gtttctggag catcacagaa ggtatattgc tagttacact ttgccctcct 1680 gcagtttctt ctctgctccc aacccccatc tcacagcatc cccctctatt tccaatgctc 1740 ctctccaacc gcttagtttc tgaatttctt ttaaattaca gttttatgaa agcatatttt 1800 atttacttgg tgttgaaata gccctcataa aacctaagca cttggaaaca caataatagt 1860 attaactaac tagatctatt gaatttcaga gaagagcctt ctaacttgtt tacacaaaaa 1920 cgagtatgat ttagcattca tactagttga aatttttaat agaatcaagg cacaaaagtc 1980 ttaaaaccat gtggaaaaat taggtaatta ttgcagattg atgtctctca atcccatgta 2040 ttgcgcttat gttacaagtt gttgtcacag ttgagactta atttctccta atttcttctg 2100 cccgaagggt aagtggtgcg tccagcttac acaatcataa ttcaaaggtt ggtgggcaat 2160 gtaatactta attaaaataa tgatggaaga gctatctgga gattatgagt aagctgattt 2220 gaattttcag tataaaactt tagtataatt gtagtttgca aagtttattt cagttcacat 2280 gtaaggtatt gcaaataaat tcttggacaa ttttgtatgg aaacttgata ttaaaaacta 2340 gtctgtggtt ctttgcagtt tcttgtaaat ttataaacca ggcacaaggt tcaagtttag 2400 attttaagca cttttataac aatgataagt gcctttttgg agatgtaact tttagcagtt 2460 tgttaacctg acatctctgc cagtctagtt tctgggcagg tttcctgtgt cagtattccc 2520 cctcctcttt gcattaatca aggtatttgg tagaggtgga atctaagtgt ttgtatgtcc 2580 aatttacttg catatgtaaa ccattgctgt gccattcaat gtttgatgca taattggacc 2640 ttgaatcgat aagtgtaaat acagcttttg atctgtaatg cttttataca aaagtttatt 2700 ttaataataa aatgtttgtt ctaacttgtc tgctttttta aaaataatct tactgtactt 2760 aattctaatt ttttcctcat atttaaataa aaggccattt ccaccttttc aaaaaaaaaa 2820 aaaaaaaaaa aaaaaaaaa 2839 <210> 4 <211> 970 <212> DNA <213> Unknown <220> <223> S100A2 <400> 4 ctcccctcac cccggtccag gatgcccagt ccccacgaca cctcccactt cccactgtgg 60 cctgggtggg ctcaggggct gcccttgacc tggcctagag ccctccccca gctggtggtg 120 gagctggcac tctctgggag ggagggggct gggagggaat gagtgggaat ggcaagaggc 180 cagggtttgg tgggatcagg ttgaggcagg tttggtttcc ttaaaatgcc aagttggggg 240 ccagtggggc ccacatataa atcctcaccc tgggagcctg gctgccttgc tctccttcct 300 gggtctgtct ctgccacctg gtctgccaca gatccatgat gtgcagttct ctggagcagg 360 cgctggctgt gctggtcact accttccaca agtactcctg ccaagagggc gacaagttca 420 agctgagtaa gggggaaatg aaggaacttc tgcacaagga gctgcccagc tttgtggggg 480 agaaagtgga tgaggagggg ctgaagaagc tgatgggcag cctggatgag aacagtgacc 540 agcaggtgga cttccaggag tatgctgttt tcctggcact catcactgtc atgtgcaatg 600 acttcttcca gggctgccca gaccgaccct gaagcagaac tcttgacttc ctgccatgga 660 tctcttgggc ccaggactgt tgatgccttt gagttttgta ttcaataaac tttttttgtc 720 tgttgataat attttaattg ctcagtgatg ttccataacc cggctggctc agctggagtg 780 ctgggagatg agggcctcct ggatcctgct cccttctggg ctctgactct cctggaaatc 840 tctccaaggc cagagctatg ctttaggtct caattttgga atttcaaaca ccagcaaaaa 900 attggaaatc gagataggtt gctgactttt attttgtcaa ataaagatat taaaaaaggc 960 aaaaaaaaaa 970 <210> 5 <211> 2187 <212> DNA <213> Unknown <220> <223> ETV4 <400> 5 cacgttctta tgtaaccgag cccgggtaaa gcagggctgc agaaagcaga aacggcgagc 60 ccggctcctg ggagcagaaa tcgcccggaa atgggagctt gcgcgaagcg ctgatcggcc 120 cgctggggaa gctcatggac ccgggctccc tgccgcccct cgactctgaa gatctcttcc 180 aggatctaag tcacttccag gagacgtggc tcgctgaagc tcaggtacca gacagtgatg 240 agcagtttgt tcctgatttc cattcagaaa acctagcttt ccacagcccc accaccagga 300 tcaagaagga gccccagagt ccccgcacag acccggccct gtcctgcagc aggaagccgc 360 cactccccta ccaccatggc gagcagtgcc tttactccag tgcctatgac ccccccagac 420 aaatcgccat caagtcccct gcccctggtg cccttggaca gtcgccccta cagccctttc 480 cccgggcaga gcaacggaat ttcctgagat cctctggcac ctcccagccc caccctggcc 540 atgggtacct cggggaacat agctccgtct tccagcagcc cctggacatt tgccactcct 600 tcacatctca gggagggggc cgggaacccc tcccagcccc ctaccaacac cagctgtcgg 660 agccctgccc accctatccc cagcagagct ttaagcaaga ataccatgat cccctgtatg 720 aacaggcggg ccagccagcc gtggaccagg gtggggtcaa tgggcacagg tacccagggg 780 cgggggtggt gatcaaacag gaacagacgg acttcgccta cgactcagat gtcaccgggt 840 gcgcatcaat gtacctccac acagagggct tctctgggcc ctctccaggt gacggggcca 900 tgggctatgg ctatgagaaa cctctgcgac cattcccaga tgatgtctgc gttgtccctg 960 agaaatttga aggagacatc aagcaggaag gggtcggtgc atttcgagag gggccgccct 1020 accagcgccg gggtgccctg cagctgtggc aatttctggt ggccttgctg gatgacccaa 1080 caaatgccca tttcattgcc tggacgggcc ggggaatgga gttcaagctc attgagcctg 1140 aggaggtcgc caggctctgg ggcatccaga agaaccggcc agccatgaat tacgacaagc 1200 tgagccgctc gctccgatac tattatgaga aaggcatcat gcagaaggtg gctggtgagc 1260 gttacgtgta caagtttgtg tgtgagcccg aggccctctt ctctttggcc ttcccggaca 1320 atcagcgtcc agctctcaag gctgagtttg accggcctgt cagtgaggag gacacagtcc 1380 ctttgtccca cttggatgag agccccgcct acctcccaga gctggctggc cccgcccagc 1440 catttggccc caagggtggc tactcttact agcccccagc ggctgttccc cctgccgcag 1500 gtgggtgctg ccctgtgtac atataaatga atctggtgtt ggggaaacct tcatctgaaa 1560 cccacagatg tctctggggc agatccccac tgtcctacca gttgccctag cccagactct 1620 gagctgctca ccggagtcat tgggaaggaa aagtggagaa atggcaagtc tagagtctca 1680 gaaactcccc tgggggtttc acctgggccc tggaggaatt cagctcagct tcttcctagg 1740 tccaagcccc ccacaccttt tccccaacca cagagaacaa gagtttgttc tgttctgggg 1800 gacagagaag gcgcttccca acttcatact ggcaggaggg tgaggaggtt cactgagctc 1860 cccagatctc ccactgcggg gagacagaag cctggactct gccccacgct gtggccctgg 1920 agggtcccgg tttgtcagtt cttggtgctc tgtgttccca gaggcaggcg gaggttgaag 1980 aaaggaacct gggatgaggg gtgctgggta taagcagaga gggatgggtt cctgctccaa 2040 gggacccttt gcctttcttc tgccctttcc taggcccagg cctgggtttg tacttccacc 2100 tccaccacat ctgccagacc ttaataaagg cccccacttc tcccattaaa aaaaaaaaaa 2160 aaaaaaaaaa aaaaaaaaaa aaaaaaa 2187 <210> 6 <211> 5753 <212> DNA <213> Unknown <220> <223> TOP2A <400> 6 gattggctgg tctgcttcgg gcgggctaaa ggaaggttca agtggagctc tcctaaccga 60 cgcgcgtctg tggagaagcg gcttggtcgg gggtggtctc gtggggtcct gcctgtttag 120 tcgctttcag ggttcttgag ccccttcacg accgtcacca tggaagtgtc accattgcag 180 cctgtaaatg aaaatatgca agtcaacaaa ataaagaaaa atgaagatgc taagaaaaga 240 ctgtctgttg aaagaatcta tcaaaagaaa acacaattgg aacatatttt gctccgccca 300 gacacctaca ttggttctgt ggaattagtg acccagcaaa tgtgggttta cgatgaagat 360 gttggcatta actataggga agtcactttt gttcctggtt tgtacaaaat ctttgatgag 420 attctagtta atgctgcgga caacaaacaa agggacccaa aaatgtcttg tattagagtc 480 acaattgatc cggaaaacaa tttaattagt atatggaata atggaaaagg tattcctgtt 540 gttgaacaca aagttgaaaa gatgtatgtc ccagctctca tatttggaca gctcctaact 600 tctagtaact atgatgatga tgaaaagaaa gtgacaggtg gtcgaaatgg ctatggagcc 660 aaattgtgta acatattcag taccaaattt actgtggaaa cagccagtag agaatacaag 720 aaaatgttca aacagacatg gatggataat atgggaagag ctggtgagat ggaactcaag 780 cccttcaatg gagaagatta tacatgtatc acctttcagc ctgatttgtc taagtttaaa 840 atgcaaagcc tggacaaaga tattgttgca ctaatggtca gaagagcata tgatattgct 900 ggatccacca aagatgtcaa agtctttctt aatggaaata aactgccagt aaaaggattt 960 cgtagttatg tggacatgta tttgaaggac aagttggatg aaactggtaa ctccttgaaa 1020 gtaatacatg aacaagtaaa ccacaggtgg gaagtgtgtt taactatgag tgaaaaaggc 1080 tttcagcaaa ttagctttgt caacagcatt gctacatcca agggtggcag acatgttgat 1140 tatgtagctg atcagattgt gactaaactt gttgatgttg tgaagaagaa gaacaagggt 1200 ggtgttgcag taaaagcaca tcaggtgaaa aatcacatgt ggatttttgt aaatgcctta 1260 attgaaaacc caacctttga ctctcagaca aaagaaaaca tgactttaca acccaagagc 1320 tttggatcaa catgccaatt gagtgaaaaa tttatcaaag ctgccattgg ctgtggtatt 1380 gtagaaagca tactaaactg ggtgaagttt aaggcccaag tccagttaaa caagaagtgt 1440 tcagctgtaa aacataatag aatcaaggga attcccaaac tcgatgatgc caatgatgca 1500 gggggccgaa actccactga gtgtacgctt atcctgactg agggagattc agccaaaact 1560 ttggctgttt caggccttgg tgtggttggg agagacaaat atggggtttt ccctcttaga 1620 ggaaaaatac tcaatgttcg agaagcttct cataagcaga tcatggaaaa tgctgagatt 1680 aacaatatca tcaagattgt gggtcttcag tacaagaaaa actatgaaga tgaagattca 1740 ttgaagacgc ttcgttatgg gaagataatg attatgacag atcaggacca agatggttcc 1800 cacatcaaag gcttgctgat taattttatc catcacaact ggccctctct tctgcgacat 1860 cgttttctgg aggaatttat cactcccatt gtaaaggtat ctaaaaacaa gcaagaaatg 1920 gcattttaca gccttcctga atttgaagag tggaagagtt ctactccaaa tcataaaaaa 1980 tggaaagtca aatattacaa aggtttgggc accagcacat caaaggaagc taaagaatac 2040 tttgcagata tgaaaagaca tcgtatccag ttcaaatatt ctggtcctga agatgatgct 2100 gctatcagcc tggcctttag caaaaaacag atagatgatc gaaaggaatg gttaactaat 2160 ttcatggagg atagaagaca acgaaagtta cttgggcttc ctgaggatta cttgtatgga 2220 caaactacca catatctgac atataatgac ttcatcaaca aggaacttat cttgttctca 2280 aattctgata acgagagatc tatcccttct atggtggatg gtttgaaacc aggtcagaga 2340 aaggttttgt ttacttgctt caaacggaat gacaagcgag aagtaaaggt tgcccaatta 2400 gctggatcag tggctgaaat gtcttcttat catcatggtg agatgtcact aatgatgacc 2460 attatcaatt tggctcagaa ttttgtgggt agcaataatc taaacctctt gcagcccatt 2520 ggtcagtttg gtaccaggct acatggtggc aaggattctg ctagtccacg atacatcttt 2580 acaatgctca gctctttggc tcgattgtta tttccaccaa aagatgatca cacgttgaag 2640 tttttatatg atgacaacca gcgtgttgag cctgaatggt acattcctat tattcccatg 2700 gtgctgataa atggtgctga aggaatcggt actgggtggt cctgcaaaat ccccaacttt 2760 gatgtgcgtg aaattgtaaa taacatcagg cgtttgatgg atggagaaga acctttgcca 2820 atgcttccaa gttacaagaa cttcaagggt actattgaag aactggctcc aaatcaatat 2880 gtgattagtg gtgaagtagc tattcttaat tctacaacca ttgaaatctc agagcttccc 2940 gtcagaacat ggacccagac atacaaagaa caagttctag aacccatgtt gaatggcacc 3000 gagaagacac ctcctctcat aacagactat agggaatacc atacagatac cactgtgaaa 3060 tttgttgtga agatgactga agaaaaactg gcagaggcag agagagttgg actacacaaa 3120 gtcttcaaac tccaaactag tctcacatgc aactctatgg tgctttttga ccacgtaggc 3180 tgtttaaaga aatatgacac ggtgttggat attctaagag acttttttga actcagactt 3240 aaatattatg gattaagaaa agaatggctc ctaggaatgc ttggtgctga atctgctaaa 3300 ctgaataatc aggctcgctt tatcttagag aaaatagatg gcaaaataat cattgaaaat 3360 aagcctaaga aagaattaat taaagttctg attcagaggg gatatgattc ggatcctgtg 3420 aaggcctgga aagaagccca gcaaaaggtt ccagatgaag aagaaaatga agagagtgac 3480 aacgaaaagg aaactgaaaa gagtgactcc gtaacagatt ctggaccaac cttcaactat 3540 cttcttgata tgcccctttg gtatttaacc aaggaaaaga aagatgaact ctgcaggcta 3600 agaaatgaaa aagaacaaga gctggacaca ttaaaaagaa agagtccatc agatttgtgg 3660 aaagaagact tggctacatt tattgaagaa ttggaggctg ttgaagccaa ggaaaaacaa 3720 gatgaacaag tcggacttcc tgggaaaggg gggaaggcca aggggaaaaa aacacaaatg 3780 gctgaagttt tgccttctcc gcgtggtcaa agagtcattc cacgaataac catagaaatg 3840 aaagcagagg cagaaaagaa aaataaaaag aaaattaaga atgaaaatac tgaaggaagc 3900 cctcaagaag atggtgtgga actagaaggc ctaaaacaaa gattagaaaa gaaacagaaa 3960 agagaaccag gtacaaagac aaagaaacaa actacattgg catttaagcc aatcaaaaaa 4020 ggaaagaaga gaaatccctg gtctgattca gaatcagata ggagcagtga cgaaagtaat 4080 tttgatgtcc ctccacgaga aacagagcca cggagagcag caacaaaaac aaaattcaca 4140 atggatttgg attcagatga agatttctca gattttgatg aaaaaactga tgatgaagat 4200 tttgtcccat cagatgctag tccacctaag accaaaactt ccccaaaact tagtaacaaa 4260 gaactgaaac cacagaaaag tgtcgtgtca gaccttgaag ctgatgatgt taagggcagt 4320 gtaccactgt cttcaagccc tcctgctaca catttcccag atgaaactga aattacaaac 4380 ccagttccta aaaagaatgt gacagtgaag aagacagcag caaaaagtca gtcttccacc 4440 tccactaccg gtgccaaaaa aagggctgcc ccaaaaggaa ctaaaaggga tccagctttg 4500 aattctggtg tctctcaaaa gcctgatcct gccaaaacca agaatcgccg caaaaggaag 4560 ccatccactt ctgatgattc tgactctaat tttgagaaaa ttgtttcgaa agcagtcaca 4620 agcaagaaat ccaaggggga gagtgatgac ttccatatgg actttgactc agctgtggct 4680 cctcgggcaa aatctgtacg ggcaaagaaa cctataaagt acctggaaga gtcagatgaa 4740 gatgatctgt tttaaaatgt gaggcgatta ttttaagtaa ttatcttacc aagcccaaga 4800 ctggttttaa agttacctga agctcttaac ttcctcccct ctgaatttag tttggggaag 4860 gtgtttttag tacaagacat caaagtgaag taaagcccaa gtgttcttta gctttttata 4920 atactgtcta aatagtgacc atctcatggg cattgttttc ttctctgctt tgtctgtgtt 4980 ttgagtctgc tttcttttgt ctttaaaacc tgatttttaa gttcttctga actgtagaaa 5040 tagctatctg atcacttcag cgtaaagcag tgtgtttatt aaccatccac taagctaaaa 5100 ctagagcagt ttgatttaaa agtgtcactc ttcctccttt tctactttca gtagatatga 5160 gatagagcat aattatctgt tttatcttag ttttatacat aatttaccat cagatagaac 5220 tttatggttc tagtacagat actctactac actcagcctc ttatgtgcca agtttttctt 5280 taagcaatga gaaattgctc atgttcttca tcttctcaaa tcatcagagg ccgaagaaaa 5340 acactttggc tgtgtctata acttgacaca gtcaatagaa tgaagaaaat tagagtagtt 5400 atgtgattat ttcagctctt gacctgtccc ctctggctgc ctctgagtct gaatctccca 5460 aagagagaaa ccaatttcta agaggactgg attgcagaag actcggggac aacatttgat 5520 ccaagatctt aaatgttata ttgataacca tgctcagcaa tgagctatta gattcatttt 5580 gggaaatctc cataatttca atttgtaaac tttgttaaga cctgtctaca ttgttatatg 5640 tgtgtgactt gagtaatgtt atcaacgttt ttgtaaatat ttactatgtt tttctattag 5700 ctaaattcca acaattttgt actttaataa aatgttctaa acattgcaac cca 5753 <210> 7 <211> 723 <212> DNA <213> Unknown <220> <223> UBE2C <400> 7 gagccattga ttggtcgacg cccccagagg gttacaattc aaacgcgggc gggcgggccc 60 gcagtcctgc agttgcagtc gtgttctccg agttcctgtc tctctgccaa cgccgcccgg 120 atggcttccc aaaaccgcga cccagccgcc actagcgtcg ccgccgcccg taaaggagct 180 gagccgagcg ggggcgccgc ccggggtccg gtgggcaaaa ggctacagca ggagctgatg 240 accctcatgg cagtggggag catcagaacc agctcaacag tttgtctact gtccggtccc 300 agagaaactc aagattctag caagcccctt gtgtggggct tgggttggga catgaggctg 360 ctgctggagc ttactctgca actgtttctc caaatgccag aacccaacat tgatagtccc 420 ttgaacacac atgctgccga gctctggaaa aaccccacag cttttaagaa gtacctgcaa 480 gaaacctact caaagcaggt caccagccag gagccctgac ccaggctgcc cagcctgtcc 540 ttgtgtcgtc tttttaattt ttccttagat ggtctgtcct ttttgtgatt tctgtatagg 600 actctttatc ttgagctgtg gtatttttgt tttgtttttg tcttttaaat taagcctcgg 660 ttgagccctt gtatattaaa taaatgcatt tttgtccttt tttagacaaa aaaaaaaaaa 720 aaa 723

Claims (18)

A composition for diagnosing lung cancer comprising an agent for measuring the level of mRNA of a UBE2C gene consisting of the nucleotide sequence represented by SEQ ID NO: 7 or a protein expressed therefrom in an individual who has or is likely to develop lung cancer.
According to claim 1,
S100P gene consisting of nucleotide sequence represented by SEQ ID NO: 1, MMP11 gene consisting of nucleotide sequence represented by SEQ ID NO: 2, CDCA7 gene consisting of nucleotide sequence represented by SEQ ID NO: 3, S100A2 consisting of nucleotide sequence represented by SEQ ID NO: 4 Genes, ETV4 gene consisting of the nucleotide sequence represented by SEQ ID NO: 5 and TOP2A gene consisting of the nucleotide sequence represented by SEQ ID NO: 6 of any one or more genes selected from the group consisting of mRNA or protein expressed therefrom to measure the level Lung cancer diagnostic composition further comprising a formulation.
According to claim 1,
The agent for measuring the mRNA level of the gene comprises a primer or probe specifically binding to the gene, lung cancer diagnostic composition.
According to claim 1,
The agent for measuring the level of the protein comprises an antibody or aptamer specific for the protein, lung cancer diagnostic composition.
According to claim 4,
The antibody is any one or more selected from the group consisting of monoclonal antibodies, polyclonal antibodies, antibody fragments and recombinant antibodies, lung cancer diagnostic composition.
According to claim 1,
The lung cancer is a non-small cell lung cancer (NSCLC), lung cancer diagnostic composition.
The method of claim 6,
The non-small cell lung cancer is at least one selected from the group consisting of adenocarcinoma, squamous cell carcinoma, large cell carcinoma, and adenosquamous cell carcinoma, lung cancer diagnostic composition.
A kit for diagnosing lung cancer, comprising the composition of any one of claims 1 to 7.
The method of claim 8,
The kit is an RT-PCR kit, a DNA chip kit or a protein chip kit.
Measuring the expression level of the mRNA of the UBE2C gene consisting of the nucleotide sequence represented by SEQ ID NO: 7 from the biological sample isolated from the individual who has or is likely to develop lung cancer or the expression level of the protein expressed therefrom (step 1) ; And
Method for providing information for diagnosing lung cancer in an individual comprising comparing the measured value with a value measured from a sample of a normal control.
The method of claim 10,
S100P gene consisting of the nucleotide sequence represented by SEQ ID NO: 1 from the biological sample isolated from the individual, MMP11 gene consisting of the nucleotide sequence represented by SEQ ID NO: 2, CDCA7 gene consisting of the nucleotide sequence represented by SEQ ID NO: 3, SEQ ID NO: 4 Expression level of mRNA of any one or more genes selected from the group consisting of the S100A2 gene consisting of the nucleotide sequence represented by, the ETV4 gene consisting of the nucleotide sequence represented by SEQ ID NO: 5 and the TOP2A gene consisting of the nucleotide sequence represented by SEQ ID NO: 6 Or further comprising the step of measuring the expression level of the protein expressed therefrom, information providing method.
The method of claim 10,
The step of measuring the expression level of the mRNA of the gene includes contacting a sample or a primer or probe specifically binding to the gene.
The method of claim 10,
The step of measuring the expression level of the protein comprises contacting an antibody or aptamer specifically binding to the protein with a sample.
The method of claim 10,
The biological sample is one or more selected from the group consisting of lung cells, lung tissue, lung cancer tissue and sputum, information providing method.
The method according to any one of claims 10 to 14,
The method further comprises the step of determining the lung cancer (step 3) when the value measured in the biological sample is higher than the value of the normal control sample.
A step of measuring the expression level of the mRNA of the UBE2C gene consisting of the nucleotide sequence represented by SEQ ID NO: 7 or the expression level of the protein expressed therefrom by treating the lung cancer treatment candidate material to a biological sample separated from the individual having lung cancer (1 step); And
And comparing the measured expression level with the expression level of a control group not treated with the candidate substance (step 2).
The method of claim 16,
Lung cancer treatment candidate material is treated with a biological sample separated from an individual who has lung cancer, the S100P gene consisting of the nucleotide sequence represented by SEQ ID NO: 1, the MMP11 gene consisting of the nucleotide sequence represented by SEQ ID NO: 2, represented by SEQ ID NO: 3 CDCA7 gene consisting of nucleotide sequence, S100A2 gene consisting of nucleotide sequence represented by SEQ ID NO: 4, ETV4 gene consisting of nucleotide sequence represented by SEQ ID NO: 5, and TOP2A gene consisting of nucleotide sequence represented by SEQ ID NO: 6 Screening method, further comprising the step of measuring the expression level of the mRNA or the expression level of the mRNA expression of any one or more genes.
The method of claim 16,
The biological sample is one or more selected from the group consisting of lung cells, lung tissue, lung cancer tissue and sputum, screening method.

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