KR20210084112A - Genetic markers for diagnosis of cervical cancer - Google Patents

Abstract

The present invention relates to a genetic marker for diagnosis of cervical cancer, and more specifically, to a composition capable of diagnosing cervical cancer by detecting a gene having a high frequency of mutation in cervical cancer patients or a method of providing useful information for diagnosis. According to the present invention, cervical cancer can be accurately diagnosed through the detection of a gene mutation, and the expression rate of the gene mutation is also closely related to the severity of cervical cancer, thereby being very usefully used to identify the cervical cancer stage of patients.

Description

Genetic markers for diagnosis of cervical cancer

The present invention relates to a genetic marker for diagnosing cervical cancer, and more particularly, by detecting a gene whose mutation is expressed at high frequency in cervical cancer patients, a composition capable of diagnosing cervical cancer or a method of providing useful information for diagnosis is about

Cervical cancer is the second leading cause of cancer deaths in women worldwide, and human papillomavirus (HPV) infection accounts for almost all of the causes of cervical cancer. It is estimated that 500,000 women worldwide are diagnosed with cervical cancer every year and 250,000 women die from cervical cancer. It is believed that most women become infected with HPV at least once in their lifetime. More than 100 types of HPV have been identified so far. Among these types, high-risk types 16, 18, 31, 33, 35, 45, 52, and 58 are known to be the main causes of cervical cancer, and types 16 and 18 account for about 70% of all cervical cancers. E6 and E7 proteins of the high-risk group HPV are the main causes of cervical cancer. E6 inhibits p53 and E7 pRB, causing genetic instability and cell cycle disturbance of cervical epithelial cells. It leads to the development of cancer by causing the immortalization of

As a diagnostic test for cervical cancer, the Pap smear test, which observes cervical cell lesions, and the hybrid capture II, a diagnostic method that detects HPV DNA, are commonly used (Abreu AL, Souza RP, Gimenes F, Consolaro ME, A review of methods for detect human papillomavirus infection, Virology Journal 9 (2012) doi: 10.1186/1743-422X-9-262). These methods are inconvenient to collect cervical cells for examination as a method using cells of the cervix. In order to alleviate this inconvenience, there have been attempts to develop a serological diagnosis method for cervical cancer through several studies. As a serological test method for cervical cancer known to date, there is a method of measuring the antibody titer to the L1 protein, E6 or E7 of the human papillomavirus.

Since the level of blood antibodies to these HPV antigens increases as the severity of cervical cancer increases, a method for measuring antibody titers in blood is considered to have significant potential for detecting the development of cervical cancer. However, it is true that there is a limit to accurately detecting the onset of cervical cancer through the detection of antibody levels because the increase of these antibodies occurs even in normal persons and low-severity patients such as CIN I.

The present invention has been devised to solve the problems of the known methods of screening for cervical cancer as described above, and the present inventors described cell-free DNA (hereinafter referred to as 'cfDNA') isolated from the blood of cervical cancer patients. ) identified a group of genes showing a high frequency of mutations, and found that cervical cancer can be diagnosed with very high accuracy through these genes, thereby completing the present invention.

Accordingly, an object of the present invention is one or more genes selected from the group consisting of ARID1A, ATM, CHD4, CTCF, EP300, FAT1, FAT4, FBXW7, KMT2C, KMT2D, NSD1, PIK3CA, PIK3R1, PTEN, RNF213, TP53, TRRAP and ZFHX3 To provide a composition for diagnosing cervical cancer comprising an agent capable of detecting a mutation of

Another object of the present invention includes analyzing a gene mutation in a biological sample provided from an individual to be diagnosed, wherein the gene mutation is ARID1A, ATM, CHD4, CTCF, EP300, FAT1, FAT4, FBXW7, KMT2C, KMT2D, NSD1 , PIK3CA, PIK3R1, PTEN, RNF213, TP53, TRRAP and one or more gene mutations selected from the group consisting of ZFHX3, to provide an information providing method for diagnosing cervical cancer.

In order to achieve the above object of the present invention, the present invention is composed of ARID1A, ATM, CHD4, CTCF, EP300, FAT1, FAT4, FBXW7, KMT2C, KMT2D, NSD1, PIK3CA, PIK3R1, PTEN, RNF213, TP53, TRRAP and ZFHX3. Provided is a composition for diagnosing cervical cancer comprising an agent capable of detecting a mutation of one or more genes selected from the group.

In order to achieve another object of the present invention, the present invention comprises the step of analyzing a gene mutation in a biological sample provided from an individual to be diagnosed, wherein the gene mutation is ARID1A, ATM, CHD4, CTCF, EP300, FAT1, FAT4, FBXW7 , KMT2C, KMT2D, NSD1, PIK3CA, PIK3R1, PTEN, RNF213, TP53, TRRAP and one or more gene mutations selected from the group consisting of TRRAP and ZFHX3 It provides an information providing method for diagnosing cervical cancer.

Hereinafter, the present invention will be described in more detail.

The present invention detects mutations in one or more genes selected from the group consisting of ARID1A, ATM, CHD4, CTCF, EP300, FAT1, FAT4, FBXW7, KMT2C, KMT2D, NSD1, PIK3CA, PIK3R1, PTEN, RNF213, TP53, TRRAP and ZFHX3 It provides a composition for diagnosing cervical cancer comprising an agent capable of doing so.

According to an embodiment of the present invention, it was confirmed that mutations of the above-listed genes were expressed with high frequency in cfDNA isolated from blood provided from cervical cancer patients. In addition, it was confirmed that the frequency of expression of the mutation in the gene decreases as cervical cancer patients are treated with anticancer drugs or received radiation therapy to improve cervical cancer.

According to another embodiment of the present invention, it was confirmed that the expression of the gene mutation in the cervical cancer patient was consistently shown in cfDNA extracted from blood and cancer tissue. This means that cervical cancer can be accurately diagnosed through a non-invasive method with less discomfort from the patient.

Accordingly, mutations in any one or more genes selected from the group consisting of ARID1A, ATM, CHD4, CTCF, EP300, FAT1, FAT4, FBXW7, KMT2C, KMT2D, NSD1, PIK3CA, PIK3R1, PTEN, RNF213, TP53, TRRAP and ZFHX3 are uterine It can be usefully utilized in the diagnosis of cervical cancer patients, and it can be seen that the agent capable of detecting the mutation of the gene will be usefully utilized in the development of a composition for diagnosing cervical cancer.

In one embodiment of the present invention, said gene is from the group consisting of ARID1A, ATM, CHD4, CTCF, EP300, FAT1, FAT4, FBXW7, KMT2C, KMT2D, NSD1, PIK3CA, PIK3R1, PTEN, RNF213, TP53, TRRAP and ZFHX3 Selected 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 species or 18 genes.

In a preferred embodiment of the present invention, the gene may be any one or more selected from the group consisting of ZFHX3, KMT2C, KMT2D, NSD1, ATM and RNF213, and more specifically, ZFHX3, KMT2C, KMT2D, NSD1, ATM and RNF213. It may be 1 type, 2 types, 3 types, 4 types, 5 types, or 6 types of genes selected from the group consisting of.

In the most preferred embodiment of the present invention, the gene may be any one or more selected from the group consisting of ZFHX3, KMT2C and KMT2D, and more specifically, one, two or three selected from the group consisting of ZFHX3, KMT2C and KMT2D. It may be a gene of a species.

The detection of the gene mutation may be to measure the expression level of each gene mutation, preferably the mRNA level in which the gene in which the mutation is expressed, that is, the amount of mRNA, and a material capable of measuring the expression is in the gene. It may include a specific primer pair, a probe, or a combination thereof. In the present invention, the primer or probe specific for the mutant gene may be a primer or probe capable of specifically amplifying the entire mutant gene or a specific region of the mutant gene, and the primer or probe is prepared through a method known in the art. can design

In the present invention, the term "primer" refers to a single compound capable of serving as an initiation point for template-directed DNA synthesis under suitable conditions (ie, four different nucleoside triphosphates and a polymerase) in a suitable temperature and in a suitable buffer. -stranded oligonucleotides. The suitable length of the primer may vary depending on various factors, such as temperature and the use of the primer. In addition, the sequence of the primer does not need to have a completely complementary sequence to a partial sequence of the template, it is sufficient as long as it has sufficient complementarity within a range capable of hybridizing with the template to perform an intrinsic function of the primer. Therefore, the primer in the present invention does not need to have a sequence that is perfectly complementary to the nucleotide sequence of the gene as a template, and it is sufficient as long as it has sufficient complementarity within the range that can hybridize to this gene sequence and act as a primer. In addition, it is preferable that the primer according to the present invention can be used in a gene amplification reaction.

In the present invention, the term "probe" means a natural or modified monomer or linear oligomer of linkages, includes deoxyribonucleotides and ribonucleotides, can hybridize specifically to a target nucleotide sequence, and is naturally present or artificially synthesized. The probe according to the present invention may be single-stranded, preferably an oligodeoxyribonucleotide. Probes of the invention may include native dNMPs (ie, dAMP, dGMP, dCMP and dTMP), nucleotide analogs or derivatives. In addition, the probe of the present invention may also contain ribonucleotides. For example, the probes of the present invention include backbone modified nucleotides, such as peptide nucleic acids (PNA) (M. Egholm et al., Nature, 365:566-568 (1993)), phosphorothioate DNA, phosphorodithioate DNA, phosphoroamidate DNA, amide-linked DNA, MMI-linked DNA, 2′-O-methyl RNA, alpha-DNA and methylphosphonate DNA, sugar modified nucleotides such as 2′-O-methyl RNA, 2'-fluoro RNA, 2'-amino RNA, 2'-O-alkyl DNA, 2'-O-allyl DNA, 2'-O-alkynyl DNA, hexose DNA, pyranosyl RNA and anhydrohexy Tall DNA, and nucleotides with base modifications such as C-5 substituted pyrimidines (substituents are fluoro-, bromo-, chloro-, iodo-, methyl-, ethyl-, vinyl-, formyl-, Tityl-, propynyl-, alkynyl-, thiazolyl-, imidazoryl-, pyridyl- including), 7-deazapurine having a C-7 substituent (substituents are fluoro-, bromo-, chloro- , iodo-, methyl-, ethyl-, vinyl-, formyl-, alkynyl-, alkenyl-, thiazolyl-, imidazoryl-, pyridyl-), inosine and diaminopurine. .

In addition, the expression of the mutant gene in the present invention includes the protein level of the mutant encoded by each gene, and a material capable of measuring the level of the protein specifically binds to the mutant protein expressed from the mutant gene. antibodies, such as polyclonal antibodies, monoclonal antibodies and recombinant antibodies. When an antibody is used to measure the protein level, the target protein in a biological sample and an antibody specific therefor form a binding compound, that is, an antigen-antibody complex, and the amount of the antigen-antibody complex formed is determined by a detection label (detection label). ) can be quantitatively measured through the magnitude of the signal. The detection label may be selected from the group consisting of an enzyme, a fluorescent substance, a ligand, a luminescent substance, a microparticle, a redox molecule, and a radioisotope, but is not limited thereto.

Methods for measuring the expression level of the mutant protein can be used without limitation, methods known in the art, for example, western blotting (western blotting), dot blotting (dot blotting), enzyme immunoassay (enzyme-linked) immunosorbent assay, ELISA), radioimmunoassay (RIA), radioimmunodiffusion, octeroni immunodiffusion, rocket immunoelectrophoresis, immunohistochemical staining, immunoprecipitation, complement fixation assay, flow cytometry (FACS) Or a protein chip (chip) method, etc., but is not limited thereto,

The level of the mutant gene is determined by amplifying mRNA or cDNA from a sample of a subject using a primer set or probe that specifically binds to the mRNA of each gene, or using a probe and hybridization to measure each of the genes in the sample. The presence and expression level of gene mRNA can be measured. Measurement of the expression level of the mutant gene can be used without limitation by a method for confirming the expression level conventional in the art, and examples of the analysis method include reverse transcription polymerase chain reaction (RT-PCR), competitive RTPCR (competitive RT- PCR), real-time RT-PCR, RNase protection assay (RPA), northern blotting, DNA microarray chip, RNA sequencing (RNA) sequencing), a hybridization method using a nanostring, and an in situ hybridization method of a tissue section, but are not limited thereto.

In the present invention, the mutation of each gene may be one or more selected from the types of each gene mutation specifically listed below. Mutation information of each gene listed below is displayed along with IDs that can be searched in the COSMIC database:

ARID1A: c.6196A>G (COSM51465), c.4532G>A (COSM3804820);

ATM: c.1235G>A(COSM352332), c.7327C>T(COSM1350997), c.9140G>A(COSM1351063), c.4315C>A(COSM1585351), c.7360_7361insA(COSM6196808);

CHD4: c.414G>T (COSM5002406), c.417G>T (COSM1363775);

CTCF: c.638_639insA (COSM4617689), c.874A>G (COSM5028152);

EP300: c.1640_1641delATinsTA(COSM1251229), c.5807C>T(COSM1205372), c.2668_2669insACAATC(COSM4385248), c.3396C>A(COSM4991529), c.2921A>G(COSM1205368);

FAT1: c.10889A>G(COSM6099746), c.13355C>T(COSM1206562), c.9425C>T(COSM1317133), c.7105A>C(COSM1429026), c.392C>T(COSM4003046), c.77G >A (COSM3683267);

FAT4: c.12079G>C(COSM6269269), c.12683T>A(COSM1051018), c.13928G>A(COSM1051038), c.262G>A(COSM5400422), c.818C>T(COSM5085683), c.1886G >A(COSM5457096), c.5336T>C(COSM211934), c.8476G>A(COSM5009595), c.13892C>A(COSM6049909), c.7070T>C(COSM732676);

FBXW7: c.2066G>A (COSM1594355);

KMT2C: c.2961C>G(COSM216053), c.1138C>T(COSM302656), c.5694T>A(COSM6471781), c.925C>T(COSM1179670), c.967A>T(COSM1488408), c.9692C >A(COSM6287770), c.11609A>G(COSM6239991), c.2959T>C(COSM253767), c.2534G>A(COSM4162013), c.2459C>T(COSM4606481), c.2080C>T(COSM1312888) , c.26T>C(COSM5694861), c.943G>A(COSM1179668);

KMT2D: c.12662_12664delAGC(COSM940003), c.11220_11222delGCA(COSM3968242), c.11220_11222delGCA(COSM3968242), c.11220_11222delGCA(COSM3968242), c.11220_11222delGCA(COSM60.9547242), c. T(COSM1717661), c.6167A>G(COSM240686), c.11220_11222delGCA(COSM3968242), c.7607T>C(COSM6342201), c.6391A>C(COSM1562071), c.11220_11222delGCA(COSM3968242), c.6190G> C(COSM4754816), c.11220_11222delGCA(COSM3968242), c.11220_11222delGCA(COSM3968242), c.11220_11222delGCA(COSM3968242), c.11220_11222delGCA(COSM3968242), c.454912G>A(COSM4990265), c.454912G>A(COSM4990) , c.326T>C (COSM5574197), c.12662_12664delAGC (COSM940003), c.11220_11222delGCA (COSM3968242);

NSD1: c.325A>T(COSM3340998), c.2176T>C(COSM4418708), c.4871C>T(COSM1496038), c.946T>G(COSM4384048), c.589A>C(COSM3341014);

PIK3CA: c.3101A>T(COSM12462), c.3134A>G(COSM729813), c.3140A>G(COSM249874);

PIK3R1: c.978G>A (COSM3727824);

PTEN: c.878G>T(COSM1349605), c.650T>C(COSM1159818), c.232A>G(COSM5075);

RNF213: c.11926C>T(COSM2803876), c.13318G>A(COSM76267), c.15275G>T(COSM2804010), c.13178C>T(COSM2153460), c.12362A>G(COSM2803900), c.12305G >A(COSM5641817), c.14282G>A(COSM1564145), c.716A>G(COSM3523349), c.13195G>A(COSM1235857);

TP53: c.937A>G(COSM44931), c.625A>G(COSM46096), c.505A>G(COSM44431);

TRRAP: c.7726_7727insA(COSM748329), c.1705G>A(COSM1093572), c.10906G>A(COSM1230633), c.4220C>A(COSM6387922), c.9896G>A(COSM1093709);

ZFHX3: c.8178_8179insC(COSM3795120), c.8176C>T(COSM165694), c.4168C>T(COSM1479080), c.3103G>A(COSM5510839), c.2922C>G(COSM248442), c.679G>A (COSM5783317), c.2536C>T (COSM973550)

The present invention also includes analyzing a gene mutation in a biological sample provided from an individual to be diagnosed, wherein the gene mutation is ARID1A, ATM, CHD4, CTCF, EP300, FAT1, FAT4, FBXW7, KMT2C, KMT2D, NSD1, PIK3CA , PIK3R1, PTEN, RNF213, TP53, TRRAP and one or more gene mutations selected from the group consisting of ZFHX3, provides an information providing method for diagnosing cervical cancer.

In the present invention, the biological sample may be a DNA sample isolated from a sample selected from the group consisting of blood, plasma, serum, saliva, nasal fluid, sputum, joint capsule fluid, amniotic fluid, ascites, cervical or vaginal secretion, urine and cerebrospinal fluid, Preferably, it may be cfDNA isolated from blood provided from an individual.

In one embodiment of the present invention, the mutation analysis of each gene amplifies the gene using each primer complementary to the gene, and analyzes the gene mutation using the sequencing data of the amplification product. can be characterized as

The sequencing includes whole genome sequencing (WGS), whole exome sequencing (WES), microarray, target sequencing, Sanger sequencing, and next-generation sequencing (NGS). ) and may be selected from the group consisting of RNA sequencing, preferably next-generation sequencing, but is not limited thereto.

In another embodiment of the present invention, the mutation analysis of the gene may be analyzed by a method of detecting mRNA of the mutant gene or a protein encoded by the mutant gene. A method of detecting the mRNA of the mutant gene or a protein encoded by the mRNA may be referred to as described above.

In another embodiment of the present invention, when a mutation of the aforementioned gene is confirmed according to the method, the method may further include determining that the individual has cervical cancer.

The present invention also provides mutations in one or more genes selected from the group consisting of ARID1A, ATM, CHD4, CTCF, EP300, FAT1, FAT4, FBXW7, KMT2C, KMT2D, NSD1, PIK3CA, PIK3R1, PTEN, RNF213, TP53, TRRAP and ZFHX3. Provided is a kit for diagnosing cervical cancer comprising a detectable agent.

The present invention also provides one or more genes selected from the group consisting of ARID1A, ATM, CHD4, CTCF, EP300, FAT1, FAT4, FBXW7, KMT2C, KMT2D, NSD1, PIK3CA, PIK3R1, PTEN, RNF213, TP53, TRRAP and ZFHX3 It provides a composition for determining the severity of cervical cancer comprising an agent capable of detecting a mutation of

The severity of cervical cancer refers to a stage according to the progression of cervical cancer, and is largely divided into stages 1 to 4. The stage 1 cervical cancer refers to a state in which the cancer is confined only within the cervix, and refers to a case in which cancer cells have invaded less than 3 mm of the basal epithelial layer (stage 1a) or infiltrated more than 3 mm (stage 1b). The stage 2 cervical cancer refers to a state in which the lesion has escaped the cervix but has not reached the pelvic wall, and is limited to the vagina as the cancer has spread to the vagina and has not spread around the uterus (stage 2a) or has infiltrated to the periphery of the uterus ( 2b) means the group. The third stage of cervical cancer refers to a state in which the cancer has invaded the pelvic wall or the lower third of the vagina, and the cancer has invaded more than 1/3 of the vaginal cavity, and has not yet invaded the pelvic wall (3a) stage) or the cancer has invaded the pelvic wall (stage 3b). The stage 4 cervical cancer refers to a case in which the cancer has invaded the bladder or rectal mucosa, which are peripheral organs, or has distantly metastasized to the liver, lung, bone, or the like.

By analyzing the expression level of the above-mentioned gene mutation in a sample provided from a subject according to the composition of the present invention, it can be determined that the higher the expression rate of the mutation, the more severe the cancer is, that is, the more advanced the cancer stage.

According to the present invention, cervical cancer can be accurately diagnosed through the detection of a gene mutation, and since the expression rate of the gene mutation is closely related to the severity of cervical cancer, it will be very usefully used to identify the stage of cervical cancer in patients. can

1 shows the result of performing next-generation sequencing using cfDNA obtained from cervical cancer patient's liquid, and matching the patient with the gene in which the mutation appeared.
2 is a result of analyzing the number of gene mutations (A) and mutation frequency (B) of each gene for each cervical cancer patient.
3 is a diagram showing a comparison of gene mutations identified in cfDNA extracted from cancer tissue and blood of cervical cancer patients (A, blue: mutation observed only in cfDNA, yellow: mutation observed only in cancer tissue, red: cfDNA and mutations observed in both cancer tissues) and 3 types of genes in which mutations were observed in both cancer tissues and cfDNA (B) are diagrams showing mutation agreement between cancer tissues and cfDNA.

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

1. NGS Analysis of Cervical Cancer Patient Blood Samples

cfDNA was extracted from the blood of a total of 24 cervical cancer patients, and the average age of the patients was 61 years. The detailed information of the patients is shown in Table 1 below.

After collecting cell free DNA and PBMC from the blood of the 24 patients, a DNA library for sequencing was prepared, and sequencing was performed according to a conventionally known method using an Ion torrent S5 manufactured by thermofischer.

The results for this are shown in FIG. 1 .

As a result of NGS analysis, 18 gene mutations were found, and the genes with the most mutations were ZFHX3 (83%), KMT2C (79%), KMT2D (79%), NSD1 (67%), and ATM ( 38%) in that order (FIG. 1). In this experiment, only cervical cancer patients were analyzed, but in the bioinformatics analysis stage, germ-line mutations including PBMCs and the list of genetic mutations expressed in 50 general people (KOREF variants) were excluded. Through this, not only the somatic gene mutation was effectively confirmed, but also the gene mutation detected in FIG. 1 was determined to be a mutation specifically expressed in cervical cancer patients because the mutation expressed in the general population was excluded.

On the other hand, all patients had at least 3 mutations, and the patient with the most mutations was the patient with 23 mutations (FIG. 2A). As a result of the analysis including the location of the gene mutation, it showed the same pattern (KMT2C, KMT2D, ZFHX3, NSD, ATM order) as simply analyzing the gene mutation pattern (FIG. 2B).

2. Monitoring the effect of chemotherapy and radiation therapy on the prediction of the prognosis of cervical cancer patients

The present inventors conducted an experiment to determine whether the gene panel showing mutations in cervical cancer patients identified in Example 1 can be utilized as a biomarker for predicting the patient's anticancer and radiotherapy prognosis.

In general, cervical cancer is progressed based on cisplatin-based chemotherapy, and paclitaxel or bevacizumab is also used together. In order to confirm the prognosis of chemotherapy and radiation therapy under the same conditions, patients who received cisplatin chemotherapy and pelvic radiation 30 times with 54 gray were selected, peripheral blood and cancer tissues were collected, and expression of mutations in the gene panel was analyzed by NGS.

The results for this are shown in FIG. 3 .

As shown in FIG. 3 , high consistency was confirmed for the top three mutations (ZFHX3, KMT2C, KMT2D) detected in cfDNA and tissues.

According to the present invention, cervical cancer can be accurately diagnosed through the detection of a gene mutation, and since the expression rate of the gene mutation is closely related to the severity of cervical cancer, it will be very usefully used to identify the stage of cervical cancer in patients. It has high industrial applicability.

Claims (10)

ARID1A, ATM, CHD4, CTCF, EP300, FAT1, FAT4, FBXW7, KMT2C, KMT2D, NSD1, PIK3CA, PIK3R1, PTEN, RNF213, TP53, TRRAP and ZFHX3 capable of detecting a mutation of one or more genes selected from the group consisting of A composition for diagnosing cervical cancer comprising an agent.
The composition for diagnosing cervical cancer according to claim 1, wherein the agent is a probe, primer pair or a combination thereof that complementarily binds to the gene.
Analyzing a gene mutation of a biological sample provided from an individual to be diagnosed, wherein the gene mutation is ARID1A, ATM, CHD4, CTCF, EP300, FAT1, FAT4, FBXW7, KMT2C, KMT2D, NSD1, PIK3CA, PIK3R1, PTEN , RNF213, TP53, TRRAP and one or more gene mutations selected from the group consisting of ZFHX3, an information providing method for diagnosing cervical cancer.
The method of claim 3, wherein the biological sample is a DNA sample isolated from a sample selected from the group consisting of blood, plasma, serum, saliva, nasal fluid, sputum, joint capsule fluid, amniotic fluid, ascites, cervical or vaginal secretion, urine, and cerebrospinal fluid. Information providing method, characterized in that.
The method of claim 3, wherein the sample is cell-free DNA.
According to claim 3, wherein the mutation analysis is characterized in that the gene is amplified using each primer complementary to the gene, and the gene mutation is analyzed using sequencing data of the amplified product. How to provide information.
The method of claim 6, wherein the sequencing comprises whole genome sequencing (WGS), whole exome sequencing (WES), microarray, target sequencing, and Sanger sequencing. ), next-generation sequencing (NGS) and RNA sequencing (RNA Sequencing), characterized in that selected from the group consisting of information providing method. The method of claim 3, further comprising determining that the individual has cervical cancer when the mutation of the gene is confirmed.
The method of claim 3, wherein the gene mutation is selected from the group consisting of ZFHX3, KMT2C and KMT2D.
10. The method of claim 9, wherein the gene mutation is selected from the gene mutations listed below:
KMT2C: c.2961C>G, c.1138C>T, c.5694T>A, c.925C>T, c.967A>T, c.9692C>A, c.11609A>G, c.2959T>C, at least one selected from the group consisting of c.2534G>A, c.2459C>T, c.2080C>T, c.26T>C and c.943G>A;
KMT2D: c.12662_12664delAGC, c.11220_11222delGCA, c.11220_11222delGCA, c.11220_11222delGCA, c.11220_11222delGCA, c.9547G>A, c.8774C>T, c.6167A>G, c.11220_11222delTCA>C, c.7607 c.6391A>C, c.11220_11222delGCA, c.6190G>C, c.11220_11222delGCA, c.11220_11222delGCA, c.11220_11222delGCA, c.11220_11222delGCA, c.4912G>A, c.8576C>A, c.326T>C, at least one selected from the group consisting of c.12662_12664delAGC and c.11220_11222delGCA; and
ZFHX3: at least one selected from the group consisting of c.8178_8179insC, c.8176C>T, c.4168C>T, c.3103G>A, c.2922C>G, c.679G>A, and c.2536C>T.

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