KR101977351B1 - Composition for predicting resistance or susceptibility to anticancer drugs - Google Patents

Abstract

The present invention relates to a composition for predicting resistance or sensitivity of an anticancer drug using a gene mutation marker, and a method for predicting resistance or sensitivity of an anticancer drug using the same. The gene mutation markers according to the present invention are highly correlated with resistance or sensitivity to anticancer drugs, especially pazopanib in neuroendocrine tumors, so that patients with high resistance or sensitivity to specific anticancer agents can be used early Can be predicted effectively. Therefore, it is possible to efficiently perform the patient-customized treatment that can achieve the optimal therapeutic effect by administering the appropriate drug to the patient.

Description

TECHNICAL FIELD The present invention relates to compositions for predicting anticancer resistance or susceptibility to anticancer drugs,

The present invention relates to a composition for predicting resistance or sensitivity of an anticancer drug using a gene mutation marker, and a method for predicting resistance or sensitivity of an anticancer drug using the same.

Biomarker is an index that can be used to detect changes induced inside living organisms due to external influences. Research is being actively conducted to diagnose various diseases or to predict or monitor the efficacy of a specific therapeutic agent. Biomarkers related to drug development include pharmacodynamic markers (PD markers) for verifying the in vivo action of drugs, Predictive markers for predicting the response of drugs before in vivo administration marker). The use of these markers is helpful in establishing a clinical strategy of drugs. For example, in the case of an efficacy prediction marker that is predicted to be efficacious through the action of a drug, it can be used in a patient selection process to enable more effective drug treatment, , It is necessary to monitor whether the drug works well in an individual patient or whether the drug has acquired resistance so that a more effective treatment strategy can be established. In addition, even in the absence of an efficacy predicting marker, if there is an efficacy test marker, it is possible to monitor the response of the individual patient to the drug more early in the drug treatment. Therefore, Enabling early screening and, consequently, more effective and successful drug treatment. In addition, the effect validation marker can be used as an indicator of the appropriate dosage of the drug by monitoring the degree of drug reactivity according to the administration concentration.

Cancer, on the other hand, is one of the leading causes of death to date. Although advances in medical technology have seen a marked change in the treatment of cancer, the five-year survival rate has only improved by about 10% over the past two decades. This is because it is difficult to diagnose and treat the appropriate period due to the rapid growth and metastasis of cancer. By introducing appropriate biomarkers into cancer therapy, the chance of cancer treatment can be greatly increased by identifying the characteristics of the cancer and increasing the opportunity to use appropriate therapeutic agents in a timely manner. For example, even in the same lung cancer patient, the characteristics of lung cancer classification, gene and secretory protein are different, and accordingly, a suitable therapeutic agent is different. Therefore, in a chemotherapy using a specific therapeutic agent, if there is a biomarker corresponding to the therapeutic agent, trial and error can be reduced and the probability of success can be further increased. Therefore, it is very important to search biomarkers for predicting or testing the efficacy of anticancer drugs. If successful biomarkers are successfully derived, the utility and value of anticancer drugs and the success rate of treatment using them will be greatly increased.

Gastroenteropancreatic neuroendocrine tumors (GET-NETs) are tumors of the gastrointestinal tract. They are classified according to their genital location and continue to increase in incidence, although they are not common tumors.

The present inventors completed the present invention by confirming the correlation between the specific gene mutation marker and the resistance / sensitivity of pachopanip while continuing the study on gastric small intestinal neuroendocrine tumors and pachopanip, the therapeutic agent thereof.

Korea Patent Publication: 10-2005-0004491 Korea Patent Publication: 10-2013-0086898

It is an object of the present invention to provide a composition for predicting anticancer resistance or sensitivity using a gene mutation marker.

It is another object of the present invention to provide an anticancer drug resistance or sensitivity prediction kit comprising the composition.

It is still another object of the present invention to provide a method for providing information on anticancer drug resistance or sensitivity prediction including identifying the sequence of the gene mutation marker site.

In order to solve the above problems, the present invention provides a polynucleotide consisting of 10 to 100 consecutive DNA sequences or a complementary polynucleotide thereof, comprising the 1799th nucleotide of SEQ ID NO: 1 or the 47th nucleotide region of SEQ ID NO: 2 A composition for predicting anticancer resistance or sensitivity.

The present invention also provides a kit for anticancer drug resistance or sensitivity prediction comprising the composition.

In addition, the present invention provides a method for providing information on anticancer drug resistance or sensitivity prediction, comprising identifying the 1799th nucleotide of SEQ ID NO: 1 or the 47th nucleotide region of SEQ ID NO: 2 from the sample DNA.

The gene mutation markers according to the present invention are highly correlated with resistance or sensitivity to anticancer drugs, especially pazopanib in neuroendocrine tumors, so that patients with high resistance or sensitivity to specific anticancer agents can be used early Can be predicted effectively. Therefore, it is possible to efficiently perform the patient-customized treatment that can achieve the optimal therapeutic effect by administering the appropriate drug to the patient.

Fig. 1 is a chart showing the results of a CT scan of patients with BRAF V600E mutations before and after treatment with Pazopapin.

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

In one embodiment, the invention provides a polynucleotide comprising 10-100 consecutive DNA sequences, or a complementary polynucleotide thereof, comprising the 1799th nucleotide of SEQ ID NO: 1 or the 47th nucleotide of SEQ ID NO: 2 A composition for predicting anticancer resistance or sensitivity.

In the present invention, "anticancer drug resistance or sensitivity prediction" means predicting whether a patient will preferentially or not preferentially respond to chemotherapeutic treatment, or predicting the risk of the chemotherapeutic drug resistance.

In the present invention, 'prediction' is used to refer to the likelihood that a patient will respond favorably or non-favorably to a chemotherapeutic treatment. In one embodiment, the prediction is about the degree of such response. For example, the prediction relates to the likelihood and / or likelihood that a patient will survive after treatment, for example, without treatment of a particular therapeutic agent and / or after surgical removal of primary tumor and / or chemotherapy for a certain period of time without cancer recurrence . The predictions of the present invention can be used clinically to determine treatment by selecting the most appropriate treatment for the patient. The predictions of the present invention may be used to determine whether a patient will respond favorably to treatment interventions, such as given therapeutic interventions, such as administration of a given therapeutic agent, surgical intervention, chemotherapy, or whether long- It is a useful tool in predicting.

In the present invention, 'resistance' refers to a condition that is not easily affected by a specific drug (anticancer drug) and has little change in disease progression, for example, cancer cell proliferation upon exposure to a specific drug (anticancer drug).

In the present invention, 'sensitivity' refers to a state that is easily affected by a specific drug (anticancer agent) and shows a state of disease progression upon exposure to a specific drug (anti-cancer agent), for example, a change in cancer cell proliferation.

In the present invention, 'anti-cancer drug' is a generic term for all types of drugs used for the treatment of cancer.

&Quot; Cancer ", which is a target disease by the composition of the present invention, is an aggressive characteristic in which cells ignore normal growth limits and divide and grow, invasive characteristics to penetrate into surrounding tissues, It is a generic term for diseases caused by cells with metastatic characteristics spreading to the site.

The anticancer agent may preferably be a therapeutic agent for neuroendocrine tumors, and more preferably a therapeutic agent for gastroenteropancreatic neuroendocrine tumors (GET-NETs).

In one embodiment of the present invention, pachopanip represented by the following formula (1) is used as the anticancer agent, but the present invention is not limited thereto.

In the present invention, the above " SEQ ID NO. 1 " to " SEQ ID NO. 2 " means a marker gene related to anticancer drug resistance or sensitivity.

Specifically, when T of the 1799th nucleotide of SEQ ID NO: 1 (CDS portion in NM_004333.4) is changed to A, valine (V), which is the 600th amino acid of the BRAF gene, is substituted with glutamic acid (E) BRAF V600E < / RTI >

In addition, when there is a deletion of T, the 47th nucleotide of SEQ ID NO: 2 (ENST00000202788, Exon part of NM_003668.3), c. (46-48) ATTfs lattice mobility mutation occurs, which is described herein as MAPKAPK5 mutation .

The fact that the two gene mutations can be used in the anticancer drug resistance or sensitivity prediction in the present invention is based on the fact that the therapeutic effect is different when the anticancer agent, especially pazopanib, is administered to neuroendocrine tumor patients.

The gene mutation markers according to the present invention are highly correlated with resistance or sensitivity to anticancer drugs, especially pazopanib in neuroendocrine tumors, so that patients with high resistance or sensitivity to specific anticancer agents can be used early Can be predicted effectively. Therefore, it is possible to efficiently perform the patient-customized treatment that can achieve the optimal therapeutic effect by administering the appropriate drug to the patient.

In another aspect, the invention is directed to a polynucleotide comprising 10-100 consecutive DNA sequences, or a complementary polynucleotide thereof, comprising the 1799th nucleotide of SEQ ID NO: 1 or the 47th nucleotide portion of SEQ ID NO: 2 The present invention provides a kit for anticancer drug resistance or sensitivity prediction, which comprises a polynucleotide that hybridizes.

A polynucleotide that specifically hybridizes with the polynucleotide or a complementary polynucleotide of the polynucleotide refers to hybridizing such that the base at the mutation site can be specifically discriminated.

The polynucleotide that specifically hybridizes with the polynucleotide or a complementary polynucleotide of the polynucleotide may be a probe or a primer, but is not limited thereto.

The term " probe " means a nucleic acid fragment such as RNA or DNA corresponding to a few nucleotides or several hundreds of nucleotides that can specifically bind to an mRNA, and is labeled to confirm the presence or expression level of a specific mRNA . The probe may be prepared in the form of an oligonucleotide probe, a single strand DNA probe, a double strand DNA probe, or an RNA probe. Selection of suitable probes and hybridization conditions can be appropriately selected according to techniques known in the art.

The term " primer " refers to a nucleic acid sequence having a short free 3 'hydroxyl group and capable of forming a base pair with a complementary template and having a short nucleic acid sequence serving as a starting point for template strand copying It says. Primers can initiate DNA synthesis in the presence of reagents for polymerization (i. E., DNA polymerase or reverse transcriptase) and four different nucleoside triphosphates at appropriate buffer solutions and temperatures. The PCR conditions, the lengths of the sense and antisense primers can be appropriately selected according to techniques known in the art.

The kit may be various types of kits depending on the method of using the polynucleotide, including, for example, a PCR kit, a DNA chip kit, a microarray, and the like.

Wherein said kit comprises the expression of a gene comprising said mutant; Or an agent for measuring the expression level of the protein of the present invention, as well as tools, reagents and the like commonly used in the art used for immunological analysis.

Examples of such tools or reagents include, but are not limited to, suitable carriers, markers capable of generating detectable signals, chromophores, solubilizers, buffers, stabilizers, and the like. When the labeling substance is an enzyme, it may include a substrate capable of measuring enzyme activity and a reaction terminator. Examples of the insoluble carrier include polystyrene, polyethylene, polypropylene, polyester, polyvinylpyrrolidone, polyvinylpyrrolidone, polyvinylpyrrolidone, polyvinylpyrrolidone, polyvinylpyrrolidone, polyvinylpyrrolidone, Acrylonitrile, fluorine resin, crosslinked dextran, polysaccharide, polymer such as magnetic fine particles plated with metal on latex, other paper, glass, metal, agarose and combinations thereof.

In another aspect, the present invention provides a method for providing information on anticancer drug resistance or sensitivity prediction, comprising identifying the 1799th nucleotide of SEQ ID NO: 1 or the 47th nucleotide region of SEQ ID NO: 2 from the sample DNA.

In this case, the method is characterized in that when T of the 1799th nucleotide of SEQ ID NO: 1 is changed to A, and BRAF V600E mutation in which valine as the 600th amino acid of BRAF gene is replaced with glutamic acid is present, it is judged to be resistant to the anticancer agent.

Also, the method is characterized in that it is judged to be susceptible to an anticancer agent when c. (46-48) ATTfs lattice mobility mutation, that is, MAPKAPK5 mutation, is present due to lack of T, which is the 47th nucleotide of SEQ ID NO: 2.

The method of providing information according to the present invention may further comprise separating DNA from the biological sample to obtain the sample DNA. The DNA can be isolated using phenol / chloroform extraction, SDS extraction, CTAB separation (Cetyl Trimethyl Ammonium Bromide; Murray et al., Nuc. Res., 4321-4325, 1980) or the like commercially available in the art , And is not limited thereto.

The biological sample includes all tissues such as blood, saliva, urine, skin cells, mucosal cells and hair of a subject, but is not limited thereto.

Gene sequence analysis may be performed to perform the step of identifying the nucleotide region. Sequence analysis can be performed using any method known in the art, for example, by using an automatic sequencer, pyrosequencing, restriction fragment length polymorphism (PCR), PCR-SSCP allele specific oligonucleotide (ASO) hybridization method, TaqMan-PCR method, MALDI-TOF / MS method, RCA (single strand conformation polymorphism), PCR-SSO method (specific sequence oligonucleotide), PCR-SSO method and dot hybridization Known methods such as rolling circle amplification, high resolution melting (HRM), primer extension, Southern blot hybridization and dot hybridization can be used, but the present invention is not limited thereto.

Hereinafter, the present invention will be described more specifically based on examples. However, the following examples are illustrative of the present invention and are not intended to limit the present invention.

Example  1. Selection of subjects and sample preparation

Biological samples were obtained from 12 gastric small intestinal neuroendocrine tumors (GEP-NET tumors) patients. For analysis, DNA was isolated from cancer tissue (n = 2) according to a conventionally known method, and paraffin-embedded cancer tissues (n = 10) fixed in formalin were prepared. The main areas of GEP-NETs are rectum, n = 3, pancreas, n = 4, small intestine, n = 2, stomach, n = 2), and all samples were undergoing liver metastasis. Pathologic analysis was performed independently by a skilled gastroenterologist. Histologic grades are divided into: carcinoid tumors and well-differentiated NETs, grade 1 tumors, anomalous calcinoids and well-differentiated neuroendocrine carcinomas, grade 2 tumors, poorly differentiated neuroendocrine carcinomas Carcinoma is grade 3 tumor. DNA was also isolated from 44 primary GEP-NETs (> 1 cm in size or> Grade 2) samples for mutagenesis in independent cohorts, and sequenced by the Sanger method.

All experiments were conducted with the approval of SMC IRB (Institutional Review Board).

Example  2. Battlefield Exome  Sequencing WES ) And data analysis

Whole-field exome sequencing was performed according to conventionally known methods. More specifically, exon regions were identified using an Agilent V2 capture probe set and sequenced using the Illumina HiSeq2000 instrument.

Experimental Example  One. Pazopanip  In resistant (non-reactive) patients BRAF V600E Mutation analysis

DNA sequencing analysis of patients with metastatic grade I neuroendocrine tumors confirmed BRAF V600E mutation. The primary mass of the patient originated from the duodenum and metastasized to a number of distant lymph nodes. The patient was prescribed capecitabine and oxaliplatin as the primary treatment. After progression of the disease according to the primary treatment, the patient enrolled in the Pachopanib clinical trial. Mutagenesis analysis of primary cancer tissues was performed before treatment with pachopanip. After two cycles of Pazopanib treatment, CT (computed tomography) scans showed cancer tissue growth corresponding to disease progression based on the RECIST 1.1 criteria for solid tumors. The results are shown in Fig.

As shown in Fig. 1, a small intestinal NET patient with a BRAF V600E mutation showed tumor progression after pachopanip treatment. From these results, it was confirmed that patients with BRAF V600E mutation were resistant to pachopanip.

Experimental Example  2. In Pazopanip  In exceptional susceptibility (reactivity) patients MAPKAPK5  Mutation analysis

A total gene sequence analysis of an exceptional susceptibility (reactivity) patient to pazopanib showed that 272 repeat mutant genes were not identified. The gene samples of the patients were subjected to four signal transduction processes (hsa04010, MAPK signaling pathway, hsa04020, calcium signaling pathway, hsa04060, hsa05200, hsa05200, pathways in cancer ) Were analyzed for the mutation status of the genes involved. As a result, a novel p.I16fs MAPKAPK5 mutation (deletion of T, nucleotide 47 of SEQ ID NO: 2) was confirmed in a patient with pancreatic NET and it was confirmed that the mutation had sensitivity to pachopanip.

These results indicate that resistance or susceptibility to pachopanip is different depending on the presence or absence of mutations in specific genes. Using these results, we can predict early and effective patients with high resistance or sensitivity to specific anticancer agents , It was confirmed that the optimal therapeutic effect can be achieved by administering a drug suitable for the patient.

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that such detail is solved by the person skilled in the art without departing from the scope of the invention. will be. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

<110> SAMSUNG LIFE PUBLIC WELFARE FOUNDATION <120> Composition for predicting resistance or susceptibility to          anticancer drugs <130> 1-33 <160> 2 <170> Kopatentin 2.0 <210> 1 <211> 2301 <212> DNA <213> Homo sapiens <400> 1 atggcggcgc tgagcggtgg cggtggtggc ggcgcggagc cgggccaggc tctgttcaac 60 ggggacatgg agcccgaggc cggcgccggc gccggcgccg cggcctcttc ggctgcggac 120 cctgccattc cggaggaggt gtggaatatc aaacaaatga ttaagttgac acaggaacat 180 atagaggccc tattggacaa atttggtggg gagcataatc caccatcaat atatctggag 240 gcctatgaag aatacaccag caagctagat gcactccaac aaagagaaca acagttattg 300 gaatctctgg ggaacggaac tgatttttct gtttctagct ctgcatcaat ggataccgtt 360 acatcttctt cctcttctag cctttcagtg ctaccttcat ctctttcagt ttttcaaaat 420 cccacagatg tggcacggag caaccccaag tcaccacaaa aacctatcgt tagagtcttc 480 ctgcccaaca aacagaggac agtggtacct gcaaggtgtg gagttacagt ccgagacagt 540 ctaaagaaag cactgatgat gagaggtcta atcccagagt gctgtgctgt ttacagaatt 600 caggatggag agaagaaacc aattggttgg gacactgata tttcctggct tactggagaa 660 gaattgcatg tggaagtgtt ggagaatgtt ccacttacaa cacacaactt tgtacgaaaa 720 acgtttttca ccttagcatt ttgtgacttt tgtcgaaagc tgcttttcca gggtttccgc 780 tgtcaaacat gtggttataa atttcaccag cgttgtagta cagaagttcc actgatgtgt 840 gttaattatg accaacttga tttgctgttt gtctccaagt tctttgaaca ccacccaata 900 ccacaggaag aggcgtcctt agcagagact gccctaacat ctggatcatc cccttccgca 960 cccgcctcgg actctattgg gccccaaatt ctcaccagtc cgtctccttc aaaatccatt 1020 ccaattccac agcccttccg accagcagat gaagatcatc gaaatcaatt tgggcaacga 1080 gaccgatcct catcagctcc caatgtgcat ataaacacaa tagaacctgt caatattgat 1140 gacttgatta gagaccaagg atttcgtggt gatggaggat caaccacagg tttgtctgct 1200 accccccctg cctcattacc tggctcacta actaacgtga aagccttaca gaaatctcca 1260 ggacctcagc gagaaaggaa gtcatcttca tcctcagaag acaggaatcg aatgaaaaca 1320 cttggtagac gggactcgag tgatgattgg gagattcctg atgggcagat tacagtggga 1380 caaagaattg gatctggatc atttggaaca gtctacaagg gaaagtggca tggtgatgtg 1440 gcagtgaaaa tgttgaatgt gacagcacct acacctcagc agttacaagc cttcaaaaat 1500 gaagtaggag tactcaggaa aacacgacat gtgaatatcc tactcttcat gggctattcc 1560 acaaagccac aactggctat tgttacccag tggtgtgagg gctccagctt gtatcaccat 1620 ctccatatca ttgagaccaa atttgagatg atcaaactta tagatattgc acgacagact 1680 gcacagggca tggattactt acacgccaag tcaatcatcc acagagacct caagagtaat 1740 aatatatttc ttcatgaaga cctcacagta aaaataggtg attttggtct agctacagtg 1800 aaatctcgat ggagtgggtc ccatcagttt gaacagttgt ctggatccat tttgtggatg 1860 gcaccagaag tcatcagaat gcaagataaa aatccataca gctttcagtc agatgatatat 1920 gcatttggaa ttgttctgta tgaattgatg actggacagt taccttattc aaacatcaac 1980 aacagggacc agataatttt tatggtggga cgaggatacc tgtctccaga tctcagtaag 2040 gtacggagta actgtccaaa agccatgaag agattaatgg cagagtgcct caaaaagaaa 2100 agagatgaga gaccactctt tccccaaatt ctcgcctcta ttgagctgct ggcccgctca 2160 ttgccaaaaa ttcaccgcag tgcatcagaa ccctccttga atcgggctgg tttccaaaca 2220 gaggatttta gtctatatgc ttgtgcttct ccaaaaacac ccatccaggc agggggatat 2280 ggtgcgtttc ctgtccactg a 2301 <210> 2 <211> 1422 <212> DNA <213> Homo sapiens <400> 2 atgtcggagg agagcgacat ggacaaagcc atcaaggaaa cttccatttt agaagaatac 60 agtatcaatt ggactcagaa gctgggagct ggaattagtg gtccagttag agtctgtgta 120 aagaaatcta ctcaagaacg gtttgcgctg aaaattcttc ttgatcgtcc aaaagctaga 180 aatgaggtac gtctgcacat gatgtgtgcc acacacccaa acatagttca gattattgaa 240 gtgtttgcta acagtgtcca gtttccccat gagtccagcc ctagggcccg actcttaatt 300 gtaatggaga tgatggaagg gggagagcta tttcacagaa tcagccagca ccggcacttt 360 acagagaagc aagccagcca agtaacaaag cagatagctt tggctctgcg gcactgtcac 420 ttgttaaaca ttgcgcacag agacctcaag cctgaaaatc tgctttttaa ggataactct 480 ttggatgccc cagtgaagtt gtgtgacttt ggatttgcca agattgacca aggtgacttg 540 atgacacccc agttcacccc ttattatgta gcaccccagg tactggaggc gcaaagaagg 600 catcagaagg agaaatctgg catcatacct acctcaccga cgccctacac ttacaacaag 660 agctgtgact tgtggtccct aggggtgatt atctatgtga tgctgtgcgg ataccctcct 720 ttttactcca aacaccacag ccggactatc ccaaaggata tgcgaagaaa gatcatgaca 780 ggcagttttg agttcccaga ggaagagtgg agtcagatct cagagatggc caaagatgtt 840 gtgaggaagc tcctgaaggt caaaccggag gagagactca ccatcgaggg agtgctggac 900 cacccctggc tcaattccac cgaggccctg gataatgtgc tgccttctgc tcagctgatg 960 atggacaagg cagtggttgc aggaatccag caggctcacg cggaacagtt ggccaacatg 1020 agaatccagg atctgaaagt cagcctcaaa cccctgcact cagtgaacaa ccccattctg 1080 cggaagagga agttacttgg caccaagcca aaggacagtg tctatatcca cgaccatgag 1140 aatggagccg aggattccaa tgttgccttg gaaaaactcc gagatgtgat tgctcagtgt 1200 attctccccc aggctggtaa aggagagaat gaagatgaga aactgaatga agtaatgcag 1260 gaggcttgga agtataaccg ggaatgcaaa ctcctaagag atactctgca gagcttcagc 1320 tggaatggtc gtggattcac agataaagta gatcgactaa aactggcaga aattgtgaag 1380 caggtgatag aagagcaaac cacgtcccac gaatcccaat aa 1422

Claims (9)

A composition for predicting anticancer resistance or sensitivity, comprising a polynucleotide consisting of 10 to 100 consecutive DNA sequences or a complementary polynucleotide thereof, comprising the 1799th nucleotide of SEQ ID NO: 1 or the 47th nucleotide region of SEQ ID NO: as,
Wherein the anticancer agent is a parasopanib represented by the following formula (1)
Wherein the anticancer agent is a therapeutic agent for gastroenteropancreatic neuroendocrine tumors (GET-NETs), neuroendocrine tumors.
[Chemical Formula 1]

delete delete delete A kit for anticancer drug resistance or sensitivity prediction comprising the composition according to claim 1.
Identifying the 1799th nucleotide of SEQ ID NO: 1 or the 47th nucleotide region of SEQ ID NO: 2 from the sample DNA, the method comprising:
The anticancer agent is a pachoparamip represented by the following formula (1)
Wherein the anticancer agent is a therapeutic agent for gastroenteropancreatic neuroendocrine tumors (GET-NETs), neuroendocrine tumors.
[Chemical Formula 1]

7. The method according to claim 6, wherein the method predicts that when the 1799th nucleotide of SEQ ID NO: 1 is A, it is predicted to be resistant to an anticancer agent.
7. The method according to claim 6, wherein the method predicts that the 47th nucleotide of SEQ ID NO: 2 is missing, the sensitivity to the anticancer agent is predicted.
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