KR20170131862A - SNP markers for predicting clinical response to anticancer drugs and prognosis in patients with non-small cell lung cancer and uses thereof - Google Patents

Abstract

The present invention relates to two SNP markers existing in 3-UTR of PD-L1 gene, and an information providing method for predicting response and prognosis with respect to anticancer agent treatment of patients with non-small cell lung cancer using the same. Specific genotypes of the SNP markers of the present invention have a significant correlation with response and survival prognosis with respect to paclitaxel-cisplatin anticancer agent treatment of patients with non-small cell lung cancer, thereby being used for conveniently and effectively predicting reactivity with respect to an anticancer agent and survival time of patients with non-small cell lung cancer.

Description

[0001] SNP markers for predicting the response and prognosis of anticancer drugs in non-small cell lung cancer patients and their use [0002]

The present invention relates to single nucleotide polymorphism (SNP) markers and their uses for anticancer drug response and prognosis prediction in patients with non-small cell lung cancer. More specifically, the present invention relates to two SNP markers present in the 3'-UTR of the PD-L1 gene, and a method of providing information for predicting the response and prognosis of anticancer drugs in patients with non-small cell lung cancer.

Lung cancer is one of the major causes of death in the world. It is classified into non-small cell lung cancer (NSCLC) and small cell lung cancer based on the size and shape of cancer cells. About 80% to 85% of lung cancers are known as non-small cell carcinoma, which is divided into squamous cell carcinoma, adenocarcinoma (large adenocarcinoma), and large cell carcinoma. Non-small cell lung cancer has a low survival rate of 15% with an average 5-year survival rate. The reason for the low survival rate of lung cancer is that a large number of patients have unresectable tumors. Although pathologic staging is currently used to predict the prognosis of lung cancer patients, there is a significant difference in the recurrence of lung cancer and the survival rate of patients in the same stage. Although chemotherapy with anticancer drugs such as paclitaxel and cisplatin is used most frequently in patients with end stage non-small cell carcinoma, the response to chemotherapy varies among patients with similar clinical characteristics, and patients with the same stage There is a significant difference in the survival period of the patients, and the overall treatment effect and prognosis is not good. Therefore, it is necessary to develop a customized diagnostic method for predicting the clinical outcome and prognosis of chemotherapy for non-small cell lung cancer and to select patients effective for specific drugs. One of the means is biomarkers such as SNPs.

- Korean Patent Publication No. 10-2015-0131269 "Biomarkers and methods for treating PD-1 and PD-L1 related conditions" - Korean Patent Publication No. 10-2014-0085880 "Marker for anticancer drug response and survival prognosis prediction of lung cancer patients" - Korean Patent Publication No. 10-2010-0136724 "BRCA1 gene haplotype marker associated with survival time of non-small cell lung cancer patients and use thereof"

- Cheng S., et al. PD-L1 gene polymorphism and high level of plasma soluble PD-L1 protein may be associated with non-small cell lung cancer, The International Journal of Biological Markers 2015; 30 (4): e364-e368.

It is an object of the present invention to provide novel single nucleotide polymorphism (SNP) markers for predicting the response and prognosis for anticancer drug therapy in patients with non-small cell lung cancer.

Another object of the present invention is to provide a method of providing information for predicting the response and prognosis of chemotherapeutic treatment of patients with non-small cell lung cancer using the marker.

It is still another object of the present invention to provide a composition, a kit and a microarray for predicting the prognosis of non-small cell lung cancer using the marker.

In order to achieve the above object, the present invention provides SNP markers for predicting the response and prognosis of anticancer drug treatment in non-small cell lung cancer patients. The SNP marker of the present invention comprises a SNP (NCBI refSNP ID: rs2297136) located at the 546th base of the nucleotide sequence shown in SEQ ID NO: 1 and a SNP (NCBI refSNP ID: rs2297136) located at the 257th nucleotide of the nucleotide sequence shown in SEQ ID NO: NCBI refSNP ID: rs4143815). The SNP (NCBI refSNP ID: rs2297136) located in the 546th base of the nucleotide sequence shown in SEQ ID NO: 1 is a 3'-amino acid sequence of the PD-L1 (Genebank accession No. NT_008413.19) It is present in the untranslated region (UTR) and corresponds to the +93th base from the end of the termination codon. In addition, the SNP (NCBI refSNP ID: rs4143815) located at the 257th base of the nucleotide sequence of SEQ ID NO: 2 is also present at the 3'-untranslated region of the PD-L1 gene, .

The refSNP ID of the NCBI for each SNP indicates the sequence and the position of the SNP. If a person skilled in the art knows the position and sequence of the SNP using the number . However, the specific sequence corresponding to the refSNP ID of the SNP registered in the NCBI may be slightly changed according to the result of continuous research on the gene, but such modified sequence should also be construed as being included within the scope of the present invention. In this specification, the SNP located at the 546th base of SEQ ID NO: 1 can be described as "rs2297136T> C" using refSNP ID, and the SNP located at the 257th base of SEQ ID NO: 2 is "rs4143815C> G" ≪ / RTI >

In one embodiment of the present invention, the SNP marker is a polynucleotide having a 546th base of T or C in the polynucleotide represented by SEQ ID NO: 1, and 10-100 consecutive DNA sequences including the 546th base Nucleotides; A polynucleotide consisting of 10-100 consecutive DNA sequences, wherein the 257th base is C or G in the polynucleotide represented by SEQ ID NO: 2, and the 257th base; And complementary polynucleotides thereof. The term " polynucleotide " However, the length of the polynucleotide or the complementary polynucleotide thereof may be changed as needed. The present invention relates to a base mutant at each SNP position in each of the nucleotide sequences of SEQ ID NOS: 1 and 2, but when such a SNP base mutation is found in a double-stranded gDNA (genomic DNA), the complementary nucleotide sequence complementary to the polynucleotide sequence It is also interpreted to include polynucleotide sequences. Thus, the base at the SNP position in the complementary polynucleotide sequence is a complementary base.

The present inventors collected potential functional polymorphisms from PD-1 , PD-L1 and CTLA- 4 genes to develop a biomarker that can easily predict the reactivity and survival prognosis of patients with non-small cell lung cancer. And 12 SNP candidate groups were selected (Table 2). We then analyzed the genotypes of the SNPs from DNA extracted from samples from patients with non-small cell lung cancer who received the first treatment with paclitaxel-cisplatin combination therapy, and analyzed the association between response to chemotherapy and overall survival. The "rs2297136T>C" was significantly associated with the response to chemotherapy and overall survival in the additive model for the C genotype, while "rs4143815C>G" (See Table 3 and Figures 1 to 3). ≪ tb >< TABLE > Furthermore, the present inventors confirmed that the haplotype comprising the combination of the SNPs of the present invention can discriminate with high accuracy the chemotherapeutic response and the survival period of patients with non-small cell lung cancer. That is, the rs2297136C-rs4143815G haplotype4, ht4 having mutant genotypes in all of the two SNPs are different from the other haplotypes (rs2297136T-rs4143815C (ht1), rs2297136T-rs4143815G (ht2), and rs2297136C-rs4143815C In comparison, chemotherapy response and overall survival were significantly associated with better outcomes (see Table 4).

Therefore, the present invention relates to a sample obtained from a subject patient, a SNP (NCBI refSNP ID: rs2297136) located in base No. 546 of the nucleotide sequence shown in SEQ ID NO: 1 and a nucleotide sequence (NCBI refSNP ID: rs4143815), which comprises the step of identifying the base of the SNP located in the base (NCBI refSNP ID: rs4143815).

In one embodiment of the present invention, the subject is preferably a non-small cell lung cancer patient who has received the first treatment with paclitaxel-cisplatin combination therapy. The term "prognosis" in the present invention means the progression and cure of the disease, such as lung cancer-induced death or the possibility of progression including lung cancer incidence, recurrence, metastatic spread and drug resistance. In one embodiment of the present invention, the prognosis refers to the response of a non-small cell lung cancer to an anticancer agent and the survival prognosis thereof, and preferably the prognosis of patients with non-small cell lung cancer treated first with paclitaxel-cisplatin chemotherapy it means.

In one embodiment of the present invention, the method comprises the step of detecting a haplotype in which the base at position of SNP (rs2297136) in SEQ ID NO: 1 is C and the base at position of SNP (rs4143815) in SEQ ID NO: 2 is G . ≪ / RTI > As used herein, the term " haplotype " In other words, a series of SNPs located on one chromosome at the time of germ cell division may be divided into several bundles according to their inherited associations. Each bundle is called a haplotype, and this haplotype is present on the same chromosome A certain SNP pattern is displayed as a combination of several SNPs.

In an embodiment of the present invention, the method is characterized in that, in the case of a patient having at least one copy of the haplotype, the patient is relatively more responsive to the anticancer drug treatment than the patient who does not have the haplotype, Or predicting that a patient having only a haplotype other than the haplotype is less responsive to the anticancer treatment and has a shorter survival time than the patient having the haplotype . In this case, since the response to paclitaxel-cisplatin anticancer therapy is low and the survival period is expected to be short, patients who do not have the haplotype are expected to use other secondary drugs or treatment methods in addition to chemotherapy by the drug Can be considered.

In one embodiment of the present invention, the sample of the patient may be a nucleic acid sample. As used herein, the term "nucleic acid" has the meaning inclusive of DNA (gDNA and cDNA) and RNA molecules. In one embodiment of the present invention, the nucleic acid can be obtained from various body parts of a patient with arsenic lung cancer, such as muscles, epidermis, blood, bones, organs, preferably from muscles or blood. The nucleic acid can be separated according to the kind of the starting material by a conventional method known in the art. For example, when the starting material is mRNA, the total RNA may be isolated according to a conventional method known in the art, and the separated total RNA may be synthesized by using reverse transcriptase. In the present invention, a method of identifying a SNP base type from a separated nucleic acid molecule can also be performed by applying various methods known in the art. For example, single base primer extension assay, fluorescence in situ hybridization (FISH), direct DNA sequencing, PFGE analysis, Southern blot analysis, single-strand conformational analysis (SSCA, Orita et al. , DNAS, USA 86: 2776 (1989)), RNase protection analysis (Finkelstein et al., Genomics, 7: 167 (1990)), dot blot analysis, denaturing gradient gel electrophoresis (DGGE, Wartell et al., Nucl. (Modrich, Ann. Rev. Genet., 25: 229-253 (1991)) using a protein recognizing a nucleotide mismatch (e.g., mutS protein of E. coli) ), And allele-specific PCR, but are not limited thereto. The genotypes of the SNPs of the present invention can be confirmed by sequencing analysis, sequencing analysis using an automatic nucleotide sequence analyzer, pyrosequencing, hybridization with a microarray, PCR-RELP (restriction fragment length polymorphism), 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 But the present invention is not limited thereto, for example, by a known method such as rolling circle amplification, high resolution melting (HRM), primer extension, Southern blot hybridization or dot hybridization. In addition, the SNP analysis result can be statistically processed using a statistical analysis method commonly used in the art.

The present invention also provides a composition for the prognosis of non-small cell lung cancer, which comprises a substance for identifying a base of the SNP of the present invention. In one embodiment of the present invention, the composition is a polynucleotide having a 546th base of T or C in the polynucleotide of SEQ ID NO: 1, and a 10-100 consecutive DNA sequences comprising the 546th base ; A polynucleotide consisting of 10-100 consecutive DNA sequences, wherein the 257th base is C or G in the polynucleotide represented by SEQ ID NO: 2, and the 257th base; And complementary polynucleotides thereof. The term " polynucleotide "

The present invention also provides a polynucleotide comprising a SNP (rs2297136) located in the 546th base of SEQ ID NO: 1; And a primer or a probe set capable of amplifying a polynucleotide comprising a SNP (rs4143815) located in the 257th base of SEQ ID NO: 2.

As used herein, the term "probe" means a linear oligomer with a natural or modified monomer or linkage comprising a deoxyribonucleotide and a ribonucleotide that can hybridize to a particular nucleotide sequence. The probe is preferably a single strand, preferably a deoxyribonucleotide, for maximum efficiency in hybridization. As the probe used in the present invention, a sequence complementary to the sequence including the SNP may be used, but a sequence substantially complementary to the sequence that does not interfere with the specific hybridization is used It is possible. Suitable conditions for hybridization can be determined by methods known in the art such as those described in Joseph Sambrook, et al., Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, Nucleic Acid Hybridization, A Practical Approach, IRL Press, Washington, DC (1985). ≪ / RTI > The stringent condition used for hybridization can be determined by controlling the temperature, the ionic strength (buffer concentration) and the presence of a compound such as an organic solvent, and such stringent conditions can be determined differently depending on the sequence to be hybridized. As used herein, the term " primer " refers to a single strand of oligonucleotides that is hybridized under suitable conditions (the presence of four different nucleoside triphosphates and a polymerase such as DNA or RNA polymerase) Quot; means acting as a starting point for initiating template-directed DNA synthesis under the buffer. The suitable length of the primer is determined by the characteristics of the primer to be used, but is usually 15 to 30 bp in length. The primer need not be exactly complementary to the sequence of the template, but should be complementary enough to form a hybrid-complex with the template. In one embodiment of the present invention, the primer or probe is an allele-specific primer or probe.

In one embodiment of the present invention, the kit comprises the essential elements necessary to perform a PCR reaction, such as test tubes, reaction buffers (varying in pH and magnesium concentration), deoxynucleotides (dNTPs), Taq polymerases and Enzymes such as reverse transcriptase, DNase, RNAse inhibitors, DEPC-water and sterile water.

Also, the present invention provides a polynucleotide comprising a polynucleotide of SEQ ID NO: 1, wherein the 546th base is T or C, and the polynucleotide comprises 10-100 consecutive DNA sequences comprising the 546th base; A polynucleotide consisting of 10-100 consecutive DNA sequences, wherein the 257th base is C or G in the polynucleotide represented by SEQ ID NO: 2, and the 257th base; And a complementary polynucleotide thereof, a polypeptide specifically encoded by the polynucleotide, or a cDNA thereof, for the prognosis of non-small cell lung cancer.

In one embodiment of the present invention, the microarray may be a conventional microarray except that it comprises the polynucleotide, polypeptide, cDNA, etc., and hybridization and hybridization of the nucleic acid on the microarray may be detected Can be carried out by methods known in the art. For example, the detection can be accomplished by labeling the nucleic acid sample with a labeling substance capable of generating a detectable signal comprising a fluorescent material, such as Cy3 and Cy5, and then hybridizing onto the microarray, A signal can be detected.

The specific genotype of the SNP markers of the present invention was found to be significantly correlated with the response to paclitaxel-cisplatin chemotherapy and the survival prognosis of patients with non-small cell lung cancer. Therefore, the present invention can be used for effectively and effectively predicting the response and survival period of anticancer drugs in non-small cell lung cancer patients, thereby effectively improving the treatment method for the patients.

FIG. 1 shows the overall survival Kaplan-Meier plot according to diploids of PD-L1 rs2297136T> C (A) and rs2297136T> C and rs4143815C> G. ( P value for multivariate Cox proportional hazards model)
Fig. 2 shows the DNA sequence of the SNP (rs2297136) in which the 546th base is T or C in the polynucleotide shown in SEQ ID NO: 1.
Fig. 3 shows the DNA sequence of the SNP (rs4143815) in which the 257th base is C or G in the polynucleotide shown in SEQ ID NO: 2.

Hereinafter, the present invention will be described in more detail with reference to Examples. These embodiments are only for illustrating the present invention, and thus the scope of the present invention is not construed as being limited by these embodiments.

< Example  1>

Materials and Methods

<1-1> Study group and evaluation standard

A total of 379 patients with stage III or IV non - small cell lung cancer who received at least 2 cycles of paclitaxel - cisplatin as a primary treatment at Kyungpook National University Hospital in Daegu from August 2005 to December 2008 were enrolled. Patients who received radiation therapy at the same time as chemotherapy as the primary treatment modality were excluded to avoid confounding effects of radiation on chemotherapy response. Combination chemotherapy was conducted in three weeks the first day method for intravenous administration over paclitaxel 175mg / m ² by intravenous administration, and cisplatin 60mg / m ² over a period of 3 hours 60 minutes every 3 weeks. Treatment was discontinued following disease progression, major toxicities, or patient and physician decisions. The determination of tumor response was made by computed tomography every two cycles.

Responses were assessed using response criteria for solid tumors. The best overall response to individual patients was recorded, and all evaluation responses were reviewed by an independent radiologist. A complete response (CR) or partial response (PR) is defined as responders, and stable disease (SD) or progressive disease (PD) is defined as non-responders. For the assessment of survival outcomes, an overall survival (OS) assessment was defined as the time between the day the chemotherapy was started and the date of death or the last study day.

Genomic DNA samples from patients were obtained from KNUH (Korea Human Resource Bank, Kyungpook National University Hospital), which is supported by Ministry of Health, Welfare and Family Affairs. This study was conducted with the approval of the Clinical Experimental Review Committee of Kyungpook National University Hospital. The study was conducted according to the approved guidelines of the clinical trial committee and all patients received consent.

<1-2> Selection of single nucleotide polymorphism and genotype analysis

The NCBI database ( http://www.ncbi.nlm.nih.gov/SNP ) and related literature were searched to collect potential functional polymorphisms from PD-1 , PD-L1 , and CTLA- 4 genes. The choice of single nucleotide polymorphism is primarily based on the location of the single nucleotide polymorphism (whether it is located in the coding region of the promoter or untranslated region or gene), whether it was previously associated with cancer, and whether it has evidence that it is functionally important lost. As a result, all 12 polymorphisms were selected, and those with a frequency (MAF) of 5% or more of minority alleles in Hapmap's Japanese genotype data (JTP) were selected and those with linkage disequilibrium coefficient r ² . Eleven polymorphisms were identified using SEQUENOM 's MassARRAY ^® iPLEX assay (SEQUENOM Inc., San Diego, Calif.), And rs4143815 was genotyped using Taqman analysis.

<1-3> Statistical analysis

The Hardy-Weinberg equation (Hardy-Weinberg equlibrium) used a fit test with a degree of freedom of 1 χ2 test. Haploview (http://broad.mit.edu/mpg/haploview) was used for linkage disequilibrium between polymorphisms. Haplotypes and frequency were used in the phase program. The genotypes for each polymorphism were analyzed for variation between the three groups, and the right molding, thermoforming, and hybrid models were also analyzed. The association between clinical variability and chemotherapy, or association between genotype and chemotherapy, was verified by odds ratio (OR), 95% confidence intervals (CIs) using unconditional logistic regression analysis. The Kaplan-Meier method was used for survival analysis. Differences in overall survival (OS) with differences in clinical factors were compared using a log-rank test. Cox proportional hazards models were used for multivariate survival analysis and hazard ratios (HR) and 95% confidence intervals (CIs) were obtained.

A P value 0.05 cut-off was applied to all statistical analyzes. Statistical data were analyzed using the Statistical Analysis System for Windows (version 9.2) [SAS Institute, USA].

< Example  2>

Patient characteristics and clinical Predictive factors

Table 1 shows the relationship between clinical pathological characteristics, response to chemotherapy, and overall survival in the experimental subjects. The overall response rate was 47.5%. Of the 379 patients, 347 (91.6%) died and the median survival time was 13.2 months (95% confidence interval = 12.5 to 14.7 months). Only the histological type of cancer was significantly associated with the response to chemotherapy. Overall survival was significantly associated with age, sex, smoking status, cancer histology, weight loss, and second - line chemotherapy.

< Example  3>

Correlation between single nucleotide polymorphisms and clinical outcomes

The summary of 12 single nucleotide polymorphisms, including single nucleotide polymorphism identification number, genetic information, and frequency of minor alleles, and their correlation with chemotherapy response and overall survival are shown in Table 2 .

Analysis of the 12 polymorphisms revealed that rs2297136T> C and rs4143815C> G located in the 3 'untranslated region (UTR) of the PD-L1 gene were significantly associated with the clinical outcome after chemotherapy. In other words, rs2297136T> C was associated with a better response to chemotherapy and better overall survival in the additive model for C genotype (adjusted odds ratio [aOR] = 1.82 , 95% confidence interval = 1.19-2.77, P = 0.01, corrected hazard ratio [aHR] = 0.76, 95% confidence interval = 0.61-0.94, p = 0.01, respectively), rs4143815C> (AOR = 1.42, 95% confidence interval = 1.05-1.93, P = 0.02) and was not significantly associated with overall survival (see Table 3 and Figure 1A).

< Example  4>

rs2297136T > C and rs4143815C > G Haplotype and  Correlation of clinical outcomes

The two polymorphic, rs2297136T> C and rs4143815C> G By accounting for 99.3% of the haplotypes in the three dominant haplotype in the subject, there is a LD ^{(| = 0.9, r 2 =} 0.22 | D '). Consistent with the individual genotyping analysis, the rs2297136C-rs4143815G haplotype4, ht4, with variant genotypes on the two genes, was found in the other haplotypes rs2297136T-rs4143815C (ht1), rs2297136T-rs4143815G (ht2), and rs2297136C- rs4143815C (AOR = 1.92, 95% CI = 1.27-2.91, P = 0.002, aHR = 0.76, 95% CI = 0.61-0.94) in comparison with chemotherapy response and overall survival , P = 0.01, see Table 4).

Next, survival results of patients with ht4 were analyzed. For analysis, the diploids derived from the four haplotypes were categorized into three groups according to whether ht4 was 0, 1 or 2 (ie, diploid 1 [dt1], ht1- 3 / ht1-3; dt2, ht1-3 / ht4; dt3, ht4 / ht4). Dt2 or dt3 with at least one ht4 was significantly associated with better chemotherapy response and overall survival compared to dt1 without ht4 (aOR = 2.13, 95% confidence interval = 1.33-3.40, P = 0.002; aHR = 0.74, 95% confidence interval = 0.58-0.95, P = 0.016, Table 4 and FIG. 1B).

The present invention has been described with reference to the preferred embodiments. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. Therefore, the disclosed embodiments should be considered in an illustrative rather than a restrictive sense. The scope of the present invention is defined by the appended claims rather than by the foregoing description, and all differences within the scope of equivalents thereof should be construed as being included in the present invention.

<110> Kyungpook National University Industry-Academic Cooperation Foundation <120> SNP markers for predicting clinical response to anticancer drugs          and prognosis in patients with non-small cell lung cancer          uses thereof <130> PN1601-023 <160> 2 <170> Kopatentin 2.0 <210> 1 <211> 1000 <212> DNA <213> 5457501-458500 of Gene Bank Acession #: NT_008413.19 from Homo sapiens <220> <221> variation <222> (546) <223> y is t or c <400> 1 agttatagag gagaccaagc accttacaaa tactccatgt tttactagat gtgagcaaat 60 cattaagcag caagtttagt ttggcgacaa aattgtaaca tctactacaa tatatcttca 120 aaagaaatca ttcacaacca cactcacatg acaagaagac ctcacagact caaaataaat 180 aggaaaaact catacataaa tactgtcccg ttccaacact gagactctca gtcatgcaga 240 aaacaaattg aggcattgag tggaggcaaa gggcacttct gcaggaactg accctcaaat 300 tagggattct caacccgtct tcctaggatg agcaatggat gatttgcttg gaggctcctt 360 gttcagaagt atcctttctc cctgtcacag gcgtcgatga gcccctcagg catttgaaag 420 tatcaaggtc tccctccagg ctccctgttt gactccatct ttcttcattc tcctcctctg 480 ctttcgccag gttccatttt cagtgcttgg gccttttaag tcccacattg cctgcatccc 540 acgggyccat tccttcctct tgtcacgctc agccccgatg aacccctaaa ccacaggttg 600 agaatccctg cttgaagatc agaagttcca atgctggatt acgtctcctc caaatgtgta 660 tctggagagt gataatagta tattaatttc atgggaagtg gtctggggaa aaagtaacaa 720 gaaatctaat aaaaaacata actcatagtt gctgatatga taaatgataa atttgaaatg 780 agagaaagca gcaggttata tttgtaccca attatcctta catgatatcc tggaaaaccc 840 ctcagtcctg agcaaattgg gatggcttgt cccccagcat gacccaaaca acatttgcta 900 cttagcttta caacacagat gatgctatgg gccacagaat gaaacttgcc tgagcttgtc 960 caggttaatt agactgcttt aaacttgggc tcattgttaa 1000 <210> 2 <211> 1000 <212> DNA <213> 5458001-459000 of Gene Bank Acession #: NT_008413.19 from Homo sapiens <220> <221> variation <222> (257) <223> y is c or g <400> 2 aaaatggaac ctggcgaaag cagaggagga gaatgaagaa agatggagtc aaacagggag 60 cctggaggga gaccttgata ctttcaaatg cctgaggggc tcatcgacgc ctgtgacagg 120 gagaaaggat acttctgaac aaggagcctc caagcaaatc atccattgct catcctagga 180 agacgggttg agaatcccta atttgagggt cagttcctgc agaagtgccc tttgcctcca 240 ctcaatgcct caatttyttt tctgcatgac tgagagtctc agtgttggaa cgggacagta 300 tttatgtatg agtttttcct atttattttg agtctgtgag gtcttcttgt catgtgagtg 360 tggttgtgaa tgatttcttt tgaagatata ttgtagtaga tgttacaatt ttgtcgccaa 420 actaaacttg ctgcttaatg atttgctcac atctagtaaa acatggagta tttgtaaggt 480 gcttggtctc ctctataact acaagtatac attggaagca taaagatcaa accgttggtt 540 gcataggatg tcacctttat ttaacccatt aatactctgg ttgacctaat cttattctca 600 gacctcaagt gtctgtgcag tatctgttcc atttaaatat cagctttaca attatgtggt 660 agcctacaca cataatctca tttcatcgct gtaaccaccc tgttgtgata accactatta 720 ttttacccat cgtacagctg aggaagcaaa cagattaagt aacttgccca aaccagtaaa 780 tagcagacct cagactgcca cccactgtcc ttttataata caatttacag ctatatttta 840 ctttaagcaa ttcttttatt caaaaaccat ttattaagtg cccttgcaat atcaatcgct 900 gtgccaggca ttgaatctac agatgtgagc aagacaaagt acctgtcctc aaggagctca 960 tagtataatg aggagattaa caagaaaatg tattattaca 1000

Claims (9)

With respect to the sample obtained from the subject patient,
A SNP (NCBI refSNP ID: rs2297136) located in the 546th base of the nucleotide sequence shown in SEQ ID NO: 1 and a SNP (NCBI refSNP ID: rs4143815) located in the 257th base of the nucleotide sequence shown in SEQ ID NO: &Lt; / RTI &gt;
Methods for providing information for predicting the response and prognosis of anticancer therapy in patients with non - small cell lung cancer. The method according to claim 1,
Wherein the anticancer agent is paclitaxel and cisplatin. The method according to claim 1,
Detecting a haplotype in which the base at the position of the SNP (rs2297136) of SEQ ID NO: 1 is C and the base at the position of SNP (rs4143815) of SEQ ID NO: 2 is G. The method of claim 3,
In the case of a patient having more than one copy of the haplotype, it is predicted that the response to the anticancer drug treatment is relatively high and the survival period is relatively longer than that of the patient who does not have the haplotype, or a haplotype The method comprising predicting that a patient having only a relatively low response to chemotherapy treatment and a relatively short survival time. A polynucleotide consisting of 10-100 consecutive DNA sequences, wherein the 546th base is T or C in the polynucleotide represented by SEQ ID NO: 1, and the 546th base; A polynucleotide consisting of 10-100 consecutive DNA sequences, wherein the 257th base is C or G in the polynucleotide represented by SEQ ID NO: 2, and the 257th base; And at least one polynucleotide selected from the group consisting of complementary polynucleotides thereof. A polynucleotide consisting of 10-100 consecutive DNA sequences, wherein the 546th base is T or C in the polynucleotide represented by SEQ ID NO: 1, and the 546th base; A polynucleotide consisting of 10-100 consecutive DNA sequences, wherein the 257th base is C or G in the polynucleotide represented by SEQ ID NO: 2, and the 257th base; And at least one polynucleotide selected from the group consisting of complementary polynucleotides thereof. A polynucleotide comprising a SNP (rs2297136) located in the 546th base of SEQ ID NO: 1; And a primer or a probe set capable of amplifying a polynucleotide comprising a SNP (rs4143815) located in the 257th base of SEQ ID NO: 2. 8. The method of claim 7,
Wherein the primer or probe is an allele-specific primer or a probe. A microarray for predicting the prognosis of non-small cell lung cancer comprising the polynucleotide of claim 5, a polypeptide specifically encoded thereby, or a cDNA thereof.

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