KR20220122269A - Diagnostic methods for prognosis of small-cell lung cancer using CD155 and CD226 SNP - Google Patents
Diagnostic methods for prognosis of small-cell lung cancer using CD155 and CD226 SNP Download PDFInfo
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- KR20220122269A KR20220122269A KR1020210026686A KR20210026686A KR20220122269A KR 20220122269 A KR20220122269 A KR 20220122269A KR 1020210026686 A KR1020210026686 A KR 1020210026686A KR 20210026686 A KR20210026686 A KR 20210026686A KR 20220122269 A KR20220122269 A KR 20220122269A
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- lung cancer
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- small cell
- single nucleotide
- polymorphism
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Abstract
Description
본 발명은 CD155 및 CD226의 단일염기다형성을 이용한 소세포폐암의 예후 진단방법에 관한 것으로, 구체적으로 CD155의 rs1058402G>A 및 CD226의 rs763361C>T 단일염기다형성을 이용하여 소세포폐암의 생존 예후를 진단 또는 예측하는 방법 및 이의 용도에 관한 것이다.The present invention relates to a method for diagnosing the prognosis of small cell lung cancer using single nucleotide polymorphisms of CD155 and CD226, and specifically, diagnosing or predicting survival prognosis of small cell lung cancer using single nucleotide polymorphisms rs1058402G>A of CD155 and rs763361C>T of CD226 It relates to methods and uses thereof.
폐암은 전 세계적으로 암 관련 사망의 주요 원인으로 알려져 있으며, 폐암은 비소세포 폐암 (NSCLC)과 소세포 폐암 (SCLC)의 두 가지 유형으로 나뉜다. 초기 단계에서 수술이 최선의 치료 옵션인 비소세포폐암은 모든 폐암의 약 85 %를 차지한다. Lung cancer is known to be the leading cause of cancer-related death worldwide, and lung cancer is divided into two types: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Non-small cell lung cancer, for which surgery is the best treatment option at an early stage, accounts for about 85% of all lung cancers.
한편, 소세포폐암은 모든 폐암의 약 15 %를 차지하는 매우 공격적인 암종이다. 소세포폐암은 신경 내분비 세포에서 유래된 것으로 예측되며, 빠른 종양 형성, 전이 및 재발률이 높은 특징을 가진다. 소세포폐암 환자의 생존과 치료 방법은 지속적으로 연구 중인 분야이다.On the other hand, small cell lung cancer is a very aggressive carcinoma, accounting for about 15% of all lung cancers. Small cell lung cancer is predicted to be derived from neuroendocrine cells, and has a high rate of rapid tumor formation, metastasis, and recurrence. Survival and treatment methods for patients with small cell lung cancer are areas of ongoing research.
또한, 암은 흔히 국소적으로 재발하거나 본래의 암 조직으로부터 원거리의 조직 및 기관으로 전이하는 특성을 가지며, 병기에 따라 치료방법을 적절하게 선택하여야 효과적인 치료가 가능한 질병이기 때문에, 치료방법에 대한 예후를 예측하는 것이 매우 중요하다.In addition, since cancer often recurs locally or metastasizes to distant tissues and organs from the original cancer tissue, it is a disease that can be effectively treated only when a treatment method is appropriately selected according to the stage. It is very important to predict
폐암의 이상적인 치료법은 조기 발견하여 수술로 완전히 암을 제거하는 것이지만, 폐암의 진단 시 환자의 반수 이상이 수술을 할 수 없을 정도로 진행된 상태이므로 조기치료는 현실적으로 어렵다. 또한, 폐암 발병 후의 경우, 특히 소세포암은 발견 시 외과적 수술을 통해 치료할 수 있는 가능성이 극히 적다. 현재 임상적 진단 방법으로는 재발할 가능성이 높은 환자에 대해 보다 공격적인 치료요법을 지시하기에 충분한 정확도로 조기 소세포폐암의 예후를 확인할 수 없다.The ideal treatment for lung cancer is to detect it early and completely remove the cancer with surgery. In addition, after the onset of lung cancer, especially small cell cancer, there is very little possibility that it can be treated through surgical operation when it is detected. Current clinical diagnostic methods cannot confirm the prognosis of early small cell lung cancer with sufficient accuracy to instruct more aggressive therapy for patients with a high risk of relapse.
따라서, 병기 및 특성에 따라 화학 치료요법의 종류를 결정하여 치료 방법을 적용할 필요가 있고, 추가 필요한 치료 방법의 사용 여부를 손쉽게 결정할 수 있도록 소세포폐암 환자의 예후를 정확하고 신속하게 판단할 수 있는 진단기술이 필요한 실정이다.Therefore, it is necessary to apply a treatment method by determining the type of chemotherapy according to the stage and characteristics, and it is necessary to determine the prognosis of small cell lung cancer patients accurately and quickly so that it is easy to determine whether to use additional necessary treatment methods. There is a need for diagnostic technology.
이에 본 발명자들은 소세포폐암(SCLC)의 발생 및 진행과 관련 있는 새로운 진단마커로서 CD155의 rs1058402G>A 단일염기다형성 또는 CD226의 rs763361C>T 단일염기다형성을 사용할 수 있으며, 이들 다형성의 특정 유전자형과 소세포폐암 환자의 생존 예후와의 관련성을 규명함으로써 본 발명을 완성하였다. Accordingly, the present inventors can use the rs1058402G>A single nucleotide polymorphism of CD155 or the rs763361C>T polymorphism of CD226 as a new diagnostic marker related to the development and progression of small cell lung cancer (SCLC), and specific genotypes of these polymorphisms and small cell lung cancer The present invention was completed by identifying the relevance to the patient's survival prognosis.
따라서 본 발명의 목적은 CD155의 rs1058402G>A 단일염기다형성 및 CD226의 rs763361C>T 단일염기다형성으로 이루어진 군 중에서 선택되는 하나 이상의 단일염기다형성을 포함하는 소세포폐암 예후 진단 및 예측을 위한 마커용 조성물을 제공하는 것이다.Accordingly, it is an object of the present invention to provide a marker composition for prognosis and prediction of small cell lung cancer comprising at least one single nucleotide polymorphism selected from the group consisting of rs1058402G>A single nucleotide polymorphism of CD155 and rs763361C>T single nucleotide polymorphism of CD226 will do
본 발명의 다른 목적은 CD155의 rs1058402G>A 단일염기다형성 및 CD226의 rs763361C>T 단일염기다형성으로 이루어진 군 중에서 선택되는 하나 이상의 단일염기다형성을 검출할 수 있는 제제를 포함하는 소세포폐암 환자의 생존 예후 예측용 조성물을 제공하는 것이다.Another object of the present invention is to predict the survival prognosis of a patient with small cell lung cancer, including an agent capable of detecting one or more single nucleotide polymorphisms selected from the group consisting of rs1058402G>A single nucleotide polymorphism of CD155 and rs763361C>T single nucleotide polymorphism of CD226 To provide a composition for
본 발명의 또 다른 목적은 상기 본 발명의 조성물을 포함하는 소세포폐암 환자의 생존 예후 예측용 키트를 제공하는 것이다.Another object of the present invention is to provide a kit for predicting survival prognosis of small cell lung cancer patients comprising the composition of the present invention.
본 발명의 또 다른 목적은 상기 본 발명의 조성물을 포함하는 소세포폐암 환자의 생존 예후 예측용 마이크로어레이를 제공하는 것이다.Another object of the present invention is to provide a microarray for predicting survival prognosis of a patient with small cell lung cancer comprising the composition of the present invention.
본 발명의 또 다른 목적은 검체로부터 추출한 핵산에 대하여, CD155의 rs1058402G>A 단일염기다형성 및 CD226의 rs763361C>T 단일염기다형성을 확인하는 단계를 포함하는, 소세포폐암 환자의 생존 예후 예측을 위한 정보를 제공하는 방법을 제공하는 것이다.Another object of the present invention is to provide information for predicting survival prognosis of patients with small cell lung cancer, including identifying the rs1058402G>A single nucleotide polymorphism of CD155 and the rs763361C>T single nucleotide polymorphism of CD226 with respect to the nucleic acid extracted from the sample. It is to provide a way to provide.
상기 본 발명의 목적을 달성하기 위해, 본 발명은 CD155의 rs1058402G>A 단일염기다형성 및 CD226의 rs763361C>T 단일염기다형성으로 이루어진 군 중에서 선택되는 하나 이상의 단일염기다형성을 포함하는, 소세포폐암 예후 진단 및 예측을 위한 마커용 조성물을 제공한다.In order to achieve the above object of the present invention, the present invention provides a prognosis diagnosis of small cell lung cancer and A composition for a marker for prediction is provided.
본 발명의 일실시예에 있어서, 상기 CD155의 rs1058402G>A 단일염기다형성은 서열번호 1로 이루어진 염기서열에서 250번째 염기에 위치하는 것이고, 상기 CD226의 rs763361C>T 단일염기다형성은 서열번호 2로 이루어진 염기서열에서 500번째 염기에 위치하는 것일 수 있다.In one embodiment of the present invention, the rs1058402G>A single nucleotide polymorphism of CD155 is located at the 250th base in the nucleotide sequence consisting of SEQ ID NO: 1, and the rs763361C>T single nucleotide polymorphism of CD226 consists of SEQ ID NO: 2 It may be located at the 500th base in the base sequence.
본 발명의 일실시예에 있어서, 상기 소세포폐암은 항암 화학요법을 사용하여 치료한 것일 수 있다.In one embodiment of the present invention, the small cell lung cancer may be treated using chemotherapy.
또한 본 발명은 CD155의 rs1058402G>A 단일염기다형성 및 CD226의 rs763361C>T 단일염기다형성으로 이루어진 군 중에서 선택되는 하나 이상의 단일염기다형성을 검출할 수 있는 제제를 포함하는, 소세포폐암 환자의 생존 예후 예측용 조성물을 제공한다.In addition, the present invention provides an agent capable of detecting one or more single nucleotide polymorphisms selected from the group consisting of rs1058402G>A single nucleotide polymorphism of CD155 and rs763361C>T single nucleotide polymorphism of CD226, for predicting survival prognosis of patients with small cell lung cancer A composition is provided.
본 발명의 일실시예에 있어서, 상기 제제는 CD155의 rs1058402G>A 단일염기다형성 또는 CD226의 rs763361C>T 단일염기다형성을 포함하는 10~100개의 연속 염기로 구성되는 폴리뉴클레오티드 또는 이의 상보적인 폴리뉴클레오티드를 증폭시킬 수 있는 프라이머 또는 프로브일 수 있다.In one embodiment of the present invention, the agent is a polynucleotide consisting of 10 to 100 consecutive bases comprising rs1058402G>A single nucleotide polymorphism of CD155 or rs763361C>T single nucleotide polymorphism of CD226 or a polynucleotide complementary thereto It may be a primer or probe capable of amplifying.
본 발명의 일실시예에 있어서, 상기 CD155의 rs1058402G>A 단일염기다형성은 서열번호 1로 이루어진 염기서열에서 250번째 염기에 위치하는 것이고, 상기 CD226의 rs763361C>T 단일염기다형성은 서열번호 2로 이루어진 염기서열에서 500번째 염기에 위치하는 것일 수 있다.In one embodiment of the present invention, the rs1058402G>A single nucleotide polymorphism of CD155 is located at the 250th base in the nucleotide sequence consisting of SEQ ID NO: 1, and the rs763361C>T single nucleotide polymorphism of CD226 consists of SEQ ID NO: 2 It may be located at the 500th base in the base sequence.
본 발명의 일실시예에 있어서, 상기 제제는 CD155의 rs1058402G>A 단일염기다형성을 검출할 수 있는 서열번호 3 및 4의 염기서열로 이루어진 프라이머 쌍; 또는 CD226의 rs763361C>T 단일염기다형성을 검출할 수 있는 서열번호 5 및 6의 염기서열로 이루어진 프라이머 쌍일 수 있다.In one embodiment of the present invention, the agent comprises a primer pair consisting of nucleotide sequences of SEQ ID NOs: 3 and 4 capable of detecting the rs1058402G>A single nucleotide polymorphism of CD155; Alternatively, it may be a primer pair consisting of the nucleotide sequences of SEQ ID NOs: 5 and 6 capable of detecting the rs763361C>T single nucleotide polymorphism of CD226.
본 발명의 일실시예에 있어서, 상기 CD155의 rs1058402G>A 단일염기다형성 또는 CD226의 rs763361C>T 단일염기다형성은 항암제에 대한 화학요법 반응(chemotherapy response), 전체생존율(Overall survival: OS) 또는 무진행 생존율(Progression-free survival: PFS)과 관련성이 있는 것일 수 있다.In one embodiment of the present invention, the rs1058402G>A single nucleotide polymorphism of CD155 or the rs763361C>T single nucleotide polymorphism of CD226 is a chemotherapy response to an anticancer agent, overall survival (OS), or progression-free It may be related to progression-free survival (PFS).
또한 본 발명은 본 발명의 조성물을 포함하는 소세포폐암 환자의 생존 예후 예측용 키트를 제공한다.The present invention also provides a kit for predicting survival prognosis of small cell lung cancer patients comprising the composition of the present invention.
또한 본 발명은 본 발명의 조성물을 포함하는 소세포폐암 환자의 생존 예후 예측용 마이크로어레이를 제공한다.The present invention also provides a microarray for predicting survival prognosis of a patient with small cell lung cancer comprising the composition of the present invention.
나아가 본 발명은, 검체로부터 추출한 핵산에 대하여, CD155의 rs1058402G>A 단일염기다형성 및 CD226의 rs763361C>T 단일염기다형성을 확인하는 단계를 포함하는, 소세포폐암 환자의 생존 예후 예측을 위한 정보를 제공하는 방법을 제공한다.Furthermore, the present invention provides information for predicting survival prognosis of patients with small cell lung cancer, including confirming the rs1058402G>A single nucleotide polymorphism of CD155 and the rs763361C>T single nucleotide polymorphism of CD226 with respect to the nucleic acid extracted from the sample. provide a way
본 발명의 일실시예에 있어서, 상기 CD155의 rs1058402G>A 다형성의 유전자형이 GG인 경우, GA 또는 AA인 경우에 비해 생존 예후가 높은 군으로 판정할 수 있다.In one embodiment of the present invention, when the genotype of the rs1058402G>A polymorphism of CD155 is GG, it can be determined as a group having a higher survival prognosis than in the case of GA or AA.
본 발명의 일실시예에 있어서, 상기 CD226의 rs763361C>T 다형성의 유전자형이 CT 또는 TT인 경우, CC에 비해 생존 예후가 높은 군으로 판정할 수 있다.In one embodiment of the present invention, when the genotype of the rs763361C>T polymorphism of CD226 is CT or TT, it can be determined as a group having a higher survival prognosis than CC.
본 발명의 일실시예에 있어서, 상기 CD155의 rs1058402G>A 다형성의 GA 또는 AA 유전자형; 또는 상기 CD226의 rs763361C>T 다형성의 CC 유전자형이 0개인 경우, 항암제에 대한 화학요법 반응이 80.4%이고, 1개인 경우, 항암제에 대한 화학요법 반응이 71.0%이고, 2개인 경우, 항암제에 대한 화학요법 반응이 61.3%일 수 있다.In one embodiment of the present invention, the GA or AA genotype of the rs1058402G>A polymorphism of CD155; Or, when the CC genotype of the rs763361C>T polymorphism of CD226 is 0, the chemotherapy response to the anticancer agent is 80.4%, and in the case of one, the chemotherapy response to the anticancer agent is 71.0%, and in the case of two, the chemotherapy response to the anticancer agent The therapy response may be 61.3%.
본 발명의 일실시예에 있어서, 상기 CD155의 rs1058402G>A 다형성에서 CD155의 67번째 아미노산인 알라닌(A)이 트레오닌(T)으로 돌연변이 되는 경우, 항암제에 대한 화학요법 반응(chemotherapy response), 전체생존율(Overall survival: OS) 또는 무진행 생존율(Progression-free survival: PFS)이 낮다고 판정할 수 있다.In one embodiment of the present invention, when alanine (A), the 67th amino acid of CD155, is mutated to threonine (T) in the rs1058402G>A polymorphism of CD155, chemotherapy response to an anticancer agent, overall survival rate (Overall survival: OS) or progression-free survival (PFS) may be determined to be low.
본 발명의 일실시예에 있어서, 상기 CD155의 rs1058402G>A 다형성에서 CD155의 67번째 아미노산인 알라닌(A)이 트레오닌(T)으로 돌연변이 되면, CD155와 CD226의 결합력이 감소되어 T 세포활성 또는 NK 세포활성이 감소될 수 있다.In one embodiment of the present invention, when alanine (A), the 67th amino acid of CD155, is mutated to threonine (T) in the rs1058402G>A polymorphism of CD155, the binding force between CD155 and CD226 is reduced, thereby reducing T cell activity or NK cell activity. activity may be reduced.
본 발명에 따른 소세포폐암 생존 예후의 예측 기술은 소세포폐암이 발병하여 항암제 치료를 받은 환자에 대하여 신속하고 정확하게 환자의 항암제 치료에 대한 예후 또는 생존 예후를 예측할 수 있고, 적절한 치료법의 선택 및 평가를 위한 방법에도 적용될 수 있으며, 나아가 소세포폐암에 대한 새로운 표적 치료를 통해 소세포폐암 환자의 생존율을 높일 수 있다.The technology for predicting the survival prognosis of small cell lung cancer according to the present invention can rapidly and accurately predict the prognosis or survival prognosis of the patient's anticancer drug treatment for a patient who has been diagnosed with small cell lung cancer and has received anticancer drug treatment. It can also be applied to the method, and furthermore, the survival rate of small cell lung cancer patients can be increased through a new targeted treatment for small cell lung cancer.
도 1은 본 발명의 일실시예에서 환자군을 선별하는 과정에 대한 모식도를 나타낸 것이다.
도 2는 본 발명의 일실시예에서 다형성에 따른 전체 생존에 대한 Kaplan-Meier 플롯을 나타낸 것으로, A는 CD155 rs1058402, B는 CD226 rs763361, (C)는 나쁜 유전자형의 조합에 대한 전체 생존율과의 관련성을 나타낸 것이다. P 값은 다변량 Cox 비례 위험 모델을 사용하여 계산하였다.
도 3은 CD226/CD155(야생형 또는 A67T 돌연변이) 복합체에 대한 구조 모델링 분석 결과를 나타낸 것으로, A는 hCD155-T67(녹색)의 구조모델과 정렬된 mCD226-ecto (회색) 및 hCD155-Domain1 (주황색) 구조 (PDB ID : 6ISC)의 3D 구조를 나타낸 것이고, B와 C는 CD226-Domain1-N116과 CD155-G73, S74, A67/T67 간의 상호작용에 대한 구조적 모형을 나타낸 것이며, D는 CD226-Domain2-E185와 CD155- 야생형/돌연변이 모델 G70 간의 상호작용에 대한 구조적 모델을 나타낸 것이다. 관련 아미노산 잔기는 막대기로 표시하였다(질소 원자 : 파란색, 산소 원자 : 빨간색). 원자간 거리(옹스트롬)는 검은색 점선으로 표시하였고, 추정 극성 접점은 빨간색 선으로 표시하였다. CD226/CD155 (야생형 대 A67T 돌연변이)의 모든 이미지는 PyMOL (https://pymol.org/2/)을 사용하여 형성하였다.1 shows a schematic diagram of a process for selecting a patient group in an embodiment of the present invention.
2 shows a Kaplan-Meier plot for overall survival according to polymorphism in an embodiment of the present invention, where A is CD155 rs1058402, B is CD226 rs763361, (C) is the association with overall survival for a combination of bad genotypes. is shown. P values were calculated using a multivariate Cox proportional hazards model.
Figure 3 shows the structural modeling analysis results for the CD226/CD155 (wild-type or A67T mutant) complex, where A is mCD226-ecto (grey) and hCD155-Domain1 (orange) aligned with the structural model of hCD155-T67 (green). The 3D structure of the structure (PDB ID: 6ISC) is shown, B and C are the structural models for the interaction between CD226-Domain1-N116 and CD155-G73, S74, A67/T67, and D is CD226-Domain2- A structural model for the interaction between E185 and CD155- wild-type/mutant model G70 is shown. Relevant amino acid residues are indicated by bars (nitrogen atom: blue, oxygen atom: red). The interatomic distance (angstroms) is indicated by the black dotted line, and the estimated polarity junction is indicated by the red line. All images of CD226/CD155 (wild-type versus A67T mutant) were formed using PyMOL (https://pymol.org/2/).
본 발명은 소세포폐암의 예후 진단 및 예측을 위한 바이오마커로서, CD155 및 CD226의 단일염기다형성을 사용할 수 있음을 규명하였고, 구체적으로 본 발명은 CD155의 rs1058402G>A 단일염기다형성 및 CD226의 rs763361C>T 단일염기다형성으로 이루어진 군 중에서 선택되는 하나 이상의 단일염기다형성을 포함하는 소세포폐암 예후 진단 및 예측을 위한 마커용 조성물을 제공함에 특징이 있다.The present invention has identified that single nucleotide polymorphisms of CD155 and CD226 can be used as biomarkers for prognostic diagnosis and prediction of small cell lung cancer. Specifically, the present invention provides rs1058402G>A single nucleotide polymorphism of CD155 and rs763361C>T of CD226 It is characterized by providing a composition for a marker for the diagnosis and prediction of prognosis of small cell lung cancer comprising one or more single nucleotide polymorphisms selected from the group consisting of single nucleotide polymorphisms.
CD155는 서열번호 1로 나타낼 수 있다.CD155 can be represented by SEQ ID NO: 1.
서열번호 1: ACACCCCACG GTCCACCGGG GATCCAGGGC CCCAGCGTGC AAGTCGCGCC AGGTGCCCGGSEQ ID NO: 1: ACACCCCACG GTCCACCGGG GATCCAGGGC CCCAGCGTGC AAGTCGCGCC AGGTGCCCGG
GCTCCTGGAG CCCCTCCCTA TCTAGTCCAA GAACGCCCCG GGTCTGACAC CTTCTCTTCG GTTCTCCGCA GGGGACGTCG TCGTGCAGGC GCCCACCCAG GTGCCCGGCT TCTTGGGCGA CTCCGTGACG CTGCCCTGCT ACCTACAGGT GCCCAACATG GAGGTGACGC ATGTGTCACA GCTGACTTGG CGCGGCATGG TGAATCTGGC AGCATGGCCG TCTTCCACCA AACGCAGGGC CCCAGCTATT CGGAGTCCAA ACGGCTGGAA TTCGTGGCAG CCAGACTGGG CGCGGAGCTG CGGAATGCCT CGCTGAGGAT GTTCGGGTTG CGCGTAGAGG ATGAAGGCAA CTACACCTGC CTGTTCGTCA CGTTCCCGCA GGGCAGCAGG AGCGTGGATA TCTGGCTCCG AGTGCTTGGT GAGCAGGGGG TTTTGGGGAGGCTCCTGGAG CCCCTCCCTA TCTAGTCCAA GAACGCCCCG GGTCTGACAC CTTCTCTTCG GTTCTCCGCA GGGGACGTCG TCGTGCAGGC GCCCACCCAG GTGCCCGGCT TCTTGGGCGA CTCCGTGACG CTGCCCTGCT ACCTACAGGT GCCCAACATG GAGGTGACGC ATGTGTCACA GCTGACTTG G CGCGGCATGG TGAATCTGGC AGCATGGCCG TCTTCCACCA AACGCAGGGC CCCAGCTATT CGGAGTCCAA ACGGCTGGAA TTCGTGGCAG CCAGACTGGG CGCGGAGCTG CGGAATGCCT CGCTGAGGAT GTTCGGGTTG CGCGTAGAGG ATGAAGGCAA CTACACCTGC CTGTTCGTCA CGTTCCCGCA GGGCAGCAGG AGCGTGGATA TCTGGCTCCG AGTGCTTGGT GAGCAGGGGG TTTTGGGGAG
CD226은 서열번호 2로 나타낼 수 있다.CD226 can be represented by SEQ ID NO:2.
서열번호 2: CATCTTGCCA ACACAAGAGG AAAGCCTGCA TGAGAGTGAG GCCAAGACCA GGGAAATGGASEQ ID NO: 2: CATCTTGCCA ACACAAGAGG AAAGCCTGCA TGAGAGTGAG GCCAAGACCA GGGAAATGGA
TCCAACACTC TGGAAAGGGA TTCAGAAGCC AGTTTATGCC CATACTTAAT TCTAGACACA ACATTTAAGC CCTGGTAAAT AGCCCTTGCC CAAAGCTTAA TCTCCCCTGG ATCATTCTGT TATATGATAC AGTAAGTTTT CTTTTGTATA TAAACCAGTT AGAGTCAGGT TTTCTGAAAC AGTTCTATGA AAAATGATTT TAGGTAATGA AGTATTTTTC CTATCAAAGT AACTCAATTC AGACAACTAG TATCTAAGGT AGACCTTGGG TAGTGGAAAA AAATTGCATA AAGATCCATG CATGAGTACA TAAGAGTCAT TACTAATGCA CTCATGTCAA GAATAAGCTT AAACTCTAGT CTTTGGTCTG CGAGAGAAGG TTGGATAGTT GACATAAATA TCCTCTCTTG TATCATCCAT GGATTGATTG GTAGGTTGAC GGTAGAGATG GGACTTCTAT AGTTATTGGG TGCCTAGAAA GACAAACAGC AGAGAGTGTC AATAATTCAC TGCATTTCAA CAACTAATGA AGACATTCAA AACATACCTC TCATAAATGC AGGCATGATA TGGGACAAGT TTCCATTATA ATTAATTTGA TAAAACATTC TCATTGTATT GAACTTCTGT TGGAAATCAT ATTCTTGACT GAGATGCAAC AGAAATCTAG TCTAGATTAA TACTTGCTGT ATTGTGCTAT GAATTACCTG TTTCAATGTA GAACTCCCTC TCCCAATGTT AAGCTATTTT GATAAGAACA ATTACTATCA TTTTTATATG GAAATTCTAA CACAGTGTCT GAACTTTAAA AAATAAGCAA CTTAACATAT AAAAAGTTAA CAAAACTGAC ATCAAGATGA TATTGTATAA TCATTAATCT TCTCTACCGT AATCAAGTCA CTTTGACCAC ATATGTATGT ATGTAACAGA AAATATGCAGTCCAACACTC TGGAAAGGGA TTCAGAAGCC AGTTTATGCC CATACTTAAT TCTAGACACA ACATTTAAGC CCTGGTAAAT AGCCCTTGCC CAAAGCTTAA TCTCCCCTGG ATCATTCTGT TATATGATAC AGTAAGTTTT CTTTTGTATA TAAACCAGTT AGAGTCAGGT TTTCTGAAAC AGTTCTATGA AAAATGATTT TAGGTAATGA AGTATTTTTC CTATCAAAGT AACTCAATTC AGACAACTAG TATCTAAGGT AGACCTTGGG TAGTGGAAAA AAATTGCATA AAGATCCATG CATGAGTACA TAAGAGTCAT TACTAATGCA CTCATGTCAA GAATAAGCTT AAACTCTAGT CTTTGGTCTG CGAGAGAAGG TTGGATAGTT GACATAAATA TCCTCTCTTG TATCATCCAT GGATTGATTG GTAGGTTGA C GGTAGAGATG GGACTTCTAT AGTTATTGGG TGCCTAGAAA GACAAACAGC AGAGAGTGTC AATAATTCAC TGCATTTCAA CAACTAATGA AGACATTCAA AACATACCTC TCATAAATGC AGGCATGATA TGGGACAAGT TTCCATTATA ATTAATTTGA TAAAACATTC TCATTGTATT GAACTTCTGT TGGAAATCAT ATTCTTGACT GAGATGCAAC AGAAATCTAG TCTAGATTAA TACTTGCTGT ATTGTGCTAT GAATTACCTG TTTCAATGTA GAACTCCCTC TCCCAATGTT AAGCTATTTT GATAAGAACA ATTACTATCA TTTTTATATG GAAATTCTAA CACAGTGTCT GAACTTTAAA AAATAAGCAA CTTAACATAT AAAAAGTTAA CAAAACTGAC ATCAAGATGA TATTGTATAA TCATTAATCT TCTCTACCGT AATCAAGTCA CTTTGACCA C ATATGTATGT ATGTAACAGA AAATATGCAG
본 발명자들은 소세포폐암 예후를 신속하고 정확하게 진단 및 예측할 수 있는 바이오마커를 발굴하기 위해 연구하던 중, 소세포폐암(SCLC)의 발생 및 진행과 관련 있는 후보 마커로서 면역 체크 포인트 유전자들과 소세포폐암과 관련성이 있는 유전자들을 선정하였고, 해당 유전자들에 존재하고 있는 단일염기다형성을 대상으로 소세포폐암 항암 화학요법을 받은 환자들에 대한 임상결과와 연관성 여부를 분석한 결과, CD155의 rs1058402G>A 단일염기다형성 및 CD226의 rs763361C>T 단일염기다형성이 유의미하게 소세포폐암에 대한 항암제의 화학요법 반응 및 환자의 생존 예후와 관련성이 있음을 확인하였다.While the present inventors were researching to discover biomarkers that can rapidly and accurately diagnose and predict the prognosis of small cell lung cancer, immune checkpoint genes and association with small cell lung cancer as candidate markers related to the development and progression of small cell lung cancer (SCLC) Selected genes with this gene and analyzed whether the single nucleotide polymorphism present in the genes was correlated with the clinical results of patients who received chemotherapy for small cell lung cancer. It was confirmed that the rs763361C>T single nucleotide polymorphism of CD226 was significantly related to the chemotherapy response to small cell lung cancer and the survival prognosis of the patient.
한편 CD155는 PVR 또는 Necl-5라고도 불리며, 면역글로불린 수퍼패밀리에 속하는 막 관통 당단백질을 인코딩한다. CD155는 처음에는 세포 부착 및 이동에 작용하는 것으로 알려졌으나 최근에는 면역학 및 종양학에도 관련성이 있는 것으로 보고되고 있다. Meanwhile, CD155, also called PVR or Necl-5, encodes a transmembrane glycoprotein belonging to the immunoglobulin superfamily. CD155 was initially known to act on cell adhesion and migration, but recently it has also been reported to have relevance in immunology and oncology.
또한 CD226은 자연살해 (NK) 세포, T 세포, B 세포의 하위 집합 및 단핵구의 표면에서 발현되는 당 단백질을 암호화하고 이들의 활성화 및 억제에 중요한 역할을 한다. 항원제시세포 또는 종양세포에 존재하는 CD155는 T 세포 및 NK 세포에 존재하는 CD226에 결합하며, CD155와 CD226의 결합은 T 세포 및 NK 세포를 활성화시키는 공동 자극제로 작용한다.CD226 also encodes for glycoproteins expressed on the surface of natural killer (NK) cells, T cells, subsets of B cells and monocytes and plays an important role in their activation and inhibition. CD155 present in antigen-presenting cells or tumor cells binds to CD226 present in T cells and NK cells, and the binding of CD155 and CD226 acts as a co-stimulator to activate T cells and NK cells.
이러한 점에서 본 발명자들은 CD155에 존재하는 rs1058402G>A 단일염기다형성 및 CD226에 존재하는 rs763361C>T 단일염기다형성에 대해 소세포폐암과의 관련성을 연구한 결과, CD155의 rs1058402G>A 다형성의 유전자형이 GG인 경우, GA 또는 AA인 경우에 비해 생존 예후가 더 높은 것으로 나타났고, CD226의 rs763361C>T 다형성의 유전자형이 CT 또는 TT인 경우, CC에 비해 생존 예후가 더 높은 것으로 나타났다.In this regard, the present inventors studied the association between the rs1058402G>A polymorphism in CD155 and the rs763361C>T polymorphism in CD226 with small cell lung cancer. As a result, the genotype of the rs1058402G>A polymorphism in CD155 is GG. case, the survival prognosis was higher than that of GA or AA, and when the genotype of the rs763361C>T polymorphism of CD226 was CT or TT, the survival prognosis was higher than that of CC.
따라서 이들 단일염기다형성의 유전자형 분석을 통해 소세포폐암 환자의 생존 예후를 예측 또는 진단할 수 있음을 알 수 있었다.Therefore, it was found that the survival prognosis of small cell lung cancer patients can be predicted or diagnosed through genotyping of these single nucleotide polymorphisms.
한편, 상기 CD155에 존재하는 rs1058402G>A 다형성은 미스 센스 돌연변이이다. rs1058402G>A는 CD155의 아미노산 코돈의 67번째 알라닌(A)이 트레오닌(T)으로 치환된 돌연변이 형태를 갖는다. 이는 본 발명의 일실시예에서 3-D 구조모델을 통해 CD155의 코돈 67번째에서 알라닌을 트레오닌으로 변경할 경우, CD155의 S74/G73까지의 거리가 단축되는 것을 확인할 수 있었다. 짧아진 거리는 CD155의 T67과 S74 사이에 새로운 수소 결합을 형성하게 되고 이러한 변화는 CD155의 S74와 CD226의 N116 사이의 거리 확장과 수소 결합의 손실이 유도된다는 것을 확인하였다.On the other hand, the rs1058402G>A polymorphism present in CD155 is a miss sense mutation. rs1058402G>A has a mutant form in which alanine (A) at position 67 of the amino acid codon of CD155 is substituted with threonine (T). In one embodiment of the present invention, it was confirmed that the distance to S74/G73 of CD155 was shortened when alanine at codon 67 of CD155 was changed to threonine through the 3-D structural model in an embodiment of the present invention. It was confirmed that the shortened distance formed a new hydrogen bond between T67 and S74 of CD155, and this change induced an extension of the distance between S74 of CD155 and N116 of CD226 and loss of hydrogen bond.
또한 rs1058402G>A(A67T)로 인한 구조 변경은 CD155의 G70과 CD226의 E185 사이의 결합 거리를 증가시켜 수소결합의 손실을 초래하는 것으로 나타났고, CD155와 CD226 사이의 상호작용에서 CD155의 S74/G70과 CD226의 N116/E185가 중요한 결합 부위라는 것을 확인할 수 있었다.In addition, the structural alteration due to rs1058402G>A(A67T) was shown to increase the bonding distance between G70 of CD155 and E185 of CD226, leading to loss of hydrogen bonds, and S74/G70 of CD155 in the interaction between CD155 and CD226. and N116/E185 of CD226 were confirmed to be important binding sites.
본 발명의 실시예에서는 CD155 rs1058402G>A(A67T) 다형성이 소세포폐암 환자에서 더 나쁜 화학요법 반응 및 전체생존율과 유의하게 관련성이 있는 것으로 나타났고, 3D 구조모델 분석을 통해 rs1058402G>A(A67T)는 CD155와 CD226 사이의 결합부위의 거리를 증가시켜 CD155와 CD226의 결합력을 약화시킨다는 것을 알 수 있었고, 이러한 결합력의 약화는 면역세포에 대한 공동 자극신호를 감소시켜 면역반응의 감소를 유도하고 결과적으로 소세포폐암 환자에서 치료효과 및 생존율에 부정적인 영향을 미친다는 것을 알 수 있었다. 본 발명에서 상기 CD155의 아미노산 서열은 서열번호 7에 나타내었고, CD155 rs1058402G>A(A67T) 변이 위치는 서열번호 7의 67번째 아미노산에 해당된다.In an example of the present invention, it was found that the CD155 rs1058402G>A(A67T) polymorphism was significantly associated with worse chemotherapy response and overall survival in patients with small cell lung cancer, and 3D structural model analysis showed that rs1058402G>A(A67T) was It was found that by increasing the distance of the binding site between CD155 and CD226, the binding force between CD155 and CD226 was weakened. It was found that the treatment effect and survival rate were negatively affected in lung cancer patients. In the present invention, the amino acid sequence of CD155 is shown in SEQ ID NO: 7, and the CD155 rs1058402G>A(A67T) mutation position corresponds to the 67th amino acid of SEQ ID NO: 7.
또한 CD226 rs763361C>T는 다형성이 소세포폐암 환자에서 더 나은 화학요법 반응 및 전체생존율과 관련성이 있는 것으로 나타났는데, rs763361C>T는 CD226의 세포질 꼬리(cytoplasmic tail)를 암호화하는 엑손 7에 위치하며, 2개의 인산화 부위가 있고 비-동의적(non-synonymous) 돌연변이다. rs763361 다형성에서 C 염기의 T로의 치환은 아미노산 코돈 307번째에서 글리신이 세린으로 치환되도록 유도한다. Gly307Ser 치환은 인산화를 변화시키거나 엑손 스플라이싱 사일런서 서열을 파괴하여 RNA 스플라이싱을 변경시켜 CD226 발현에 영향을 미친다는 것을 알 수 있었다. In addition, the CD226 rs763361C>T polymorphism was shown to be associated with better chemotherapy response and overall survival in patients with small cell lung cancer, where rs763361C>T is located in exon 7, encoding the cytoplasmic tail of CD226, 2 It has two phosphorylation sites and is a non-synonymous mutation. In the rs763361 polymorphism, the substitution of the C base with T leads to the substitution of serine for glycine at amino acid codon 307. It was found that the Gly307Ser substitution affects CD226 expression by altering phosphorylation or by disrupting the exon splicing silencer sequence to alter RNA splicing.
본 발명에서 상기 CD226의 아미노산 서열은 서열번호 8에 나타내었고, rs763361C>T(Gly307Ser) 변이 위치는 서열번호 8의 307번째 아미노산에 해당된다.In the present invention, the amino acid sequence of CD226 is shown in SEQ ID NO: 8, and the mutation position of rs763361C>T (Gly307Ser) corresponds to the 307th amino acid of SEQ ID NO: 8.
따라서 본 발명에서는 면역 체크포인트 유전자인 CD155와 CD226의 다형성은 화학요법을 받은 소세포폐암 환자의 생존 결과와 관련성이 있고, 또한, CD155 및 CD226의 변이는 화학요법 단독보다 면역요법 단독 또는 화학요법과 면역요법의 병행 처치에 따른 임상 결과를 예측하는데 더 큰 영향을 미칠 수 있음을 알 수 있었다.Therefore, in the present invention, polymorphisms in the immune checkpoint genes CD155 and CD226 are related to the survival outcome of small cell lung cancer patients who have received chemotherapy, and mutations in CD155 and CD226 are more important than immunotherapy alone or chemotherapy and immunity than chemotherapy alone. It was found that it can have a greater influence on predicting clinical outcomes according to the combination treatment of therapy.
나아가 본 발명에서는 면역 체크포인트 유전자의 변이체와 돌연변이체인 CD155 rs1058402G>A(A67T) 및 CD226 rs763361C>T(G307S)는 화학요법 반응 및 전체생존율과 관련성이 있음을 확인하였고, 특히 CD155 rs1058402G>A(A67T)는 CD155와 CD226 간의 상호작용 및 결합력에 영향을 미칠 수 있음을 알 수 있었다. Furthermore, in the present invention, it was confirmed that mutants and mutants of the immune checkpoint gene, CD155 rs1058402G>A(A67T) and CD226 rs763361C>T(G307S), are related to chemotherapy response and overall survival, in particular, CD155 rs1058402G>A(A67T). ) could affect the interaction and binding force between CD155 and CD226.
그러므로 본 발명은 CD155의 rs1058402G>A 단일염기다형성 및 CD226의 rs763361C>T 단일염기다형성으로 이루어진 군 중에서 선택되는 하나 이상의 단일염기다형성을 포함하는, 소세포폐암 예후 진단 및 예측을 위한 마커용 조성물을 제공할 수 있다.Therefore, the present invention provides a marker composition for diagnosing and predicting the prognosis of small cell lung cancer, comprising one or more single nucleotide polymorphisms selected from the group consisting of rs1058402G>A single nucleotide polymorphism of CD155 and rs763361C>T single nucleotide polymorphism of CD226. can
본 발명에서 상기 CD155의 rs1058402G>A 단일염기다형성은 서열번호 1로 이루어진 염기서열에서 250번째 염기에 위치하고,상기 CD226의 rs763361C>T 단일염기다형성은 서열번호 2로 이루어진 염기서열에서 500번째 염기에 위치한다.In the present invention, the rs1058402G>A single nucleotide polymorphism of CD155 is located at the 250th nucleotide in the nucleotide sequence consisting of SEQ ID NO: 1, and the rs763361C>T single nucleotide polymorphism of CD226 is located at the 500th nucleotide in the nucleotide sequence consisting of SEQ ID NO: 2 do.
또한 본 발명은 CD155의 rs1058402G>A 단일염기다형성 및 CD226의 rs763361C>T 단일염기다형성으로 이루어진 군 중에서 선택되는 하나 이상의 단일염기다형성을 검출할 수 있는 제제를 포함하는, 소세포폐암 환자의 생존 예후 예측용 조성물을 제공한다.In addition, the present invention provides an agent capable of detecting one or more single nucleotide polymorphisms selected from the group consisting of rs1058402G>A single nucleotide polymorphism of CD155 and rs763361C>T single nucleotide polymorphism of CD226, for predicting survival prognosis of patients with small cell lung cancer A composition is provided.
상기 제제는 CD155의 rs1058402G>A 단일염기다형성 또는 CD226의 rs763361C>T 단일염기다형성을 포함하는 10~100개의 연속 염기로 구성되는 폴리뉴클레오티드 또는 이의 상보적인 폴리뉴클레오티드를 증폭시킬 수 있는 프라이머 또는 프로브일 수 있다.The agent may be a primer or probe capable of amplifying a polynucleotide consisting of 10 to 100 consecutive bases containing rs1058402G>A single nucleotide polymorphism of CD155 or rs763361C>T polymorphism of CD226 or a complementary polynucleotide thereof have.
바람직하게 상기 제제는 CD155의 rs1058402G>A 단일염기다형성을 검출할 수 있는 서열번호 3 및 4의 염기서열로 이루어진 프라이머 쌍 또는 CD226의 rs763361C>T 단일염기다형성을 검출할 수 있는 서열번호 5 및 6의 염기서열로 이루어진 프라이머 쌍일 수 있다. Preferably, the agent is a primer pair consisting of nucleotide sequences of SEQ ID NOs: 3 and 4 capable of detecting rs1058402G>A single nucleotide polymorphism of CD155 or rs763361C>T of SEQ ID NOs: 5 and 6 capable of detecting rs763361C>T single nucleotide polymorphism of CD226 It may be a primer pair consisting of a nucleotide sequence.
또한 본 발명에 따른 상기 CD155의 rs1058402G>A 단일염기다형성 또는 CD226의 rs763361C>T 단일염기다형성은 항암제에 대한 화학요법 반응(chemotherapy response), 전체생존율(Overall survival: OS) 또는 무진행 생존율(Progression-free survival: PFS)과 관련성이 있다.In addition, according to the present invention, the rs1058402G>A single nucleotide polymorphism of CD155 or the rs763361C>T single nucleotide polymorphism of CD226 according to the present invention is a chemotherapy response, overall survival (OS) or progression-free survival rate (Progression-) free survival (PFS)).
본 발명에서 상기 "예후"는 폐암과 같은 질환의 발병, 재발, 전이성 확산, 및 약물 내성을 비롯한 폐암-기인성 사망 또는 진행의 가능성 등의 병의 경과 및 완치 여부를 의미한다. 본 발명의 목적상 예후는 폐암, 바람직하게는 소세포폐암의 발병 위험성 및 발병 후의 생존 예후를 의미한다.In the present invention, the "prognosis" refers to the progress and cure of diseases such as the onset, recurrence, metastatic spread, and the possibility of lung cancer-induced death or progression, including drug resistance, of a disease such as lung cancer. For the purposes of the present invention, the prognosis means the risk of developing lung cancer, preferably small cell lung cancer, and the prognosis for survival after the onset.
"예측"이란 환자가 폐암, 바람직하게는 소세포폐암이 발병할 가능성이 있는지를 판별하고, 화학요법 또는 방사선 치료 등 치료법에 대해 선호적으로 또는 비선호적으로 반응하여 환자의 치료, 예를 들어 특정 치료제, 및/또는 원발성 종양의 수술로 제거, 및/또는 암 재발 없이 특정 시기 동안 화학요법으로 치료된 후 생존할 여부 및/또는 가능성과 관련된다."Prediction" means determining whether a patient is likely to develop lung cancer, preferably small cell lung cancer, and responding favorably or unfavorably to a treatment, such as chemotherapy or radiation, to treat the patient, e.g., a specific therapeutic agent. , and/or surgical removal of the primary tumor, and/or survival and/or likelihood of survival after treatment with chemotherapy for a specified period of time without cancer recurrence.
본 발명의 예측 방법은 임의의 특정 환자에 대한 소세포폐암 발병 위험성이 높은 환자로서 특별하고 적절한 관리를 통하여 발병 시기를 늦추거나 발병하지 않도록 하거나, 소세포폐암 발병 환자에 대한 가장 적절한 치료 방식을 선택함으로써 치료 결정을 하기 위해 임상적으로 사용될 수 있다. 본 발명의 예측 방법은 환자가 예를 들어 소정 치료제 또는 조합물, 외과적 개입, 화학요법 등의 투여를 비롯한 소정 치료 처방과 같은 치료 처방에 선호적으로 반응하는지를 확인하거나, 치료 처방 후 환자의 장기 생존이 가능한지 여부를 예측할 수 있다.The prediction method of the present invention is a patient with a high risk of developing small cell lung cancer for any specific patient, and through special and appropriate management, the onset time is delayed or the onset is not delayed, or the treatment is performed by selecting the most appropriate treatment method for the small cell lung cancer patient. It can be used clinically to make decisions. The predictive method of the present invention determines whether a patient responds favorably to a treatment regimen, such as a prescribed treatment regimen, including, for example, administration of a given therapeutic agent or combination, surgical intervention, chemotherapy, etc. It is possible to predict whether or not survival is possible.
"유전적 다형성(genetic polymorphism)"은 인구집단에서 적어도 1% 이상의 빈도로 유전자 변이가 나타나는 경우를 말한다. DNA에서 한 개의 뉴클레오티드의 삽입, 소실, 또는 치환이 일어나는 것을 단일염기다형성(single nucleotide polymorphism, SNP) 이라고 한다."Genetic polymorphism" refers to the occurrence of a genetic mutation with a frequency of at least 1% or more in a population. The insertion, deletion, or substitution of one nucleotide in DNA is called single nucleotide polymorphism (SNP).
"다형성"이라는 용어는 군집 내에서 변하는 유전자의 서열에서의 배치를 지칭한다. 다형성은 상이한 "대립유전자"로 구성된다. 이러한 다형성의 배치는 유전자에서의 그의 위치 및 그에서 발견되는 상이한 아미노산 또는 염기에 의해 확인될 수 있다. 이러한 아미노산 변이는 2개의 상이한 대립유전자인, 2개의 가능한 변이체 염기의 결과이다. 유전자형은 2개의 다른 별개의 대립유전자로 구성되기 때문에, 여러 가능한 변이체 중 임의의 변이체가 어느 한 개체에서 관찰될 수 있다. 개개의 다형성은 또한 당업자에게 공지되어 있고, 예를 들면, NCBI 웹사이트 상에서 이용가능한 뉴클레오티드 염기 변이의 단일 뉴클레오티드 다형성 데이터베이스(Single Nucleotide Polymorphism Database (dbSNP) of Nucleotide Sequence Variation)에서 사용되는 것인, 지정된 독특한 식별자 ("기준 SNP", "refSNP" 또는 "rs#")이다.The term "polymorphism" refers to the placement in the sequence of a gene that varies within a population. Polymorphisms consist of different “alleles”. The placement of such polymorphisms can be identified by their position in the gene and the different amino acids or bases found therein. These amino acid variations are the result of two different alleles, two possible variant bases. Because the genotype consists of two different distinct alleles, any of several possible variants can be observed in any one individual. Individual polymorphisms are also known to those skilled in the art and are used, for example, in the Single Nucleotide Polymorphism Database (dbSNP) of Nucleotide Sequence Variation available on the NCBI website. Identifier ("reference SNP", "refSNP" or "rs#").
"단일염기다형성(single nucleotide polymorphism, SNP)"은 게놈에서 단일염기(A, T, C 또는 G)가 종의 멤버들간 또는 한 개체(individual)의 쌍 염색체 간에 다른 경우에 발생하는 DNA 서열의 다양성을 의미한다. 예를 들어, 서로 다른 개체의 세 개의 DNA 단편들(예: AAGT[A/A]AG, AAGT[A/G]AG,AAGT[G/G]AG)처럼 단일염기에서 차이를 포함하는 경우, 두 개의 대립 유전자(A 또는 G)라고 부르며, 일반적으로 거의 모든 SNPs는 두 개의 대립 유전자를 가진다. 한 집단(population)내에서, SNP는 소수 대립인자 빈도(minor allele frequency, MAF; 특정 집단에서 발견되는 유전자위치(locus)에서 가장 낮은 대립인자 빈도)로 할당될 수 있다. 단일염기는 폴리뉴클레오타이드 서열에 변화(대체), 제거(결실) 또는 첨가(삽입)될 수 있다. SNP는 번역 프레임의 변화를 유발할 수 있다."Single nucleotide polymorphism (SNP)" is the diversity of DNA sequences that occurs when a single nucleotide (A, T, C, or G) in the genome differs between members of a species or between pairs of chromosomes in an individual. means For example, when three DNA fragments from different individuals (eg, AAGT[A/A]AG, AAGT[A/G]AG, AAGT[G/G]AG) contain differences in a single base, Called two alleles (A or G), in general almost all SNPs have two alleles. Within a population, SNPs can be assigned a minor allele frequency (MAF; the lowest allele frequency at a locus found in a particular population). A single base can be changed (replaced), removed (deleted), or added (inserted) into the polynucleotide sequence. SNPs can cause changes in the translation frame.
"유전자형(genotype)"이라는 용어는 세포 또는 조직 샘플에서 특정 유전자의 특이적 대립유전자를 지칭한다.The term “genotype” refers to a specific allele of a particular gene in a cell or tissue sample.
"대립인자" 또는 '대립 유전자'란 같은 염색체 위치(same chromosomal locus) 를 점유하는 한 유전자의 둘 또는 그 이상의 선택적인 형태(alternative forms) 중 하나를 뜻한다."Allele" or "allele" means one of two or more alternative forms of a gene that occupy the same chromosomal locus.
"진단"은 병리 상태의 존재 또는 특징을 확인하는 것을 의미한다. 그 중에서도 본 발명은 특히 소세포폐암의 재발(Recurrence), 진행(progression), 전이(metastasis) 등을 예측하는 것을 포함한다. 이에, 소세포폐암의 재발 및 진행을 정확히 예측할 수 있는 지표가 매우 중요하며 조직의 분화도와 병기와 같은 임상적 지표를 보완하면서 치료의 반응을 예측할 수 있는 인자가 필요한데, 본 발명의 CD155의 rs1058402G>A SNP 또는 CD226의 rs763361C>T SNP가 이러한 지표 기능을 하므로 소세포폐암 진단 인자로 이용할 수 있다. 즉, 이러한 유전자들의 다형성 특성 측정은 소세포폐암의 분화도 및 병기, 진행을 예측하는데 유용한 지표(진단 마커)로 사용될 수 있다."Diagnosing" means identifying the presence or character of a pathological condition. Among them, the present invention particularly includes predicting recurrence, progression, metastasis, and the like of small cell lung cancer. Therefore, an indicator that can accurately predict the recurrence and progression of small cell lung cancer is very important, and a factor that can predict the response to treatment while supplementing clinical indicators such as the degree of differentiation and stage of the tissue is needed. Since the rs763361C>T SNP of SNP or CD226 functions as such an indicator, it can be used as a diagnostic factor for small cell lung cancer. That is, measurement of polymorphism of these genes can be used as a useful indicator (diagnostic marker) for predicting the degree of differentiation, stage, and progression of small cell lung cancer.
"진단용 마커 또는 진단 마커(diagnosis marker)" 란 소세포폐암을 가진 세포를 정상 세포와 구분하여 진단할 수 있는 물질로, 정상 세포에 비하여 소세포폐암을 가진 세포에서 증가 양상을 보이는 폴리펩타이드 또는 핵산(예: mRNA 등), 지질, 당지질, 당단백질, 당(단당류, 이당류, 다당류 등) 등과 같은 유기 생체 분자 등을 포함한다."Diagnostic marker or diagnostic marker" is a substance that can differentiate and diagnose cells with small cell lung cancer from normal cells, and a polypeptide or nucleic acid (e.g., : mRNA, etc.), lipids, glycolipids, glycoproteins, and organic biomolecules such as sugars (monosaccharides, disaccharides, polysaccharides, etc.).
"소세포폐암 환자의 생존 예후 예측용 마커" 란 소세포폐암 발병 위험성, 발병한 소세포폐암의 완치 여부, 혹은 경과를 예측할 수 있는 다형성을 가진 마커를 의미하며, 바람직하게는 상기에서 서술한 뉴클레오티드를 의미한다. 또한, 상기 환자는 소세포폐암 발병 위험성을 판별하기 위한 환자 또는 소세포폐암에 대하여 항암 화학 요법을 시행한 환자를 의미한다. "Marker for predicting survival prognosis of patients with small cell lung cancer" means a marker having a polymorphism that can predict the risk of small cell lung cancer, whether or not the onset of small cell lung cancer is cured, or the course, and preferably refers to the nucleotides described above. . In addition, the patient refers to a patient for determining the risk of developing small cell lung cancer or a patient who has undergone chemotherapy for small cell lung cancer.
"대상" 또는 "환자"는 인간, 소, 개, 기니아 피그, 토끼, 닭, 곤충 등을 포함하여 치료가 요구되는 임의의 단일 개체를 의미한다. 또한, 임의의 질병 임상 소견을 보이지 않는 임상 연구 시험에 참여한 임의의 대상 또는 역학연구에 참여한 대상 또는 대조군으로 사용된 대상이 대상에 포함된다."Subject" or "patient" means any single individual in need of treatment, including humans, cattle, dogs, guinea pigs, rabbits, chickens, insects, and the like. Also included in the subject are any subjects who participated in a clinical study trial that do not show any clinical manifestations of any disease, or subjects who participated in epidemiological studies or subjects used as controls.
"조직 또는 세포 샘플"은 대상 또는 환자의 조직으로부터 얻은 유사한 세포의 집합체를 의미한다. 조직 또는 세포 샘플의 공급원은 신선한, 동결된 및/또는 보존된 장기 또는 조직 샘플 또는 생검 또는 흡인물로부터의 고형조직; 혈액 또는 임의의 혈액 구성분; 대상의 임신 또는 발생의 임의의 시점의 세포일 수 있다. 조직 샘플은 또한 1차 또는 배양 세포 또는 세포주일 수 있다."Tissue or cell sample" means a collection of similar cells obtained from the tissue of a subject or patient. Sources of tissue or cell samples may include solid tissue from fresh, frozen and/or preserved organ or tissue samples or biopsies or aspirates; blood or any blood component; The cells may be at any time of conception or development in a subject. A tissue sample may also be a primary or cultured cell or cell line.
"핵산"은 임의의 DNA 또는 RNA, 예를 들어, 조직 샘플에 존재하는 염색체, 미토콘드리아, 바이러스 및/또는 세균 핵산을 포함하는 의미이다. 이중 가닥 핵산 분자의 하나 또는 두개 모두의 가닥을 포함하고, 무손상 핵산 분자의 임의의 단편 또는 일부를 포함한다."Nucleic acid" is meant to include any DNA or RNA, eg, chromosomal, mitochondrial, viral and/or bacterial nucleic acids present in a tissue sample. It includes one or both strands of a double-stranded nucleic acid molecule, and includes any fragment or portion of an intact nucleic acid molecule.
"유전자"는 단백질 코딩 또는 전사시에 또는 다른 유전자 발현의 조절시에 기능적 역할을 갖는 임의의 핵산 서열 또는 그의 일부를 의미한다. 유전자는 기능적 단백질을 코딩하는 모든 핵산 또는 단백질을 코딩 또는 발현하는 핵산의 일부만으로 이루어질 수 있다. 핵산 서열은 엑손, 인트론, 개시 또는 종료 영역, 프로모터 서열, 다른 조절 서열 또는 유전자에 인접한 특유한 서열 내에 유전자 이상을 포함할 수 있다.By “gene” is meant any nucleic acid sequence or portion thereof that has a functional role in protein coding or transcription or in the regulation of other gene expression. A gene may consist of any nucleic acid encoding a functional protein or only a portion of a nucleic acid encoding or expressing a protein. Nucleic acid sequences may include gene abnormalities within exons, introns, initiation or termination regions, promoter sequences, other regulatory sequences, or unique sequences adjacent to the gene.
"프라이머"는 상보성 RNA 또는 DNA 표적 폴리뉴클레오티드에 혼성화 하고 예를 들어 폴리머라제 연쇄 반응에서 발생하는 뉴클레오티딜 트랜스퍼라제의 작용에 의해 모노뉴클레오티드로부터 폴리뉴클레오티드의 단계적 합성을 위한 출발점으로 기능하는 올리고뉴클레오티드 서열을 의미한다.A "primer" is an oligonucleotide sequence that hybridizes to a complementary RNA or DNA target polynucleotide and serves as a starting point for the stepwise synthesis of polynucleotides from mononucleotides, for example, by the action of nucleotidyl transferases occurring in the polymerase chain reaction. means
"단백질"은 또한 기준 단백질과 본질적으로 동일한 생물 활성 또는 기능을 보유하는, 단백질의 단편, 유사체 및 유도체를 포함하는 것이다"Protein" also includes fragments, analogs and derivatives of proteins that retain essentially the same biological activity or function as a reference protein.
"치료"는 이롭거나 바람직한 임상적 결과를 수득하기 위한 접근을 의미한다. 본 발명의 목적을 위해서, 이롭거나 바람직한 임상적 결과는 비 제한적으로, 증상의 완화, 질병 범위의 감소, 질병 상태의 안정화 (즉, 악화되지 않음), 질병 진행의 지연 또는 속도의 감소, 질병 상태의 개선 또는 일시적 완화 및 경감 (부분적이거나 전체적으로), 검출 가능하거나 또는 검출되지 않거나의 여부를 포함한다. 또한, "치료"는 치료를 받지 않았을 때 예상되는 생존율과 비교하여 생존율을 늘이는 것을 의미할 수도 있다. 치료는 치료학적 치료 및 예방적 또는 예방조치 방법 모두를 가리킨다. 상기 치료들은 예방되는 장애뿐만 아니라 이미 발생한 장애에 있어서 요구되는 치료를 포함한다. 질병을 "완화(Palliating)"하는 것은 치료를 하지 않은 경우와 비교하여, 질병상태의 범위 및/또는 바람직하지 않은 임상적 징후가 감소되거나 및/또는 진행의 시간적 추이(time course)가 늦춰지거나 길어지는 것을 의미한다."Treatment" means an approach for obtaining beneficial or desirable clinical results. For the purposes of the present invention, beneficial or desirable clinical outcomes include, but are not limited to, alleviation of symptoms, reduction of the extent of the disease, stabilization (ie, not worsening) of the disease state, delay or reduction in the rate of disease progression, disease state improvement or temporary alleviation and alleviation (partial or total), detectable or undetectable. "Treatment" may also mean increasing survival as compared to the expected survival rate if not receiving treatment. Treatment refers to both therapeutic treatment and prophylactic or prophylactic methods. Such treatments include the treatment required for the disorder being prevented as well as the disorder that has already occurred. "Palliating" a disease means that the extent and/or undesirable clinical signs of the disease state are reduced and/or the time course of progression is delayed or prolonged, compared to no treatment. means to lose
또한 본 발명은 본 발명에 따른 조성물을 포함하는 소세포폐암 환자의 생존 예후 예측용 키트를 제공할 수 있고, 나아가 본 발명에 따른 조성물을 포함하는 소세포폐암 환자의 생존 예후 예측용 마이크로어레이를 제공할 수 있다.In addition, the present invention can provide a kit for predicting the survival prognosis of a small cell lung cancer patient comprising the composition according to the present invention, and further, it is possible to provide a microarray for predicting the survival prognosis of a small cell lung cancer patient comprising the composition according to the present invention. have.
본 발명의 키트는 소세포폐암 생존 예후의 예측용 마커인, CD155의 rs1058402G>A 또는 CD226의 rs763361C>T의 다형성 부위를 확인함으로써 소세포폐암 생존 예후를 예측하는 용도로 사용될 수 있다. 본 발명의 소세포폐암 생존 예후의 예측용 키트에는 상기 다형성을 확인하기 위한 폴리뉴클레오티드, 프라이머 또는 프로브 뿐만 아니라 분석 방법에 적합한 한 종류 또는 그 이상의 다른 구성 성분 조성물, 용액 또는 장치가 포함될 수 있다.The kit of the present invention can be used for predicting small cell lung cancer survival prognosis by identifying polymorphic sites of rs1058402G>A of CD155 or rs763361C>T of CD226, which are markers for predicting small cell lung cancer survival prognosis. The kit for predicting the survival prognosis of small cell lung cancer of the present invention may include polynucleotides, primers or probes for confirming the polymorphism, as well as one or more other component compositions, solutions or devices suitable for the analysis method.
또한, 본 발명의 키트는 PCR을 수행하기 위해 필요한 필수 요소를 포함하는 키트일 수 있다. PCR 키트는, 상기 SNP에 대한 특이적인 폴리뉴클레오티드, 프라이머 또는 프로브 외에도 테스트 튜브 또는 다른 적절한 컨테이너, 반응 완충액 (pH 및 마그네슘 농도는 다양), 데옥시뉴클레오타이드 (dNTPs), Taq-폴리머라아제 및 역전사효소와 같은 효소, DNase, RNAse 억제제, DEPC-수 (DEPC-water) 및 멸균수 등을 포함할 수 있다.In addition, the kit of the present invention may be a kit including essential elements necessary for performing PCR. The PCR kit contains, in addition to polynucleotides, primers or probes specific for the SNP, a test tube or other suitable container, reaction buffer (with varying pH and magnesium concentrations), deoxynucleotides (dNTPs), Taq-polymerase and reverse transcriptase. enzymes such as DNase, RNAse inhibitors, DEPC-water and sterile water, and the like.
또한 본 발명의 상기 마이크로어레이는 본 발명의 폴리뉴클레오티드, 프라이머 또는 프로브를 포함하는 것을 제외하고는 통상적인 마이크로어레이로 이루어질 수 있다.In addition, the microarray of the present invention may be composed of a conventional microarray except for containing the polynucleotide, primer or probe of the present invention.
마이크로어레이 상에서의 핵산의 혼성화 및 혼성화 결과의 검출은 당업계에 잘 알려져 있다. 상기 검출은 예를 들면, 핵산 시료를 형광 물질, 예를 들면, Cy3 및 Cy5와 같은 물질을 포함하는 검출가능한 신호를 발생시킬 수 있는 표지 물질로 표지한 다음, 마이크로어레이 상에 혼성화하고 상기 표지 물질로부터 발생하는 신호를 검출함으로써 혼성화 결과를 검출할 수 있다.Hybridization of nucleic acids on microarrays and detection of hybridization results are well known in the art. The detection is, for example, labeling the nucleic acid sample with a labeling material capable of generating a detectable signal including a fluorescent material, for example, a material such as Cy3 and Cy5, and then hybridizing on a microarray and the labeling material. A hybridization result can be detected by detecting a signal generated from
상기 마이크로어레이(Microarray) 방법은 종양 내의 수천 또는 심지어 수만 개의 유전자의 RNA 발현을 동시에 연구할 수 있어, 인간 질병의 분자적 기초에 대한 포괄적 통찰력을 보다 효과적으로 얻을 수 있게 해준다.The microarray method can simultaneously study the RNA expression of thousands or even tens of thousands of genes within a tumor, allowing more effective insight into the molecular basis of human disease.
또한, 이를 이용하여 종양 분류에서의 유전자 발현 패턴, 임상학적 결과 및 화학적 치료요법에 대한 반응의 평가가 가능하다.It can also be used to evaluate gene expression patterns in tumor classification, clinical outcomes, and response to chemotherapy.
나아가 본 발명은 소세포폐암 환자의 생존 예후 예측을 위한 정보를 제공하는 방법을 제공할 수 있는데, 상기 방법은 바람직하게, 검체로부터 추출한 핵산에 대하여, CD155의 rs1058402G>A 단일염기다형성 및 CD226의 rs763361C>T 단일염기다형성을 확인하는 단계를 포함한다.Furthermore, the present invention can provide a method for providing information for predicting the survival prognosis of a patient with small cell lung cancer, wherein the method preferably includes rs1058402G>A single nucleotide polymorphism of CD155 and rs763361C> of CD226 with respect to the nucleic acid extracted from the sample. and identifying the T single nucleotide polymorphism.
이때, 상기 CD155의 rs1058402G>A 다형성의 유전자형이 GG인 경우, GA 또는 AA인 경우에 비해 생존 예후가 높은 군으로 판정할 수 있고, 또한 상기 CD226의 rs763361C>T 다형성의 유전자형이 CT 또는 TT인 경우, CC에 비해 생존 예후가 높은 군으로 판정할 수 있다.In this case, when the genotype of the rs1058402G>A polymorphism of CD155 is GG, it can be determined as a group having a higher survival prognosis compared to the case of GA or AA, and when the genotype of the rs763361C>T polymorphism of CD226 is CT or TT , it can be determined as a group with a higher survival prognosis than CC.
본 발명의 일실시예에서는 상기 2가지 다형성에 대한 유전자형에 대해 예후가 좋지 않은 CD155의 rs1058402G>A 다형성의 GA 또는 AA 유전자형; 또는 상기 CD226의 rs763361C>T 다형성의 CC 유전자형;의 개수를 측정하고 상기 나쁜 유전자형의 개수와 항암제에 대한 화학요법 반응과의 관련성을 분석하였는데, 그 결과, 상기 나쁜 유전자형의 개수가 0개인 경우, 항암제에 대한 화학요법 반응이 80.4%이고, 1개인 경우, 항암제에 대한 화학요법 반응이 71.0%이고, 2개인 경우, 항암제에 대한 화학요법 반응이 61.3%인 것으로 나타났다. In one embodiment of the present invention, the GA or AA genotype of rs1058402G>A polymorphism of CD155 with poor prognosis for the genotypes for the two polymorphisms; Alternatively, the number of CC genotypes of the rs763361C>T polymorphism of CD226 was measured and the relationship between the number of the bad genotypes and the chemotherapy response to the anticancer agent was analyzed. As a result, the number of the bad genotypes was 0. The chemotherapy response to chemotherapy was 80.4%, and in the case of one patient, the chemotherapy response to the anticancer agent was 71.0%, and in the case of two patients, the chemotherapy response to the anticancer agent was 61.3%.
또한 CD155의 rs1058402G>A 다형성의 돌연변이와 단백질 구조분석을 통해, CD155의 rs1058402G>A 다형성에서 CD155의 67번째 아미노산인 알라닌(A)에서 트레오닌(T)으로 돌연변이 되는 경우, 항암제에 대한 화학요법 반응(chemotherapy response), 전체생존율(Overall survival: OS) 또는 무진행 생존율(Progression-free survival: PFS)이 낮다고 판단할 수 있고, 또한, CD155와 CD226의 결합력이 감소되어 T 세포활성 또는 NK 세포활성이 감소된다.In addition, through mutation and protein structure analysis of the rs1058402G>A polymorphism of CD155, mutations from alanine (A), the 67th amino acid of CD155, to threonine (T) in the rs1058402G>A polymorphism of CD155, chemotherapy response to anticancer drugs ( chemotherapy response), overall survival (OS), or progression-free survival (PFS) can be judged to be low, and the binding force between CD155 and CD226 is reduced, resulting in a decrease in T cell activity or NK cell activity do.
한편, 본 발명에 따른 상기 소세포폐암 환자의 생존 예후 예측을 위한 정보를 제공하는 방법에서, 상기 다형성을 확인하는 방법은 상기 CD155의 rs1058402G>A 및 CD226의 rs763361C>T 다형성의 유전자형을 확인하는 방법으로 수행될 수 있는데, 상기 유전자형의 확인은 시퀀싱 분석, 자동염기서열분석기를 사용한 시퀀싱 분석, 파이로시퀀싱(pyrosequencing), 마이크로어레이에 의한 혼성화, PCR-RELP법 (restriction fragment length polymorphism), PCR-SSCP법(single strand conformation polymorphism), PCR-SSO법(specific sequence oligonucleotide), PCR-SSO법과 도트 하이브리드화법을 조합한 ASO(allele specific oligonucleotide) 하이브리드화법, TaqMan-PCR법, MALDI-TOF/MS법, RCA법(rolling circle amplification), HRM (high resolution melting)법, 프라이머 신장법, 서던 블롯 하이브리드화법, 도트 하이브리드화법 등의 공지의 방법에 의하여 수행될 수 있다.On the other hand, in the method of providing information for predicting the survival prognosis of the small cell lung cancer patient according to the present invention, the method of confirming the polymorphism is a method of confirming the genotype of the rs1058402G>A of CD155 and rs763361C>T of the CD226 polymorphism. The genotype can be confirmed by sequencing analysis, sequencing analysis using an automatic sequencing analyzer, pyrosequencing, hybridization by microarray, PCR-RELP method (restriction fragment length polymorphism), PCR-SSCP method (single strand conformation polymorphism), PCR-SSO method (specific sequence oligonucleotide), ASO (allele specific oligonucleotide) hybridization method combining PCR-SSO method and dot hybridization method, TaqMan-PCR method, MALDI-TOF/MS method, RCA method (rolling circle amplification), HRM (high resolution melting) method, primer extension method, Southern blot hybridization method, it can be carried out by a known method such as a dot hybridization method.
또한, 상기 SNP 다형성의 결과들은 당업계에서 일반적으로 사용되는 통계학적 분석 방법을 이용하여 통계처리할 수 있으며, 예를 들면, 스튜던트 t-검정(Student's t-test), 카이-스퀘어 테스트 (Chi-square test), 선형회귀선 분석(linear regression line analysis), 다변량 로지스틱 회귀분석 (multiple logistic regression analysis) 등을 통해 얻은 연속 변수 (continuous variables), 절대 변수 (categorical variables), 대응비(odds ratio) 및 95% 신뢰구간 (confidence interval) 등의 변수를 이용하여 분석할 수 있다.In addition, the results of the SNP polymorphism can be statistically processed using statistical analysis methods commonly used in the art, for example, Student's t-test, chi-square test (Chi-) square test), linear regression line analysis, and multiple logistic regression analysis, such as continuous variables, categorical variables, odds ratio, and 95 It can be analyzed using variables such as % confidence interval.
또한, 상기 진단 방법은 소세포폐암에 따른 특정 마커의 발현 특징을 조사하는 것에 관한 것이고, 본 명세서에 개시된 방법은 소세포폐암 환자 치료를 위해 적절하거나 효과적인 요법을 평가할 때 유용한 데이터 및 정보를 얻기 위한 편리하고, 효율적이며, 비용 효과적인 수단을 제공할 수 있을 것이다.In addition, the diagnostic method relates to examining the expression characteristics of specific markers according to small cell lung cancer, and the method disclosed herein is convenient and useful for obtaining useful data and information when evaluating an appropriate or effective therapy for treating a patient with small cell lung cancer. , it will be possible to provide an efficient and cost-effective means.
소세포폐암 환자의 핵산은 이들 환자로부터 획득한 조직, 세포, 전혈, 혈청, 혈장, 타액, 객담, 뇌척수액 또는 뇨 등의 시료로부터 수득할 수 있으며, 그 핵산 시료는 DNA, mRNA, 또는 mRNA로부터 합성되는 cDNA를 포함한다.Nucleic acids from small cell lung cancer patients can be obtained from samples such as tissues, cells, whole blood, serum, plasma, saliva, sputum, cerebrospinal fluid or urine obtained from these patients, and the nucleic acid sample is DNA, mRNA, or synthesized from mRNA. contains cDNA.
상기 소세포폐암 환자의 핵산은 페놀/클로로포름 추출법 및 프로테아제 K 처리방법과 같은 통상의 방법과 분리방법에 의하여 수행될 수 있으며, 또한 표적 핵산을 PCR을 통하여 증폭하고 이를 정제하여 얻을 수 있다.The nucleic acid of the small cell lung cancer patient can be performed by conventional methods and separation methods such as phenol/chloroform extraction and protease K treatment, and can also be obtained by amplifying the target nucleic acid through PCR and purifying it.
또한 본 발명은 소세포폐암에 대한 항암화학요법 치료 후 재발 또는 전이 방지를 위해 필요한 항암제 투여량 및 투여방법 결정을 위한 정보도 제공할 수 있다.In addition, the present invention can also provide information for determining the amount and administration method of an anticancer agent necessary to prevent recurrence or metastasis after chemotherapy treatment for small cell lung cancer.
즉, 본 발명은 소세포폐암 환자로부터 분리된 생물학적 시료로부터 CD155의 rs1058402G>A 다형성 및 CD226의 rs763361C>T 다형성을 확인하여 예후가 나쁜 경우와 그렇지 않은 경우에 따라 추가적으로 투여할 항암제의 종류, 양 및 농도 등 항암제 투여 방법을, 해당 암의 종류에 따라 적합하도록 서로 상이하게 적용할 수 있다.That is, the present invention confirmed the rs1058402G>A polymorphism of CD155 and the rs763361C>T polymorphism of CD226 from a biological sample isolated from a patient with small cell lung cancer, and the type, amount, and concentration of the anticancer agent to be additionally administered depending on the case of poor prognosis or otherwise Anticancer drug administration methods, such as, may be applied differently to suit the type of cancer.
이하, 본 발명의 구성요소와 기술적 특징을 다음의 실시예들을 통하여 보다 상세하게 설명하고자 한다. 그러나 하기 실시예들은 본 발명의 내용을 예시하는 것일 뿐 발명의 범위가 실시예에 의해 한정되는 것은 아니다.Hereinafter, the components and technical features of the present invention will be described in more detail through the following examples. However, the following examples are merely illustrative of the content of the present invention, and the scope of the present invention is not limited by the examples.
<실험재료 및 방법><Test materials and methods>
1. 연구대상 선정1. Selection of research subjects
본 연구는 관찰 후향적 연구로 진행하였다. 2001년 3월부터 2017년 11월까지 대구 경북대학교 병원(KNUH)에서 임상 진단을 받은 261명의 소세포폐암(SCLC) 환자를 대상으로 하였다. 환자 선택 과정은 도 1에 나타내었다. 모든 환자는 1차 치료로서 백금 이중 화학요법이 시행되었고 최소 2 주기로 항암요법 치료를 받았다. 또한, 방사선 요법과 함께 화학요법을 받은 제한 단계(limited-stage)의 SCLC 환자는 화학요법 반응에 대한 방사선의 혼란 효과를 피하기 위해 본 실험에서 제외시켰다. 2주기의 화학요법 후, 방사선 요법을 순차적으로 시행한 환자들은 포함시켰다. 이 경우 2주기 화학요법 후의 반응을 화학요법에 대한 최선의 반응으로 고려하였다. 환자들에게는 2가지의 화학요법을 적용하였는데, 1가지 방법은 1일차에 시스플라틴 60 mg/m2을 투여하고 매 3주마다 에토포사이드 100 mg/m2를 1일, 2일 및 3일 차에 투여하였다. 다른 방법은 1일 차에 시스플라틴 60 mg/m2를 투여하고, 매 4주마다 이리노테칸 60 mg//m2를 1일, 8일, 15일 차에 투여하였다. 환자의 질병 진행, 주요 독성 또는 환자 또는 의사의 결정에 따라 치료 유지여부를 결정하였다. 고형 종양의 반응 평가 기준을 사용하여 화학요법에 대한 반응을 평가하였다. 화학요법 반응 범주는 반응자와 무반응자로 구분하였다. 반응자에 대하여 완전 반응 또는 부분 반응을 갖는 환자를 최상의 반응자로 간주하였고, 안정된 질환 또는 진행성 질환을 갖는 환자는 비반응자로 간주하였다.This study was conducted as an observational retrospective study. From March 2001 to November 2017, 261 small cell lung cancer (SCLC) patients who were clinically diagnosed at Daegu Kyungpook National University Hospital (KNUH) were included. The patient selection process is shown in FIG. 1 . All patients received platinum doublet chemotherapy as the primary treatment and received at least 2 cycles of chemotherapy. In addition, patients with limited-stage SCLC who received chemotherapy in conjunction with radiation therapy were excluded from this study to avoid confounding effects of radiation on chemotherapy response. Patients who received radiotherapy sequentially after 2 cycles of chemotherapy were included. In this case, the response after 2 cycles of chemotherapy was considered as the best response to chemotherapy. Two chemotherapy regimens were applied to the patients, one of which was cisplatin 60 mg/m 2 on
본 연구는 한국과학기술원 기관 심의위원회의 승인을 받아서 진행하였다. 유전형 검사용 혈액 샘플은 보건복지부가 지원하는 국립보건원 국립 바이오뱅크로부터 제공받아 사용하였다. 모든 혈액 샘플은 1차 화학요법 전에 채취하였고, 모든 피험자는 18세 이상이며 화학요법 전 사전 동의를 얻어 진행하였다. This study was conducted with the approval of the institutional review committee of the Korea Advanced Institute of Science and Technology. Blood samples for genotyping were provided and used by the National Institutes of Health, National Biobank, supported by the Ministry of Health and Welfare. All blood samples were collected prior to first-line chemotherapy, and all subjects were 18 years of age or older, and informed consent was obtained prior to chemotherapy.
2. 다형성 선정 및 지노타이핑2. Polymorphism Selection and Genotyping
공공 데이터베이스 및 관련 문헌을 검색하여 면역 체크 포인트 경로에 관련된 38개의 유전자를 선택하였다. 면역 체크 포인트 유전자의 다형성을 수집하기 위해 공개 SNP 데이터베이스 (http://www.ncbi.nlm.nih.gov/SNP) 및 RegulomeDB (http://www.regulomedb.org/)를 사용하였다. HapMap JPT 데이터를 기반으로 ≤0.05의 마이너 대립 유전자 빈도를 제외한 후, SNPinfo 웹 서버 (https://snpinfo.niehs.nih.gov/)에서 기능적 SNP 예측을 위한 FuncPred 유틸리티를 사용하여 216개의 잠재적 기능성을 갖는 SNP를 수집하였다. LD 태그된 SNP 선택을 위해 TagSNP 유틸리티를 사용하여 연관불균형 (LD) 계수 r2이 0.8 이상인 것을 제외하여 123개의 SNP를 선택하였다. 123개의 SNP 중 call rate가 95 % 미만이거나 Hardy-Weinberg 평형 (HWE)에 대한 P 값이 0.05 미만인 27개는 분석에서 제외시켰다. 33개의 면역 체크 포인트 유전자에서 96개의 SNP를 연관성 및 반응연구를 위한 분석 대상으로 선정하였다. 또한, Sequenom MassARRAY iPLEX Platform (Agena Bioscience, San Diego, USA)을 사용하여 유전형 분석을 수행하였다. 모든 유전형 분석은 환자 상태와 관련하여 블라인드 상태로 수행하였고, 모든 방법은 관련 지침 및 규정에 따라 수행하였다.38 genes involved in immune checkpoint pathways were selected by searching public databases and related literature. The public SNP database (http://www.ncbi.nlm.nih.gov/SNP) and RegulomeDB (http://www.regulomedb.org/) were used to collect polymorphisms of immune checkpoint genes. After excluding minor allele frequencies of ≤0.05 based on HapMap JPT data, 216 potential functionalities were identified using the FuncPred utility for functional SNP prediction on the SNPinfo web server (https://snpinfo.niehs.nih.gov/). SNPs were collected. For LD-tagged SNP selection, 123 SNPs were selected using the TagSNP utility, excluding those with linkage disequilibrium (LD) coefficient r 2 greater than or equal to 0.8. Of the 123 SNPs, 27 with a call rate of less than 95% or a P value of less than 0.05 for Hardy-Weinberg equilibrium (HWE) were excluded from the analysis. 96 SNPs from 33 immune checkpoint genes were selected for analysis for association and response studies. In addition, genotyping was performed using the Sequenom MassARRAY iPLEX Platform (Agena Bioscience, San Diego, USA). All genotyping analyzes were performed blindly with respect to the patient's condition, and all methods were performed according to the relevant guidelines and regulations.
3. 통계처리3. Statistical processing
HWE는 자유도가 1인 적합도 χ2 테스트를 사용하여 분석하였다. 임상 변수 또는 유전형과 화학요법 반응 간의 비교를 위해 로지스틱 회귀 분석을 사용하여 오즈비(Odds ratio: OR)와 95 % 신뢰 구간 (CI)을 계산하였다. 전체 생존율(OS)은 첫 번째 화학요법 처리부터 사망 또는 마지막 후속 조치까지 분석하였다. 무진행 생존율(Progression-free survival: PFS)은 1차 화학 요법 당일부터 질병이 진행되거나 어떤 원인으로든 사망할 때까지 분석하였다. Kaplan-Meier 방법은 생존 결과를 추정하는 데 사용하였고, 로그 순위 테스트는 여러 그룹 또는 유전자형에서 OS를 비교하는 데 사용하였다. 다변량 Cox 비례 위험 모델을 사용하여 위험 비율(HR) 및 95 % CI를 추정하였다. 조정 요인은 연령, 성별, 흡연 상태, 병기, ECOG (Eastern Cooperative Oncology Group) 수행 상태, 체중 감소, NSE(neuron specific enolase) 수준, 1차 화학요법, 2차 화학요법 및 원발 종양에 대한 방사선으로 하였다. 0.05 미만의 P 값을 통계적으로 유의미한 것으로 간주하였고, 통계 분석은 Windows 용 통계 분석 시스템 버전 9.4 (SAS Institute, Cary, NC, USA)를 사용하여 수행하였다. HWE was analyzed using the goodness-of-fit χ2 test with 1 degree of freedom. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression analysis for comparisons between clinical variables or genotype and chemotherapy response. Overall survival (OS) was analyzed from first chemotherapy treatment to death or last follow-up. Progression-free survival (PFS) was analyzed from the day of first-line chemotherapy until disease progression or death from any cause. The Kaplan-Meier method was used to estimate survival outcomes, and the log-rank test was used to compare OS in different groups or genotypes. Hazard ratios (HR) and 95% CI were estimated using a multivariate Cox proportional hazards model. Adjustment factors were age, sex, smoking status, stage, ECOG (Eastern Cooperative Oncology Group) performance status, weight loss, neuron specific enolase (NSE) level, first-line chemotherapy, second-line chemotherapy, and radiation for primary tumor. . P values less than 0.05 were considered statistically significant, and statistical analysis was performed using Statistical Analysis System Version 9.4 for Windows (SAS Institute, Cary, NC, USA).
4. CD155 A67T 변이에 대한 구조 모델링4. Structural Modeling for the CD155 A67T Mutation
CD155의 rs1058402G>A 다형성에 대하여 코돈 67에서 알라닌(A)의 트레오닌(T)으로의 변이에 대한 효과를 확인하기 위해, CD155(A67T)의 돌연변이 구조를 MODELLER v9.12를 사용하여 야생형 CD155의 결정 구조(PDB : 6ISC)와 비교하여 모델링하였다. 적어도 10개의 구조 위반이 UCSF Chimera v1.14를 이용한 모델/정밀루프(루프 모델링 프로토콜 DOPE)에 의해 확인되었고, 구조는 위반을 보이지 않았으며 가장 낮은 에너지를 모델로 선택했다. CD226/CD155 (야생형 VS A67T 돌연변이)의 모든 이미지는 PyMOL (https://pymol.org/2/)을 이용하여 제작하였다. To confirm the effect on the mutation of alanine (A) to threonine (T) at codon 67 on the rs1058402G>A polymorphism of CD155, the mutant structure of CD155 (A67T) was used to determine wild-type CD155 using MODELLER v9.12. The model was compared with the structure (PDB: 6ISC). At least 10 structural violations were identified by model/fine loop (loop modeling protocol DOPE) using UCSF Chimera v1.14, the structure showed no violations and the lowest energy was chosen as the model. All images of CD226/CD155 (wild-type VS A67T mutant) were generated using PyMOL (https://pymol.org/2/).
<실시예 1> 환자특성 및 임상학적 예측 인자<Example 1> Patient characteristics and clinical predictors
환자들의 임상적 특성에 따른 화학요법 반응과 전체생존율(OS)의 결과를 하기 표 1에 나타내었다. 전체 반응률은 72.8 % (95 % CI = 67.4-78.2 %)인 것으로 나타났다. 생존 시간의 중앙 값(MST)은 10.4 개월(95 % CI = 9.1-11.1 개월)인 것으로 나타났다. 반응률은 에토포사이드/시스플라틴 요법보다 이리노테칸/시스플라틴 요법에서 더 높은 것으로 나타났고(78.7 % vs 67.2 %, P = 0.04), OS는 요법에 따라 다르지 않은 것으로 나타났다(MST, 10.0 개월 vs 10.7 개월, P = 0.88, 표 1). OS와 연령, 단계, ECOG 수행 상태, 체중 감소, NSE 수준, 2차 화학요법 및 종양 방사선과 관련성은 하기 표 1(화학요법 반응 및 임상 변수에 따른 전체 생존에 대한 일변량 분석결과)에 나타내었다.The results of the chemotherapy response and overall survival (OS) according to the clinical characteristics of the patients are shown in Table 1 below. The overall response rate was found to be 72.8% (95% CI = 67.4-78.2%). The median survival time (MST) was found to be 10.4 months (95% CI = 9.1-11.1 months). The response rate was higher with the irinotecan/cisplatin regimen than with the etoposide/cisplatin regimen (78.7% vs 67.2%, P = 0.04), and the OS did not differ according to the regimen (MST, 10.0 months vs 10.7 months, P = 0.88, Table 1). OS, age, stage, ECOG performance status, weight loss, NSE level, second-line chemotherapy and tumor radiation and the correlation are shown in Table 1 (univariate analysis results for overall survival according to chemotherapy response and clinical variables).
<실시예 2> 다형성이 치료 결과에 미치는 영향 분석<Example 2> Analysis of the effect of polymorphism on treatment outcome
선정된 96개의 다형성 중에서, CD155 rs1058402G>A (Ala67Thr, A67T) 및 CD226 rs763361C>T (Gly307Ser, G307S) 다형성은 화학요법 반응과 OS 모두에서 관련성이 있는 것으로 나타났다. rs1058402G>A는 더 나쁜 화학요법 반응 및 OS와 유의하게 연관성이 있는 것으로 나타났다(dominant 모델(dominant model)에서 조정된 OR [aOR] = 0.52, 95 % CI = 0.27-0.99, P = 0.05 및 조정된 HR [aHR] = 1.55, 95 % CI). = 1.12-2.14, P = 0.01; 표 2 및 도 2A). 구체적으로, rs1058402 다형성의 유전자형으로 GA 또는 AA인 경우, GG에 비해 화학요법 반응 및 OS의 예후가 나쁘게 나타났다. PFS에 대한 rs1058402 다형성의 영향은 OS와 동일한 경향을 보였으나 통계적으로 유의하지 않았다(dominant 모델에서 aHR = 1.30, 95 % CI = 0.96-1.76, P = 0.09). 또한, rs763361C>T 다형성은 각각 유의하게 rs1058402 다형성에 비해 더 좋은 화학요법 반응, OS 및 PFS를 나타내었다(dominant 모델에서 조정된 aOR = 2.03, 95 % CI = 1.10-3.75, P = 0.02; aHR = 0.69, 95 % CI = 0.51-0.94 , P = 0.02; aHR = 0.73, 95 % CI = 0.54-0.97, P = 0.03, 표 2 및 도 2B). rs763361 다형성과 소세포폐암에 대한 화학요법 반응, OS 및 PFS 반응에 있어서 상기 다형성의 유전자형 분석결과는, rs763361 다형성의 유전자형이 CT 또는 TT인 경우, CC 인 경우에 비해 예후가 더 좋은 것으로 나타났다(표 2; CD155 rs1058402 및 CD226 rs763361 다형성의 유전자형에 따른 화학요법 반응 및 생존 결과에 대한 연관성 분석결과). Of the 96 selected polymorphisms, the CD155 rs1058402G>A (Ala67Thr, A67T) and CD226 rs763361C>T (Gly307Ser, G307S) polymorphisms were found to be associated with both chemotherapy response and OS. rs1058402G>A was found to be significantly associated with worse chemotherapy response and OS (adjusted OR [aOR] = 0.52, 95% CI = 0.27-0.99, P = 0.05 in the dominant model and adjusted for HR [aHR] = 1.55, 95% CI). = 1.12-2.14, P = 0.01; Table 2 and Figure 2A). Specifically, when the genotype of the rs1058402 polymorphism was GA or AA, the prognosis of chemotherapy response and OS was worse than that of GG. The effect of the rs1058402 polymorphism on PFS showed the same trend as that of OS, but was not statistically significant (aHR = 1.30, 95% CI = 0.96-1.76, P = 0.09 in the dominant model). In addition, the rs763361C>T polymorphism each showed significantly better chemotherapy response, OS and PFS compared to the rs1058402 polymorphism (adjusted aOR = 2.03, 95% CI = 1.10-3.75, P = 0.02; aHR = in the dominant model) 0.69, 95% CI = 0.51-0.94, P = 0.02; aHR = 0.73, 95% CI = 0.54-0.97, P = 0.03, Table 2 and Figure 2B). The genotyping results of the rs763361 polymorphism and the chemotherapy response, OS and PFS response to small cell lung cancer showed that when the genotype of the rs763361 polymorphism was CT or TT, the prognosis was better than that of CC (Table 2). ; Results of association analysis on chemotherapy response and survival outcomes according to genotype of CD155 rs1058402 and CD226 rs763361 polymorphisms).
본 발명자들은 또한 확장 병기(extensive stage)에서의 생존 결과도 분석하였다. 확장 병기의 SCLC에서 rs1058402 및 rs763361은 모두 일변량 분석에서 OS와 연관성이 있는 것으로 나타났고(dominant 모델에서 각각 Log Rank P = 0.03 및 0.006), 다변량 분석에서는 rs1058402 다형성만이 OS와 연관성이 있는 것으로 나타났다(dominant 모델에서 aHR = 1.75, 95 % CI = 1.21-2.53, P = 0.003). 또한 PFS는 OS와 동일한 경향을 보였으나 통계적으로 유의하지 않았다(dominant 모델에서 rs1058402의 aHR = 1.34, 95 % CI = 0.94-1.90, P = 0.11, rs763361의 aHR = 0.79, 95 % CI = 0.56- 1.10, P = 0.16)(표 3 참조).We also analyzed survival outcomes in the extensive stage. In extended-stage SCLC, both rs1058402 and rs763361 were found to be associated with OS in univariate analysis (Log Rank P = 0.03 and 0.006 in the dominant model, respectively), and only the rs1058402 polymorphism was found to be associated with OS in multivariate analysis. (aHR = 1.75, 95% CI = 1.21-2.53, P = 0.003 in the dominant model). Also, PFS showed the same trend as OS, but was not statistically significant (in the dominant model, aHR = 1.34 for rs1058402, 95% CI = 0.94-1.90, P = 0.11, aHR = 0.79 for rs763361, 95% CI = 0.56- 1.10 , P = 0.16) (see Table 3).
rs1058402 및 rs763361의 다형성 변이가 화학요법 반응 및 OS에 미치는 영향은 화학요법 반응에 대한 화학요법 양생법(chemotherapy regimen)을 제외하고는 연령, 성별 등 임상 변수에 따라 차이가 없는 것으로 나타났다(표 4 참조).The effect of polymorphic mutations in rs1058402 and rs763361 on chemotherapy response and OS did not differ according to clinical variables such as age and sex, except for the chemotherapy regimen for chemotherapy response (see Table 4). .
<실시예 3> rs1058402 및 rs763361의 조합에 의한 치료 결과에 미치는 영향 분석<Example 3> Analysis of effects on treatment results by the combination of rs1058402 and rs763361
본 발명자들은 rs1058402 및 rs763361 다형성의 조합과 소세포폐암 치료와의 관련성에 대한 분석을 수행하였다.The present inventors performed an analysis on the association of the combination of polymorphisms rs1058402 and rs763361 with the treatment of small cell lung cancer.
그 결과, rs1058402 다형성의 유전자형이 GA 또는 AA인 경우와 rs763361 다형성의 유전자형이 CC인 경우, 화학요법 반응 및 OS에서 좋지 않은 결과와 관련성이 있는 것으로 나타났다. 따라서 상기 다형성의 유전자형을 나쁜 유전자형으로 간주하였고, 나쁜 유전자형의 수가 증가함에 따라 화학요법 반응이 감소하는 것으로 나타났다(나쁜 유전자형 0개-80.4 % 반응자, 1개 나쁜 유전자형- 71.0 % 반응자, 2 개 나쁜 유전자형 61.3 % 반응자; aOR = 0.52, 95 % CI = 0.33-0.81, Ptrend = 0.004; 표 5). 또한 MST는 나쁜 유전자형의 수가 증가함에 따라 유의하게 감소하는 것으로 나타났다(MST = 0개 나쁜 유전자형에서 11.5 개월, 1개 나쁜 유전자형에서 9.5 개월, 2개의 나쁜 유전자형에서 7.2 개월, aHR = 1.48, 95 % CI = 1.19-1.84, Ptrend = 4 × 10-4; 표 5 및 도 2C). 또한, 나쁜 유전자형의 수가 증가함에 따라 PFS도 크게 감소하는 것으로 나타났다(Ptrend = 0.009)(표 5; 화학요법 반응 및 생존분석과 rs1058402G> A 및 rs763361C> T 유전자형의 조합과의 관련성 분석결과). As a result, when the genotype of the rs1058402 polymorphism was GA or AA, and the genotype of the rs763361 polymorphism was CC, it was found that the chemotherapy response and OS were associated with poor outcomes. Thus, the polymorphic genotype was considered a bad genotype and showed a decrease in chemotherapy response as the number of bad genotypes increased (0 bad genotypes - 80.4% responders, 1 bad genotype - 71.0% responders, 2 bad genotypes) 61.3% responders; aOR = 0.52, 95% CI = 0.33-0.81, Ptrend = 0.004; Table 5). MST also appeared to decrease significantly with increasing number of bad genotypes (MST = 11.5 months for 0 bad genotypes, 9.5 months for 1 bad genotype, 7.2 months for 2 bad genotypes, aHR = 1.48, 95% CI = 1.19-1.84, Ptrend = 4 × 10-4 (Table 5 and Figure 2C). In addition, it was shown that PFS also decreased significantly with increasing number of bad genotypes (Ptrend = 0.009) (Table 5; analysis of association between chemotherapy response and survival analysis and the combination of rs1058402G > A and rs763361C > T genotypes).
확장 병기를 가진 환자만을 분석한 결과, rs1058402와 rs763361 다형성의 조합 효과는 각각 화학요법 반응, OS 및 PFS에서 여전히 유의미한 것으로 나타났다(aOR = 0.55, 95 % CI = 0.33-0.93, Ptrend = 0.03; aHR = 1.55, 95 % CI = 1.21-1.98, Ptrend = 6 × 10-4 : aHR = 1.28, 95 % CI = 1.07-1.59, Ptrend = 0.04).Analysis of only patients with expanded stage showed that the combined effects of the rs1058402 and rs763361 polymorphisms were still significant on chemotherapy response, OS and PFS, respectively (aOR = 0.55, 95% CI = 0.33-0.93, Ptrend = 0.03; aHR = 1.55, 95% CI = 1.21-1.98, Ptrend = 6 × 10-4: aHR = 1.28, 95% CI = 1.07-1.59, Ptrend = 0.04).
<실시예 4> CD 155 rs1058402 G>A(A67T) 다형성의 구조분석을 통한 기능성 예측<Example 4> Functional prediction through structural analysis of CD 155 rs1058402 G>A(A67T) polymorphism
CD155 유전자의 rs1058402 G>A 다형성은 CD155 단백질의 코돈 67번째에서 알라닌이 트레오닌으로 돌연변이가 발생한다. CD155는 면역세포의 CD226에 결합하여 공동 자극 신호로 작용한다. PyMOL (https://pymol.org/2/)을 사용하여 3차원 구조 모델을 생성하고 이러한 아미노산 변화가 CD155의 기능에 영향을 미치는지를 분석하였다.In the rs1058402 G>A polymorphism of the CD155 gene, alanine to threonine at codon 67 of the CD155 protein is mutated. CD155 binds to CD226 of immune cells and acts as a co-stimulatory signal. A three-dimensional structural model was generated using PyMOL (https://pymol.org/2/) and analyzed whether these amino acid changes affect the function of CD155.
그 결과, 도 3에 나타낸 바와 같이, CD155 코돈 67번째 알라닌이 트레오닌으로의 변화에 의해 CD155의 S74 및 G73까지의 거리가 단축되는 것을 알 수 있었다(각각 6.3Å에서 2.9Å으로, 4.4Å에서 3.3Å으로 단축, 도 3B, 3C). T67과 S74 사이의 짧은 거리는 새로운 수소 결합이 생성된 것으로 나타났다(도 3C). 이러한 변화로 인해 CD155의 S74와 CD226의 N116 사이의 거리가 멀어지게 되고(2.7Å에서 6.0Å으로) 수소 결합이 손실되는 것으로 나타났다(도 3B, 3C). 또한, CD155 A67T는 CD155의 G70과 CD226의 E185 사이의 거리 확장(3.3Å에서 6.0Å까지)에 의해 다른 중요한 상호작용에 영향을 미쳐 수소 결합이 손실됨을 알 수 있었다(도 3D). 따라서 증가된 거리와 수소 결합의 손실은 CD155와 CD226 사이의 결합 활성을 약화시킬 수 있다는 것을 알 수 있었다. 따라서 CD155 코돈 67에서 알라닌이 트레오닌으로의 변이는 CD155와 CD226의 결합을 방해하여 T 세포활성을 감소시킴으로써 궁극적으로 암세포의 활성은 증가시키고 암세포를 억제하는 활성을 감소시켜 암 환자의 암의 진행을 더욱 악화시킬 수 있음을 알 수 있었다.As a result, as shown in FIG. 3 , it was found that the distance from CD155 to S74 and G73 was shortened by the change of the 67th alanine of CD155 codon to threonine (from 6.3 Å to 2.9 Å and 4.4 Å to 3.3 Å, respectively). shortened to Å, Figures 3B, 3C). The short distance between T67 and S74 indicated that new hydrogen bonds were created (Fig. 3C). This change resulted in an increase in the distance between S74 of CD155 and N116 of CD226 (from 2.7 Å to 6.0 Å) and loss of hydrogen bonding (Figs. 3B, 3C). In addition, it was found that CD155 A67T affected other important interactions by distance extension (from 3.3 Å to 6.0 Å) between G70 of CD155 and E185 of CD226, resulting in loss of hydrogen bonds (Fig. 3D). Therefore, it was found that the increased distance and loss of hydrogen bonds could weaken the binding activity between CD155 and CD226. Therefore, the mutation of alanine to threonine at CD155 codon 67 interferes with the binding of CD155 and CD226 and reduces T cell activity, ultimately increasing the activity of cancer cells and decreasing the activity of inhibiting cancer cells, thereby further prolonging cancer progression in cancer patients. I knew it could make it worse.
이제까지 본 발명에 대하여 그 바람직한 실시예들을 중심으로 살펴보았다. 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자는 본 발명이 본 발명의 본질적인 특성에서 벗어나지 않는 범위에서 변형된 형태로 구현될 수 있음을 이해할 수 있을 것이다. 그러므로 개시된 실시예들은 한정적인 관점이 아니라 설명적인 관점에서 고려되어야 한다. 본 발명의 범위는 전술한 설명이 아니라 특허청구범위에 나타나 있으며, 그와 동등한 범위 내에 있는 모든 차이점은 본 발명에 포함된 것으로 해석되어야 할 것이다.So far, with respect to the present invention, the preferred embodiments have been looked at. Those of ordinary skill in the art to which the present invention pertains will understand that the present invention can be implemented in a modified form without departing from the essential characteristics of the present invention. Therefore, the disclosed embodiments are to be considered in an illustrative rather than a restrictive sense. The scope of the present invention is indicated in the claims rather than the foregoing description, and all differences within the scope equivalent thereto should be construed as being included in the present invention.
<110> Kyungpook National University Industry-Academic Cooperation Foundation <120> Diagnostic methods for prognosis of small-cell lung cancer using CD155 and CD226 SNP <130> PN2012-624 <160> 8 <170> KoPatentIn 3.0 <210> 1 <211> 500 <212> DNA <213> Artificial Sequence <220> <223> CD155 <400> 1 acaccccacg gtccaccggg gatccagggc cccagcgtgc aagtcgcgcc aggtgcccgg 60 gctcctggag cccctcccta tctagtccaa gaacgccccg ggtctgacac cttctcttcg 120 gttctccgca ggggacgtcg tcgtgcaggc gcccacccag gtgcccggct tcttgggcga 180 ctccgtgacg ctgccctgct acctacaggt gcccaacatg gaggtgacgc atgtgtcaca 240 gctgacttgg cgcggcatgg tgaatctggc agcatggccg tcttccacca aacgcagggc 300 cccagctatt cggagtccaa acggctggaa ttcgtggcag ccagactggg cgcggagctg 360 cggaatgcct cgctgaggat gttcgggttg cgcgtagagg atgaaggcaa ctacacctgc 420 ctgttcgtca cgttcccgca gggcagcagg agcgtggata tctggctccg agtgcttggt 480 gagcaggggg ttttggggag 500 <210> 2 <211> 1000 <212> DNA <213> Artificial Sequence <220> <223> CD226 <400> 2 catcttgcca acacaagagg aaagcctgca tgagagtgag gccaagacca gggaaatgga 60 tccaacactc tggaaaggga ttcagaagcc agtttatgcc catacttaat tctagacaca 120 acatttaagc cctggtaaat agcccttgcc caaagcttaa tctcccctgg atcattctgt 180 tatatgatac agtaagtttt cttttgtata taaaccagtt agagtcaggt tttctgaaac 240 agttctatga aaaatgattt taggtaatga agtatttttc ctatcaaagt aactcaattc 300 agacaactag tatctaaggt agaccttggg tagtggaaaa aaattgcata aagatccatg 360 catgagtaca taagagtcat tactaatgca ctcatgtcaa gaataagctt aaactctagt 420 ctttggtctg cgagagaagg ttggatagtt gacataaata tcctctcttg tatcatccat 480 ggattgattg gtaggttgac ggtagagatg ggacttctat agttattggg tgcctagaaa 540 gacaaacagc agagagtgtc aataattcac tgcatttcaa caactaatga agacattcaa 600 aacatacctc tcataaatgc aggcatgata tgggacaagt ttccattata attaatttga 660 taaaacattc tcattgtatt gaacttctgt tggaaatcat attcttgact gagatgcaac 720 agaaatctag tctagattaa tacttgctgt attgtgctat gaattacctg tttcaatgta 780 gaactccctc tcccaatgtt aagctatttt gataagaaca attactatca tttttatatg 840 gaaattctaa cacagtgtct gaactttaaa aaataagcaa cttaacatat aaaaagttaa 900 caaaactgac atcaagatga tattgtataa tcattaatct tctctaccgt aatcaagtca 960 ctttgaccac atatgtatgt atgtaacaga aaatatgcag 1000 <210> 3 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> rs1058402 forward primer <400> 3 tacaggtgcc caacatggag 20 <210> 4 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> rs1058402 reverse primer <400> 4 gctgccagat tcaccat 17 <210> 5 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> rs763361 forward primer <400> 5 ccatggattg attggtag 18 <210> 6 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> rs763361 reverse primer <400> 6 gtttgtcttt ctaggcaccc 20 <210> 7 <211> 343 <212> PRT <213> Artificial Sequence <220> <223> CD155 <400> 7 Met Ala Arg Ala Met Ala Ala Ala Trp Pro Leu Leu Leu Val Ala Leu 1 5 10 15 Leu Val Leu Ser Trp Pro Pro Pro Gly Thr Gly Asp Val Val Val Gln 20 25 30 Ala Pro Thr Gln Val Pro Gly Phe Leu Gly Asp Ser Val Thr Leu Pro 35 40 45 Cys Tyr Leu Gln Val Pro Asn Met Glu Val Thr His Val Ser Gln Leu 50 55 60 Thr Trp Ala Arg His Gly Glu Ser Gly Ser Met Ala Val Phe His Gln 65 70 75 80 Thr Gln Gly Pro Ser Tyr Ser Glu Ser Lys Arg Leu Glu Phe Val Ala 85 90 95 Ala Arg Leu Gly Ala Glu Leu Arg Asn Ala Ser Leu Arg Met Phe Gly 100 105 110 Leu Arg Val Glu Asp Glu Gly Asn Tyr Thr Cys Leu Phe Val Thr Phe 115 120 125 Pro Gln Gly Ser Arg Ser Val Asp Ile Trp Leu Arg Val Leu Ala Lys 130 135 140 Pro Gln Asn Thr Ala Glu Val Gln Lys Val Gln Leu Thr Gly Glu Pro 145 150 155 160 Val Pro Met Ala Arg Cys Val Ser Thr Gly Gly Arg Pro Pro Ala Gln 165 170 175 Ile Thr Trp His Ser Asp Leu Gly Gly Met Pro Asn Thr Ser Gln Val 180 185 190 Pro Gly Phe Leu Ser Gly Thr Val Thr Val Thr Ser Leu Trp Ile Leu 195 200 205 Val Pro Ser Ser Gln Val Asp Gly Lys Asn Val Thr Cys Lys Val Glu 210 215 220 His Glu Ser Phe Glu Lys Pro Gln Leu Leu Thr Val Asn Leu Thr Val 225 230 235 240 Tyr Tyr Pro Pro Glu Val Ser Ile Ser Gly Tyr Asp Asn Asn Trp Tyr 245 250 255 Leu Gly Gln Asn Glu Ala Thr Leu Thr Cys Asp Ala Arg Ser Asn Pro 260 265 270 Glu Pro Thr Gly Tyr Asn Trp Ser Thr Thr Met Gly Pro Leu Pro Pro 275 280 285 Phe Ala Val Ala Gln Gly Ala Gln Leu Leu Ile Arg Pro Val Asp Lys 290 295 300 Pro Ile Asn Thr Thr Leu Ile Cys Asn Val Thr Asn Ala Leu Gly Ala 305 310 315 320 Arg Gln Ala Glu Leu Thr Val Gln Val Lys Glu Gly Pro Pro Ser Glu 325 330 335 His Ser Gly Met Ser Arg Asn 340 <210> 8 <211> 336 <212> PRT <213> Artificial Sequence <220> <223> CD226 <400> 8 Met Asp Tyr Pro Thr Leu Leu Leu Ala Leu Leu His Val Tyr Arg Ala 1 5 10 15 Leu Cys Glu Glu Val Leu Trp His Thr Ser Val Pro Phe Ala Glu Asn 20 25 30 Met Ser Leu Glu Cys Val Tyr Pro Ser Met Gly Ile Leu Thr Gln Val 35 40 45 Glu Trp Phe Lys Ile Gly Thr Gln Gln Asp Ser Ile Ala Ile Phe Ser 50 55 60 Pro Thr His Gly Met Val Ile Arg Lys Pro Tyr Ala Glu Arg Val Tyr 65 70 75 80 Phe Leu Asn Ser Thr Met Ala Ser Asn Asn Met Thr Leu Phe Phe Arg 85 90 95 Asn Ala Ser Glu Asp Asp Val Gly Tyr Tyr Ser Cys Ser Leu Tyr Thr 100 105 110 Tyr Pro Gln Gly Thr Trp Gln Lys Val Ile Gln Val Val Gln Ser Asp 115 120 125 Ser Phe Glu Ala Ala Val Pro Ser Asn Ser His Ile Val Ser Glu Pro 130 135 140 Gly Lys Asn Val Thr Leu Thr Cys Gln Pro Gln Met Thr Trp Pro Val 145 150 155 160 Gln Ala Val Arg Trp Glu Lys Ile Gln Pro Arg Gln Ile Asp Leu Leu 165 170 175 Thr Tyr Cys Asn Leu Val His Gly Arg Asn Phe Thr Ser Lys Phe Pro 180 185 190 Arg Gln Ile Val Ser Asn Cys Ser His Gly Arg Trp Ser Val Ile Val 195 200 205 Ile Pro Asp Val Thr Val Ser Asp Ser Gly Leu Tyr Arg Cys Tyr Leu 210 215 220 Gln Ala Ser Ala Gly Glu Asn Glu Thr Phe Val Met Arg Leu Thr Val 225 230 235 240 Ala Glu Gly Lys Thr Asp Asn Gln Tyr Thr Leu Phe Val Ala Gly Gly 245 250 255 Thr Val Leu Leu Leu Leu Phe Val Ile Ser Ile Thr Thr Ile Ile Val 260 265 270 Ile Phe Leu Asn Arg Arg Arg Arg Arg Glu Arg Arg Asp Leu Phe Thr 275 280 285 Glu Ser Trp Asp Thr Gln Lys Ala Pro Asn Asn Tyr Arg Ser Pro Ile 290 295 300 Ser Thr Gly Gln Pro Thr Asn Gln Ser Met Asp Asp Thr Arg Glu Asp 305 310 315 320 Ile Tyr Val Asn Tyr Pro Thr Phe Ser Arg Arg Pro Lys Thr Arg Val 325 330 335 <110> Kyungpook National University Industry-Academic Cooperation Foundation <120> Diagnostic methods for prognosis of small-cell lung cancer using CD155 and CD226 SNPs <130> PN2012-624 <160> 8 <170> KoPatentIn 3.0 <210> 1 <211> 500 <212> DNA <213> Artificial Sequence <220> <223> CD155 <400> 1 acaccccacg gtccaccggg gatccagggc cccagcgtgc aagtcgcgcc aggtgcccgg 60 gctcctggag cccctcccta tctagtccaa gaacgccccg ggtctgacac cttctcttcg 120 gttctccgca ggggacgtcg tcgtgcaggc gccccacccag gtgcccggct tcttgggcga 180 ctccgtgacg ctgccctgct acctacaggt gcccaacatg gaggtgacgc atgtgtcaca 240 gctgacttgg cgcggcatgg tgaatctggc agcatggccg tcttccacca aacgcagggc 300 cccagctatt cggagtccaa acggctggaa ttcgtggcag ccagactggg cgcggagctg 360 cggaatgcct cgctgaggat gttcgggttg cgcgtagagg atgaaggcaa ctacacctgc 420 ctgttcgtca cgttcccgca gggcagcagg agcgtggata tctggctccg agtgcttggt 480 gagcaggggg ttttggggag 500 <210> 2 <211> 1000 <212> DNA <213> Artificial Sequence <220> <223> CD226 <400> 2 catcttgcca acacaagagg aaagcctgca tgagagtgag gccaagcca gggaaatgga 60 tccaacactc tggaaaggga ttcagaagcc agtttatgcc catacttaat tctagacaca 120 acatttaagc cctggtaaat agcccttgcc caaagcttaa tctcccctgg atcattctgt 180 tatatgatac agtaagtttt cttttgtata taaaccagtt agagtcaggt tttctgaaac 240 agttctatga aaaatgattt taggtaatga agtatttttc ctatcaaagt aactcaattc 300 agacaactag tatctaaggt agaccttggg tagtggaaaa aaattgcata aagatccatg 360 catgagtaca taagagtcat tactaatgca ctcatgtcaa gaataagctt aaactctagt 420 ctttggtctg cgagagaagg ttggatagtt gacataaata tcctctcttg tatcatccat 480 ggattgattg gtaggttgac ggtagagatg ggacttctat agttattggg tgcctagaaa 540 gacaaacagc agagagtgtc aataattcac tgcatttcaa caactaatga agacattcaa 600 aacatacctc tcataaatgc aggcatgata tgggacaagt ttccattata attaatttga 660 taaaacattc tcattgtatt gaacttctgt tggaaatcat attcttgact gagatgcaac 720 agaaatctag tctagattaa tacttgctgt attgtgctat gaattacctg tttcaatgta 780 gaactccctc tcccaatgtt aagctatttt gataagaaca attactatca tttttatatg 840 gaaattctaa cacagtgtct gaactttaaa aaataagcaa cttaacatat aaaaagttaa 900 caaaactgac atcaagatga tattgtataa tcattaatct tctctaccgt aatcaagtca 960 ctttgaccac atatgtatgt atgtaacaga aaatatgcag 1000 <210> 3 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> rs1058402 forward primer <400> 3 tacaggtgcc caacatggag 20 <210> 4 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> rs1058402 reverse primer <400> 4 gctgccagat tcaccat 17 <210> 5 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> rs763361 forward primer <400> 5 ccatggattg attggtag 18 <210> 6 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> rs763361 reverse primer <400> 6 gtttgtcttt ctaggcaccc 20 <210> 7 <211> 343 <212> PRT <213> Artificial Sequence <220> <223> CD155 <400> 7 Met Ala Arg Ala Met Ala Ala Ala Trp Pro Leu Leu Leu Val Ala Leu 1 5 10 15 Leu Val Leu Ser Trp Pro Pro Pro Gly Thr Gly Asp Val Val Val Gln 20 25 30 Ala Pro Thr Gln Val Pro Gly Phe Leu Gly Asp Ser Val Thr Leu Pro 35 40 45 Cys Tyr Leu Gln Val Pro Asn Met Glu Val Thr His Val Ser Gln Leu 50 55 60 Thr Trp Ala Arg His Gly Glu Ser Gly Ser Met Ala Val Phe His Gln 65 70 75 80 Thr Gln Gly Pro Ser Tyr Ser Glu Ser Lys Arg Leu Glu Phe Val Ala 85 90 95 Ala Arg Leu Gly Ala Glu Leu Arg Asn Ala Ser Leu Arg Met Phe Gly 100 105 110 Leu Arg Val Glu Asp Glu Gly Asn Tyr Thr Cys Leu Phe Val Thr Phe 115 120 125 Pro Gln Gly Ser Arg Ser Val Asp Ile Trp Leu Arg Val Leu Ala Lys 130 135 140 Pro Gln Asn Thr Ala Glu Val Gln Lys Val Gln Leu Thr Gly Glu Pro 145 150 155 160 Val Pro Met Ala Arg Cys Val Ser Thr Gly Gly Arg Pro Pro Ala Gln 165 170 175 Ile Thr Trp His Ser Asp Leu Gly Gly Met Pro Asn Thr Ser Gln Val 180 185 190 Pro Gly Phe Leu Ser Gly Thr Val Thr Val Thr Ser Leu Trp Ile Leu 195 200 205 Val Pro Ser Ser Gln Val Asp Gly Lys Asn Val Thr Cys Lys Val Glu 210 215 220 His Glu Ser Phe Glu Lys Pro Gln Leu Leu Thr Val Asn Leu Thr Val 225 230 235 240 Tyr Tyr Pro Pro Glu Val Ser Ile Ser Gly Tyr Asp Asn Asn Trp Tyr 245 250 255 Leu Gly Gln Asn Glu Ala Thr Leu Thr Cys Asp Ala Arg Ser Asn Pro 260 265 270 Glu Pro Thr Gly Tyr Asn Trp Ser Thr Thr Met Gly Pro Leu Pro Pro 275 280 285 Phe Ala Val Ala Gln Gly Ala Gln Leu Leu Ile Arg Pro Val Asp Lys 290 295 300 Pro Ile Asn Thr Thr Leu Ile Cys Asn Val Thr Asn Ala Leu Gly Ala 305 310 315 320 Arg Gln Ala Glu Leu Thr Val Gln Val Lys Glu Gly Pro Ser Glu 325 330 335 His Ser Gly Met Ser Arg Asn 340 <210> 8 <211> 336 <212> PRT <213> Artificial Sequence <220> <223> CD226 <400> 8 Met Asp Tyr Pro Thr Leu Leu Leu Ala Leu Leu His Val Tyr Arg Ala 1 5 10 15 Leu Cys Glu Glu Val Leu Trp His Thr Ser Val Pro Phe Ala Glu Asn 20 25 30 Met Ser Leu Glu Cys Val Tyr Pro Ser Met Gly Ile Leu Thr Gln Val 35 40 45 Glu Trp Phe Lys Ile Gly Thr Gln Gln Asp Ser Ile Ala Ile Phe Ser 50 55 60 Pro Thr His Gly Met Val Ile Arg Lys Pro Tyr Ala Glu Arg Val Tyr 65 70 75 80 Phe Leu Asn Ser Thr Met Ala Ser Asn Asn Met Thr Leu Phe Phe Arg 85 90 95 Asn Ala Ser Glu Asp Asp Val Gly Tyr Tyr Ser Cys Ser Leu Tyr Thr 100 105 110 Tyr Pro Gln Gly Thr Trp Gln Lys Val Ile Gln Val Val Gln Ser Asp 115 120 125 Ser Phe Glu Ala Ala Val Pro Ser Asn Ser His Ile Val Ser Glu Pro 130 135 140 Gly Lys Asn Val Thr Leu Thr Cys Gln Pro Gln Met Thr Trp Pro Val 145 150 155 160 Gln Ala Val Arg Trp Glu Lys Ile Gln Pro Arg Gln Ile Asp Leu Leu 165 170 175 Thr Tyr Cys Asn Leu Val His Gly Arg Asn Phe Thr Ser Lys Phe Pro 180 185 190 Arg Gln Ile Val Ser Asn Cys Ser His Gly Arg Trp Ser Val Ile Val 195 200 205 Ile Pro Asp Val Thr Val Ser Asp Ser Gly Leu Tyr Arg Cys Tyr Leu 210 215 220 Gln Ala Ser Ala Gly Glu Asn Glu Thr Phe Val Met Arg Leu Thr Val 225 230 235 240 Ala Glu Gly Lys Thr Asp Asn Gln Tyr Thr Leu Phe Val Ala Gly Gly 245 250 255 Thr Val Leu Leu Leu Leu Phe Val Ile Ser Ile Thr Thr Ile Ile Val 260 265 270 Ile Phe Leu Asn Arg Arg Arg Arg Arg Glu Arg Arg Asp Leu Phe Thr 275 280 285 Glu Ser Trp Asp Thr Gln Lys Ala Pro Asn Asn Tyr Arg Ser Pro Ile 290 295 300 Ser Thr Gly Gln Pro Thr Asn Gln Ser Met Asp Asp Thr Arg Glu Asp 305 310 315 320 Ile Tyr Val Asn Tyr Pro Thr Phe Ser Arg Arg Pro Lys Thr Arg Val 325 330 335
Claims (16)
상기 CD155의 rs1058402G>A 단일염기다형성은 서열번호 1로 이루어진 염기서열에서 250번째 염기에 위치하는 것이고,
상기 CD226의 rs763361C>T 단일염기다형성은 서열번호 2로 이루어진 염기서열에서 500번째 염기에 위치하는 것을 특징으로 하는, 소세포폐암 예후 진단 및 예측을 위한 마커용 조성물.According to claim 1,
The rs1058402G>A single nucleotide polymorphism of CD155 is located at the 250th base in the nucleotide sequence consisting of SEQ ID NO: 1,
The rs763361C>T single nucleotide polymorphism of CD226 is a marker composition for prognosis and prediction of small cell lung cancer, characterized in that it is located at the 500th base in the nucleotide sequence consisting of SEQ ID NO: 2.
상기 소세포폐암은 항암 화학요법을 사용하여 치료한 것을 특징으로 하는, 소세포폐암 예후 진단 및 예측을 위한 마커용 조성물.According to claim 1,
The small cell lung cancer is characterized in that the treatment using chemotherapy, marker composition for the diagnosis and prediction of the prognosis of small cell lung cancer.
상기 제제는 CD155의 rs1058402G>A 단일염기다형성 또는 CD226의 rs763361C>T 단일염기다형성을 포함하는 10~100개의 연속 염기로 구성되는 폴리뉴클레오티드 또는 이의 상보적인 폴리뉴클레오티드를 증폭시킬 수 있는 프라이머 또는 프로브인 것을 특징으로 하는, 소세포폐암 환자의 생존 예후 예측용 조성물.5. The method of claim 4,
The agent is a primer or probe capable of amplifying a polynucleotide consisting of 10 to 100 consecutive bases containing rs1058402G>A single nucleotide polymorphism of CD155 or rs763361C>T single nucleotide polymorphism of CD226 or a complementary polynucleotide thereof. A composition for predicting survival prognosis of small cell lung cancer patients, characterized in that.
상기 CD155의 rs1058402G>A 단일염기다형성은 서열번호 1로 이루어진 염기서열에서 250번째 염기에 위치하는 것이고,
상기 CD226의 rs763361C>T 단일염기다형성은 서열번호 2로 이루어진 염기서열에서 500번째 염기에 위치하는 것을 특징으로 하는, 소세포폐암 환자의 생존 예후 예측용 조성물.5. The method of claim 4,
The rs1058402G>A single nucleotide polymorphism of CD155 is located at the 250th base in the nucleotide sequence consisting of SEQ ID NO: 1,
The composition for predicting survival prognosis of small cell lung cancer patients, characterized in that the rs763361C>T single nucleotide polymorphism of CD226 is located at the 500th base in the nucleotide sequence consisting of SEQ ID NO: 2.
상기 제제는 CD155의 rs1058402G>A 단일염기다형성을 검출할 수 있는 서열번호 3 및 4의 염기서열로 이루어진 프라이머 쌍; 또는 CD226의 rs763361C>T 단일염기다형성을 검출할 수 있는 서열번호 5 및 6의 염기서열로 이루어진 프라이머 쌍;인 것을 특징으로 하는, 소세포폐암 환자의 생존 예후 예측용 조성물. 5. The method of claim 4,
The agent comprises a primer pair consisting of the nucleotide sequences of SEQ ID NOs: 3 and 4 capable of detecting the rs1058402G>A single nucleotide polymorphism of CD155; Or a pair of primers consisting of the nucleotide sequences of SEQ ID NOs: 5 and 6 capable of detecting rs763361C>T single nucleotide polymorphism of CD226;
상기 CD155의 rs1058402G>A 단일염기다형성 또는 CD226의 rs763361C>T 단일염기다형성은 항암제에 대한 화학요법 반응(chemotherapy response), 전체생존율(Overall survival: OS) 또는 무진행 생존율(Progression-free survival: PFS)과 관련성이 있는 것을 특징으로 하는, 소세포폐암 환자의 생존 예후 예측용 조성물.5. The method of claim 4,
The rs1058402G>A single nucleotide polymorphism of CD155 or the rs763361C>T single nucleotide polymorphism of CD226 is a chemotherapy response to an anticancer agent, overall survival (OS) or progression-free survival (PFS). A composition for predicting survival prognosis of small cell lung cancer patients, characterized in that it is related to.
상기 CD155의 rs1058402G>A 다형성의 유전자형이 GG인 경우, GA 또는 AA인 경우에 비해 생존 예후가 높은 군으로 판정하는 것을 특징으로 하는, 소세포폐암 환자의 생존 예후 예측을 위한 정보를 제공하는 방법.12. The method of claim 11,
When the genotype of the rs1058402G>A polymorphism of CD155 is GG, it is characterized in that the survival prognosis is determined as a group having a higher survival prognosis than in the case of GA or AA. A method of providing information for predicting survival prognosis of patients with small cell lung cancer.
상기 CD226의 rs763361C>T 다형성의 유전자형이 CT 또는 TT인 경우, CC에 비해 생존 예후가 높은 군으로 판정하는 것을 특징으로 하는, 소세포폐암 환자의 생존 예후 예측을 위한 정보를 제공하는 방법.12. The method of claim 11,
When the genotype of the rs763361C>T polymorphism of CD226 is CT or TT, a method of providing information for predicting survival prognosis of small cell lung cancer patients, characterized in that the group has a higher survival prognosis than CC.
상기 CD155의 rs1058402G>A 다형성의 GA 또는 AA 유전자형; 또는 상기 CD226의 rs763361C>T 다형성의 CC 유전자형이 0개인 경우, 항암제에 대한 화학요법 반응이 80.4%이고, 1개인 경우, 항암제에 대한 화학요법 반응이 71.0%이고, 2개인 경우, 항암제에 대한 화학요법 반응이 61.3%인 것을 특징으로 하는, 소세포폐암 환자의 생존 예후 예측을 위한 정보를 제공하는 방법.12. The method of claim 11,
GA or AA genotype of the rs1058402G>A polymorphism of CD155; Or, when the CC genotype of the rs763361C>T polymorphism of CD226 is 0, the chemotherapy response to the anticancer agent is 80.4%, and in the case of one, the chemotherapy response to the anticancer agent is 71.0%, and in the case of two, the chemotherapy response to the anticancer agent A method for providing information for predicting survival prognosis of patients with small cell lung cancer, characterized in that the response to therapy is 61.3%.
상기 CD155의 rs1058402G>A 다형성에서 CD155의 67번째 아미노산인 알라닌(A)이 트레오닌(T)으로 돌연변이 되는 경우, 항암제에 대한 화학요법 반응(chemotherapy response), 전체생존율(Overall survival: OS) 또는 무진행 생존율(Progression-free survival: PFS)이 낮다고 판정하는 것을 특징으로 하는, 소세포폐암 환자의 생존 예후 예측을 위한 정보를 제공하는 방법.12. The method of claim 11,
In the rs1058402G>A polymorphism of CD155, when alanine (A), the 67th amino acid of CD155, is mutated to threonine (T), a chemotherapy response to an anticancer agent, overall survival (OS), or progression-free A method of providing information for predicting survival prognosis of small cell lung cancer patients, characterized in that the survival rate (Progression-free survival: PFS) is determined to be low.
상기 CD155의 rs1058402G>A 다형성에서 CD155의 67번째 아미노산인 알라닌(A)이 트레오닌(T)으로 돌연변이 되면, CD155와 CD226의 결합력이 감소되어 T 세포활성 또는 NK 세포활성이 감소되는 것을 특징으로 하는, 소세포폐암 환자의 생존 예후 예측을 위한 정보를 제공하는 방법.
16. The method of claim 15,
In the rs1058402G>A polymorphism of CD155, when alanine (A), the 67th amino acid of CD155, is mutated to threonine (T), the binding force between CD155 and CD226 is reduced, characterized in that T cell activity or NK cell activity is reduced, A method for providing information for predicting survival prognosis in patients with small cell lung cancer.
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