인슐린양 성장 인자 결합 단백-3 유전자 -202 좌위의 다형성에 따른 비소세포폐암의 위험도 Promoter -202 A/C Polymorphism of Insulin-like Growth Factor Binding Protein-3 Gene and Non-small Cell Lung Cancer Risk원문보기
인슐린양 성장 인자 결합 단백-3(Insulin-like growth factor (IGF) binding protein-3 (IGFBP-3))는 혈액 내에서 IGF와 결합하여 복합체 혹은 저장소로 작용함으로써, IGF가 수용체에 결합하는 것을 방해하여 IGF의 항세포사멸(antiapoptosis) 및 세포분열 촉진의 기능을 억제한다. 하지만, 특정 상황에서는 도리어 IGFBP-3가 IGF의 파괴를 억제하여 IGF에 의한 암세포의 분화 및 성장을 촉진할 수도 있다는 것이 알려져 있다. 대부분의 환자에서 혈액내 IGFBP-3 수치는 IGFBP-3 유전자의 -202 좌위(locus)의 다형성(polymorphism)에 의해 크게 영향을 받는다. 따라서, 저자 등은 제한 효소(restriction enzyme)를 이용하여 비소세포폐암 환자의 IGFBP-3 유전자 -202 좌위의 다형성을 분석함으로써, 이 좌위의 다형성이 비소세포폐암의 위험도와 연관되어 있는지 조사하였다. 본 연구는 104명의 비소세포폐암 환자군과, 연령, 성별, 흡연력이 비슷한 104명의 대조군을 비교 분석하였다. 대조군에서 -202 좌위 유전자 다형성의 빈도는 AA형 48명 (46.2%), AC형 45명 (43.3%), CC형 11명 (10.5%)이었고, 비소세포폐암 환자군에서 -202 좌위 유전자 다형성의 빈도는 AA형 67명(64.4%), AC형 35명 (33.7%), CC형 2명 (1.9%)이었다. -202 좌위의 유전자 다형성에 있어서 대조군과 비소세포폐암 환자군 사이에 유의한 빈도 차이가 있었으며 (p < 0.05, Pearson's ${\chi}^2-test$), 비소세포폐암의 위험도는 -202 좌위의 AA형에서 가장 높고 CC형에서 가장 낮았다. CC형을 기준으로 하면 AC형의 비교 위험도는 2.60 (95% 신뢰구간: 0.89 - 8.60)이었으며 AA형의 비교 위험도는 5.89 (95% 신뢰구간: 1.92 - 21.16)이었다. 본 연구 결과는, IGFBP-3 유전자의 -202 좌위(locus)의 다형성(polymorphism)이 비소세포폐암의 위험인자 중의 하나일 가능성을 제시하며, 따라서 비소세포폐암에 대한 항암치료 개발에 있어서 새로운 표적이 될 가능성을 시사한다.
인슐린양 성장 인자 결합 단백-3(Insulin-like growth factor (IGF) binding protein-3 (IGFBP-3))는 혈액 내에서 IGF와 결합하여 복합체 혹은 저장소로 작용함으로써, IGF가 수용체에 결합하는 것을 방해하여 IGF의 항세포사멸(antiapoptosis) 및 세포분열 촉진의 기능을 억제한다. 하지만, 특정 상황에서는 도리어 IGFBP-3가 IGF의 파괴를 억제하여 IGF에 의한 암세포의 분화 및 성장을 촉진할 수도 있다는 것이 알려져 있다. 대부분의 환자에서 혈액내 IGFBP-3 수치는 IGFBP-3 유전자의 -202 좌위(locus)의 다형성(polymorphism)에 의해 크게 영향을 받는다. 따라서, 저자 등은 제한 효소(restriction enzyme)를 이용하여 비소세포폐암 환자의 IGFBP-3 유전자 -202 좌위의 다형성을 분석함으로써, 이 좌위의 다형성이 비소세포폐암의 위험도와 연관되어 있는지 조사하였다. 본 연구는 104명의 비소세포폐암 환자군과, 연령, 성별, 흡연력이 비슷한 104명의 대조군을 비교 분석하였다. 대조군에서 -202 좌위 유전자 다형성의 빈도는 AA형 48명 (46.2%), AC형 45명 (43.3%), CC형 11명 (10.5%)이었고, 비소세포폐암 환자군에서 -202 좌위 유전자 다형성의 빈도는 AA형 67명(64.4%), AC형 35명 (33.7%), CC형 2명 (1.9%)이었다. -202 좌위의 유전자 다형성에 있어서 대조군과 비소세포폐암 환자군 사이에 유의한 빈도 차이가 있었으며 (p < 0.05, Pearson's ${\chi}^2-test$), 비소세포폐암의 위험도는 -202 좌위의 AA형에서 가장 높고 CC형에서 가장 낮았다. CC형을 기준으로 하면 AC형의 비교 위험도는 2.60 (95% 신뢰구간: 0.89 - 8.60)이었으며 AA형의 비교 위험도는 5.89 (95% 신뢰구간: 1.92 - 21.16)이었다. 본 연구 결과는, IGFBP-3 유전자의 -202 좌위(locus)의 다형성(polymorphism)이 비소세포폐암의 위험인자 중의 하나일 가능성을 제시하며, 따라서 비소세포폐암에 대한 항암치료 개발에 있어서 새로운 표적이 될 가능성을 시사한다.
Background : IGFBP-3 inhibits the mitogenic and anti-apoptotic activity of IGF by blocking the binding of IGF to its receptor. However, under certain circumstances, IGFBP-3 can enhance the activity of IGF by protecting IGF from its degradation. More than half of the interindividual variations in IGF...
Background : IGFBP-3 inhibits the mitogenic and anti-apoptotic activity of IGF by blocking the binding of IGF to its receptor. However, under certain circumstances, IGFBP-3 can enhance the activity of IGF by protecting IGF from its degradation. More than half of the interindividual variations in IGFBP-3 levels are known to be genetically determined by the polymorphism at -202 locus of IGFBP-3 gene. Method : We attempted to ascertain whether A-202C polymorphic variation of IGFBP-3 gene constitutes a risk factor for non-small cell lung cancer (NSCLC), using PCR-restriction fragment length polymorphism (RFLP). Our study included 104 NSCLC patients and 104 age-, gender-, and smoking status-matched control subjects. Result : In the 104 NSCLC subjects, the genotypic frequencies at the -202 site were as follows: AA = 67 (64.4%), AC = 35 (33.7%), and CC = 2 (1.9%). We did detect significant differences in the genotypic distribution between the NSCLC and the control subjects (pAC>CC). Using CC genotype as a reference, the odds ratio (OR) for the subjects with AC genotype was 2.60 (95% CI: 0.89 - 8.60), and the OR associated with AA genotype was 5.89 (95% CI: 1.92 - 21.16). Conclusion : These results indicate that the dysregulation of IGF axis should now be considered as another important risk factor for NSCLC, and a potential target for novel antineoplastic therapies and/or preventative strategies in high-risk groups.
Background : IGFBP-3 inhibits the mitogenic and anti-apoptotic activity of IGF by blocking the binding of IGF to its receptor. However, under certain circumstances, IGFBP-3 can enhance the activity of IGF by protecting IGF from its degradation. More than half of the interindividual variations in IGFBP-3 levels are known to be genetically determined by the polymorphism at -202 locus of IGFBP-3 gene. Method : We attempted to ascertain whether A-202C polymorphic variation of IGFBP-3 gene constitutes a risk factor for non-small cell lung cancer (NSCLC), using PCR-restriction fragment length polymorphism (RFLP). Our study included 104 NSCLC patients and 104 age-, gender-, and smoking status-matched control subjects. Result : In the 104 NSCLC subjects, the genotypic frequencies at the -202 site were as follows: AA = 67 (64.4%), AC = 35 (33.7%), and CC = 2 (1.9%). We did detect significant differences in the genotypic distribution between the NSCLC and the control subjects (pAC>CC). Using CC genotype as a reference, the odds ratio (OR) for the subjects with AC genotype was 2.60 (95% CI: 0.89 - 8.60), and the OR associated with AA genotype was 5.89 (95% CI: 1.92 - 21.16). Conclusion : These results indicate that the dysregulation of IGF axis should now be considered as another important risk factor for NSCLC, and a potential target for novel antineoplastic therapies and/or preventative strategies in high-risk groups.
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문제 정의
Also, A allele at the -202 site of IGFBP-3 gene was associated with a greater risk of NSCLC than was C allele. To our knowledge, this is the first study of the relationship between the -202 site polymorphism of IGFBP-3 gene and the lung cancer risk. However, as we mentioned above, much larger studies including the measurements of the IGF and IGFBP-3 levels are warranted.
제안 방법
2 mM of each deoxyribonucleotide triphosphate (dATP, dCTP, dGTP, and dTTP), 1 mM of MgCl2, 50 pM of each primer, and 1 unit of Ampli-Taq Gold DNA polymerase (PerkinElmer, Branchburg, NJ). After an initial denaturation step for 10 minutes at 95°C, 40 cycles of PCR reactions consisting of 95°C for 30 seconds, 66°C for 1 minute, and 72°C for 1 minute were carried out, which were followed by a final extension step for 15 minutes at 72°C in a thermal cycler (GeneAmp PCR System 9700; Perkin-Elmer). After confirming the successful PCR amplification by 2% agarose gel electrophoresis, each PCR product was digested overnight with 5 units of FspI enzyme at 37°C (New England Biolabs, Inc.
In order to determine whether the NSCLC risk is related to the genotype, the logistic regression analyses were conducted with adjustments for the age at the time of diagnosis. Compared with the CC genotype subjects, the subjects with AA or AC genotype harbored a significantly higher risk of NSCLC.
We were unable to prove that the tumor aggressiveness was associated with the IGFBP-3 gene A-202C polymorphism. In order to prove this in the NSCLC subpopulations, it will be required to conduct an analysis of long-term follow-up data regarding overall, disease-free and disease-specific survivals.
The 168-base-pair (bp) fragment encompassing the A-202C polymorphic site in the IGFBP-3 gene was amplified using the specific primers: 5’- CTGAGTTGGCCAGGAGTGACT-3’ in sense and 5’-CGAGCTCGGGGGCGTGCA-3’ in antisense. The PCR reactions were performed in a 25μl volume containing 20 ng of genomic DNA, 10X PCR buffer supplied by a manufacturer, 0.2 mM of each deoxyribonucleotide triphosphate (dATP, dCTP, dGTP, and dTTP), 1 mM of MgCl2, 50 pM of each primer, and 1 unit of Ampli-Taq Gold DNA polymerase (PerkinElmer, Branchburg, NJ). After an initial denaturation step for 10 minutes at 95°C, 40 cycles of PCR reactions consisting of 95°C for 30 seconds, 66°C for 1 minute, and 72°C for 1 minute were carried out, which were followed by a final extension step for 15 minutes at 72°C in a thermal cycler (GeneAmp PCR System 9700; Perkin-Elmer).
–test was employed in the comparison of genotypic frequencies between the NSCLC and the control group (Table 2). The odds ratio (OR) and the 95% confidence intervals (CI) with regard to the IGFBP-3 genotypes were calculated using multiple logistic regression analysis adjusted for age. The statistical modeling was performed on the relative risk of AA or AC genotype against CC genotype.
The odds ratio (OR) and the 95% confidence intervals (CI) with regard to the IGFBP-3 genotypes were calculated using multiple logistic regression analysis adjusted for age. The statistical modeling was performed on the relative risk of AA or AC genotype against CC genotype. The relationship of the genotype with the pathologic stage (Table 3) and the histologic subtype(Table 4) was also assessed, using Fisher’s exact test.
대상 데이터
We attempted to ascertain whether A-202C polymorphic variation of IGFBP-3 gene constitutes a risk factor for non-small cell lung cancer (NSCLC), using PCR-restriction fragment length polymorphism (RFLP). Our study included 104 NSCLC patients and 104 age-, gender-, and smoking status-matched control subjects.
Regarding the tumor stage, our study included 40 patients with pathologic stage (pstage) I (IA and IB), 19 with pstage II (IIA and IIB), and 45 with pstage III (IIIA and IIIB). The genotype of the IGFBP-3 gene -202 locus had no appreciable influence on the tumor pstage at the time of initial diagnosis (Table 3).
The age-, gender-, and smoking status-matched control subjects’ blood samples were randomly selected from a blood bank comprising 1038 subjects who visited the Yong-in Severance Hospital in 2003 for an annual health examination conducted by the National Health Insurance Institute. The matched control subjects included 82 male and 22 female participants with the mean age of 61.0 ±9.6 years (Table 1).
데이터처리
The statistical modeling was performed on the relative risk of AA or AC genotype against CC genotype. The relationship of the genotype with the pathologic stage (Table 3) and the histologic subtype(Table 4) was also assessed, using Fisher’s exact test.
Pearson’s χ2–test was employed in the comparison of genotypic frequencies between the NSCLC and the control group (Table 2). The odds ratio (OR) and the 95% confidence intervals (CI) with regard to the IGFBP-3 genotypes were calculated using multiple logistic regression analysis adjusted for age.
성능/효과
In conclusion, the genotypic frequency of -202 site polymorphism of IGFBP-3 gene in the Korean population differs from that in the North American multiethnic population. Also, A allele at the -202 site of IGFBP-3 gene was associated with a greater risk of NSCLC than was C allele.
9%) (Table 2). Significant differences in the allele frequency were apparent when the NSCLC patients (A=0.81, C=0.19) were compared with the gender-, age-, and smoking status-matched control subjects (A=0.68, C=0.32) (p<0.05).
Compared with the CC genotype subjects, the subjects with AA or AC genotype harbored a significantly higher risk of NSCLC. Using CC genotype as a reference (OR=1.0), the OR for AC genotype was 2.60 (95% CI: 0.89 - 8.60), and the OR associated with AA genotype was 5.89 (95% CI:1.92 - 21.16).
05), and the NSCLC risk correlated significantly with AA genotype at the -202 locus (AA]AC>CC). Using CC genotype as a reference, the odds ratio (OR) for the subjects with AC genotype was 2.60 (95% CI: 0.89 - 8.60), and the OR associated with AA genotype was 5.89 (95% CI: 1.92 - 21.16).
후속연구
. Therefore, further studies regarding the relationships between the IGF/IGFBP-3 levels, the cancer risk, and the factors mentioned above will be required in the future.
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