血管内皮生长因子基因多态性与上皮性卵巢癌发病风险的关联研究
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摘要
目的:卵巢恶性肿瘤是女性生殖器三大恶性肿瘤之一,由于其发病隐匿,缺乏特异性早期发病指征,往往在确诊时就已发生转移,因此卵巢癌患者的5年生存率仅30%左右,其死亡率居妇科恶性肿瘤首位。虽然迄今卵巢癌的病因和发病机制尚不明确,但已有研究表明,血管生成在包括卵巢癌在内的人类实体肿瘤的发生、发展和浸润、转移中起重要作用。在已知的血管生成因子中,血管内皮生长因子(vascular endothelial growth factor,VEGF)是一种特异的、强烈的血管内皮细胞促分裂因子和血管生成因子,它与肿瘤的生长、浸润及转移密切相关。人类的VEGF基因启动子区存在一些多态性位点,这些多态性位点可能通过改变基因的转录活性而影响蛋白的表达,导致了人类对癌症易感性的个体差异。本研究旨在探讨VEGF基因启动子区-1154G/A、-460C/T单核苷酸多态性(single nucleotide polymorphism, SNP)与上皮性卵巢癌发病风险的关系,从分子生物学水平为卵巢癌的预防及诊治提供依据。
方法:本研究采用病例-对照研究方法,收集303例上皮性卵巢癌患者和303例健康对照个体的静脉抗凝血各5ml,同时记录其病史和个人及家族相关资料。采用蛋白酶K消化-饱和氯化钠盐析法提取外周血白细胞DNA,采用聚合酶链反应-限制性片段长度多态性(polymerase chain reaction -restriction fragment length polymorphism,PCR-RFLP)分析方法检测VEGF基因启动子区-1154G/A、-460C/T基因多态位点的基因型频率分布。
数据统计分析采用SPSS11.5版软件包(SPSS Company, Chicago, Illinois, USA)进行。病例组与对照组的年龄差异行t检验。比较各位点基因型频率的观察值与预期值并进行卡方检验行Hardy-Weinberg平衡分析。两组间的基因型分布比较采用行×列表χ2检验。以非条件Logistic回归法计算表示相对风险度的比值比(odds ratio,OR)及95%可信区间(confidence interval, CI)。采用EH软件和2LD软件分别分析VEGF基因启动子区-460C/T,-1154 G/A 2个多态性位点的单倍型频率和等位基因连锁不平衡状态。P<0.05作为差异有显著性的标准。
结果:
1.健康对照组中VEGF基因启动子区-1154G/A、-460C/T两个多态位点基因型频率分布均符合Hardy-weinberg平衡(P﹥0.05)。
2.在卵巢癌组和对照组中,VEGF基因启动子区-1154G/A多态的三种基因型频率(A/A、G/A、G/G)分别是1.7%、17.8%、80.5%和2.3%、26.1%、71.6%,两组比较差异有统计学意义(P=0.037);在卵巢癌组和对照组中,等位基因频率分布(G、A)分别是89.4%、10.6%和84.7%、15.3%,两组比较差异有统计学意义(P=0.013);与G/A+ A/A基因型相比,携带G/G基因型可能明显增加上皮性卵巢癌的发病风险(OR=1.64,95%CI=1.12~2.39)。
3. VEGF基因启动子区-460C/T多态C、T等位基因频率在卵巢癌组和对照组分别为19.3%、21.3%和80.7%、78.7%,两组相比差异无统计学意义(P﹥0.05);C/C、C/T、T/T基因型频率在卵巢癌组和对照组分别为4.0%、30.7%、65.3%和5.6%、31.4%、63%,两组相比差异无统计学意义(P﹥0.05);与C/T+T/T基因型相比,T/T基因型可能与卵巢癌的发病风险无关,OR值为1.11(95%CI= 0.79~1.54)。
4. VEGF基因启动子区-1154G/A和-460C/T SNPs位点间不存在连锁不平衡(D’=0.426)。
结论:
1. VEGF基因启动子区-1154G/A多态可能与上皮性卵巢癌的发病风险明显相关,即携带G/G基因型可能显著增加上皮性卵巢癌的发病风险。
2. VEGF基因启动子区-460C/T单核苷酸多态可能与上皮性卵巢癌的发病风险无关。
3. VEGF基因启动子区-1154G/A和-460C/T SNPs位点间不存在连锁不平衡。
Objective:Ovarian cancer is one of the three most common malignant gynecologic neoplasm. Early ovarian cancer is a silent and often asymptomatic disease. Many patients diagnosed with epithelial ovarian cancer have advanced disease. The overall 5-year survival rate for ovarian cancer is 30%. It is the leading cause of death from gynecologic cancer. The causes of ovarian cancer are poorly understood, but angiogenesis has been associated with the disease. Angiogenesis is an essential process in the development, growth and metastasis of malignant tumors, including ovarian cancer. A key mediator in angiogenesis is vascular endothelial growth factor (VEGF). VEGF is a major angiogenic factor involved in a number of pathologic processes, including neovascularization, a crucial step in the development of solid malignancies. At least 30 single nucleotide polymorphisms (SNPs) exist in the VEGF gene. Among them, the two VEGF polymorphisms (-1154G/A and -460C/T) have been reported to affect the expression of the gene and indicated to be involved in the development of diseases. The aim of this study was to investigate the association of polymorphisms in the VEGF gene with the susceptibility to epithelial ovarian cancer.
Methods: This case-contral study included 303 patients with epithelial ovarian cancer and 303 frequency-matched healthy control women. Five milliliter of venous blood from each subject was drawn in Vacutainer tubes containing EDTA and stored at 4℃, while the information of every subject was obtained. The genomic DNA was extracted within one week after bleeding by using proteinase K digestion followed by a salting out procedure. Genotypes of the VEGF-1154G/A, -460C/T genes were analyzed by polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP) method. Statistical analysis was performed using SPSS11.5 software package. A probability level of 5% was considered significant. The age difference of cases and frequency-matched controls was analyzed by the t-test. Hardy-Weinberg analysis was performed by comparing the observed and expected genotype frequencies in study groups using Chi-square test. Comparison of the VEGF genotype and allelotype distribution in patients and healthy controls was performed by means of two-sided contingency tables using Chi-square test. The odds ratio (OR) and 95% confidence Interval (CI) were calculated using an unconditional logistic regression model.
Results:
1. The distribution of the VEGF -1154G/A , -460C/T genotypes in the control group did not significantly deviate from that expected for a Hardy-Weinberg equilibrium (P>0.05).
2. The genotype frequencies of the VEGF -460 C/C, C/T and T/T in patients and controls were 4.0%/5.6%, 30.7%/31.4% and 65.3%/63.0%, respectively; the C and T allele frequencies were 19.3%/21.3% and 80.7%/78.7%, respectively. There was no statistically significant difference in the genotype distributions or allele frequencies of VEGF -460C/T between the patients and controls (P>0.05; Table 1). Compared with the C/T+T/T genotypes, the C/T genotype could not significantly modify the risk of developing epithelial ovarian cancer. The odds ratio was 1.11 (95% CI=0.79~1.54).
3. The genotype frequencies of the VEGF -1154 A/A, G/A, and G/G in patients and controls were 1.7%/2.3%, 17.8%/26.1% and 80.5%/71.6%, respectively; the A and G allele frequencies were 10.6%/15.3% and 89.4%/84.7%, respectively. There was significant difference in genotype and allele distributions of the VEGF -1154G/A between two groups (P=0.037, 0.013, respectively) (Table 3). Compared with the G/A+ A/A genotypes, the G/G genotype significantly increased the risk of developing epithelial ovarian cancer. The odds ratio was 1.64 (95% CI=1.12~2.39) (Table 4).
4. The promoter polymorphisms -1154G/A and the -460C/T was not linkage disequilibrium (D’=0.426).
Conclusions:
1. VEGF -1154G/A polymorphism was associated with susceptibility to epithelial ovarian cancer, carrying G allele may significantly increase the risk of developing epithelial ovarian cancer.
2. No significant association of the -460C/T polymorphism with the risk of developing epithelial ovarian cancer.
3. The promoter polymorphisms -1154G/A and the -460C/T were not linkage disequilibrium.
方法:本研究采用病例-对照研究方法,收集303例上皮性卵巢癌患者和303例健康对照个体的静脉抗凝血各5ml,同时记录其病史和个人及家族相关资料。采用蛋白酶K消化-饱和氯化钠盐析法提取外周血白细胞DNA,采用聚合酶链反应-限制性片段长度多态性(polymerase chain reaction -restriction fragment length polymorphism,PCR-RFLP)分析方法检测VEGF基因启动子区-1154G/A、-460C/T基因多态位点的基因型频率分布。
数据统计分析采用SPSS11.5版软件包(SPSS Company, Chicago, Illinois, USA)进行。病例组与对照组的年龄差异行t检验。比较各位点基因型频率的观察值与预期值并进行卡方检验行Hardy-Weinberg平衡分析。两组间的基因型分布比较采用行×列表χ2检验。以非条件Logistic回归法计算表示相对风险度的比值比(odds ratio,OR)及95%可信区间(confidence interval, CI)。采用EH软件和2LD软件分别分析VEGF基因启动子区-460C/T,-1154 G/A 2个多态性位点的单倍型频率和等位基因连锁不平衡状态。P<0.05作为差异有显著性的标准。
结果:
1.健康对照组中VEGF基因启动子区-1154G/A、-460C/T两个多态位点基因型频率分布均符合Hardy-weinberg平衡(P﹥0.05)。
2.在卵巢癌组和对照组中,VEGF基因启动子区-1154G/A多态的三种基因型频率(A/A、G/A、G/G)分别是1.7%、17.8%、80.5%和2.3%、26.1%、71.6%,两组比较差异有统计学意义(P=0.037);在卵巢癌组和对照组中,等位基因频率分布(G、A)分别是89.4%、10.6%和84.7%、15.3%,两组比较差异有统计学意义(P=0.013);与G/A+ A/A基因型相比,携带G/G基因型可能明显增加上皮性卵巢癌的发病风险(OR=1.64,95%CI=1.12~2.39)。
3. VEGF基因启动子区-460C/T多态C、T等位基因频率在卵巢癌组和对照组分别为19.3%、21.3%和80.7%、78.7%,两组相比差异无统计学意义(P﹥0.05);C/C、C/T、T/T基因型频率在卵巢癌组和对照组分别为4.0%、30.7%、65.3%和5.6%、31.4%、63%,两组相比差异无统计学意义(P﹥0.05);与C/T+T/T基因型相比,T/T基因型可能与卵巢癌的发病风险无关,OR值为1.11(95%CI= 0.79~1.54)。
4. VEGF基因启动子区-1154G/A和-460C/T SNPs位点间不存在连锁不平衡(D’=0.426)。
结论:
1. VEGF基因启动子区-1154G/A多态可能与上皮性卵巢癌的发病风险明显相关,即携带G/G基因型可能显著增加上皮性卵巢癌的发病风险。
2. VEGF基因启动子区-460C/T单核苷酸多态可能与上皮性卵巢癌的发病风险无关。
3. VEGF基因启动子区-1154G/A和-460C/T SNPs位点间不存在连锁不平衡。
Objective:Ovarian cancer is one of the three most common malignant gynecologic neoplasm. Early ovarian cancer is a silent and often asymptomatic disease. Many patients diagnosed with epithelial ovarian cancer have advanced disease. The overall 5-year survival rate for ovarian cancer is 30%. It is the leading cause of death from gynecologic cancer. The causes of ovarian cancer are poorly understood, but angiogenesis has been associated with the disease. Angiogenesis is an essential process in the development, growth and metastasis of malignant tumors, including ovarian cancer. A key mediator in angiogenesis is vascular endothelial growth factor (VEGF). VEGF is a major angiogenic factor involved in a number of pathologic processes, including neovascularization, a crucial step in the development of solid malignancies. At least 30 single nucleotide polymorphisms (SNPs) exist in the VEGF gene. Among them, the two VEGF polymorphisms (-1154G/A and -460C/T) have been reported to affect the expression of the gene and indicated to be involved in the development of diseases. The aim of this study was to investigate the association of polymorphisms in the VEGF gene with the susceptibility to epithelial ovarian cancer.
Methods: This case-contral study included 303 patients with epithelial ovarian cancer and 303 frequency-matched healthy control women. Five milliliter of venous blood from each subject was drawn in Vacutainer tubes containing EDTA and stored at 4℃, while the information of every subject was obtained. The genomic DNA was extracted within one week after bleeding by using proteinase K digestion followed by a salting out procedure. Genotypes of the VEGF-1154G/A, -460C/T genes were analyzed by polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP) method. Statistical analysis was performed using SPSS11.5 software package. A probability level of 5% was considered significant. The age difference of cases and frequency-matched controls was analyzed by the t-test. Hardy-Weinberg analysis was performed by comparing the observed and expected genotype frequencies in study groups using Chi-square test. Comparison of the VEGF genotype and allelotype distribution in patients and healthy controls was performed by means of two-sided contingency tables using Chi-square test. The odds ratio (OR) and 95% confidence Interval (CI) were calculated using an unconditional logistic regression model.
Results:
1. The distribution of the VEGF -1154G/A , -460C/T genotypes in the control group did not significantly deviate from that expected for a Hardy-Weinberg equilibrium (P>0.05).
2. The genotype frequencies of the VEGF -460 C/C, C/T and T/T in patients and controls were 4.0%/5.6%, 30.7%/31.4% and 65.3%/63.0%, respectively; the C and T allele frequencies were 19.3%/21.3% and 80.7%/78.7%, respectively. There was no statistically significant difference in the genotype distributions or allele frequencies of VEGF -460C/T between the patients and controls (P>0.05; Table 1). Compared with the C/T+T/T genotypes, the C/T genotype could not significantly modify the risk of developing epithelial ovarian cancer. The odds ratio was 1.11 (95% CI=0.79~1.54).
3. The genotype frequencies of the VEGF -1154 A/A, G/A, and G/G in patients and controls were 1.7%/2.3%, 17.8%/26.1% and 80.5%/71.6%, respectively; the A and G allele frequencies were 10.6%/15.3% and 89.4%/84.7%, respectively. There was significant difference in genotype and allele distributions of the VEGF -1154G/A between two groups (P=0.037, 0.013, respectively) (Table 3). Compared with the G/A+ A/A genotypes, the G/G genotype significantly increased the risk of developing epithelial ovarian cancer. The odds ratio was 1.64 (95% CI=1.12~2.39) (Table 4).
4. The promoter polymorphisms -1154G/A and the -460C/T was not linkage disequilibrium (D’=0.426).
Conclusions:
1. VEGF -1154G/A polymorphism was associated with susceptibility to epithelial ovarian cancer, carrying G allele may significantly increase the risk of developing epithelial ovarian cancer.
2. No significant association of the -460C/T polymorphism with the risk of developing epithelial ovarian cancer.
3. The promoter polymorphisms -1154G/A and the -460C/T were not linkage disequilibrium.
引文
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9 Zhai R, Liu G, Zhou W, et al. Vascular endothelial growth factor genotypes, haplotypes, gender, and the Risk of non-small cell lung cancer. Clin Cancer Res, 2008, 14: 612-617.
10 McCarron SL, Edwards S, Evans PR, et al. Influence of cytokine gene polymorphisms on the development of prostate cancer. Cancer Res. 2002, 62: 3369-3372.
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29 Zhai R, Liu G, Zhou W, et al. Vascular endothelial growth factor genotypes, haplotypes, gender, and the Risk of non-small cell lung cancer. Clin Cancer Res, 2008, 14: 612-617.
30 McCarron SL, Edwards S, Evans PR, et al. Influence of cytokine gene polymorphisms on the development of prostate cancer. Cancer Res, 2002, 62: 3369-3372.
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42 Ku KT, Wan L, Peng HC, et al. Vascular endothelial growth factor gene -460C/T polymorphism is a biomarker for oral cancer. Oral Oncol, 2005, 41: 497-502.
43 Zhai R, Liu G, Zhou W, et al. Vascular endothelial growth factor genotypes, haplotypes, gender, and the Risk of non-small cell lung cancer. Clin Cancer Res, 2008, 14: 612-617.
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13沈文荣,钱云铉,原发性卵巢恶性肿瘤的CT诊断.中华放射学杂志, 1998, 32 (4) :271.
14丁莹莹,高德培,卢玉波.卵巢上皮癌CT诊断.中国医学影像技术, 2000, 11 (5):323.
15 Ghossain MA, Buy JN, Ligneres C, et al. Epithelial tumors of ovary: comparis on of MR and CT finding. Radiology, 1991, 181(3): 863.
16 Fayed ST, Ahmad SM, Kassim SK, et al. The value of CA125 and CA724 in management of patients with epithelial ovarian cancer. Dis Markers, 1998, 14(3):155.
17 Kudoh K, Kikuchi Y, Kita T, et al. Preoperative determination of several serum tumor markers in patients with primary epithelial ovarian carcinoma. Gynecol Obstet Invest, 1999, 47 (1):52.
18董春雷.卵巢癌患者血清CA125、SI L-2R联检的临床意义.放射免疫学杂志, 2004, 17(1):74.
19张忠嘉.卵巢肿瘤的CT诊断价值[J] .中国医学影像技术, 1997, 13 :80.
20续晋铭,吴辅仁.卵巢肿瘤的MPI诊断[J].中国临床医学影像杂志, 1999, 10 (1):41.
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24 Morice P, Viala J, Pautier P, et al. Port-site metastasis after laparoscopic surgery for gynecologic cancer. A report of six cases [J]. Reprod Med, 2000, 45 (10): 837 - 840.
25 Finn CB, Luesleg DM, Buxton EJ, et al. Is stage I epithelial ovarian cancer overtreated both Surgically and systemically? Results of a five year cancer rigistry review. Brit J obstet Gynecal, 1992, 99:54.
26 Dembo AJ, Davy MLJ, Stenwing AE, et al. Prognostive factors in patients with stage I epithelial ovarian cancer. Obstet Gynecal, 1990, 75:263.
27温宏武,刘书文.Ⅰ期卵巢上皮性癌的预后因素.中华妇产科杂志, 1994, 29:235.
28李孟达,黄欣.中晚期卵巢癌综合治疗疗效及影响因素分析.中华妇产科杂志, 1996, 31:621.
29 Burger CW, Prinssen HM, Beak JPA, et al. The management of borderline epithelial tumors of the ovary [J]. Int J Gynecol Cancer, 2000, 10: 181-197.
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12 Bast RC J r. Siegal FP, Runowicz C, et al. Elevation of serum CA125prior to diagnosis of an epithlial ovarian carcinoma [J]. Gynecol Oncol, 1985, 22 (1):115.
13沈文荣,钱云铉,原发性卵巢恶性肿瘤的CT诊断.中华放射学杂志, 1998, 32 (4) :271.
14丁莹莹,高德培,卢玉波.卵巢上皮癌CT诊断.中国医学影像技术, 2000, 11 (5):323.
15 Ghossain MA, Buy JN, Ligneres C, et al. Epithelial tumors of ovary: comparis on of MR and CT finding. Radiology, 1991, 181(3): 863.
16 Fayed ST, Ahmad SM, Kassim SK, et al. The value of CA125 and CA724 in management of patients with epithelial ovarian cancer. Dis Markers, 1998, 14(3):155.
17 Kudoh K, Kikuchi Y, Kita T, et al. Preoperative determination of several serum tumor markers in patients with primary epithelial ovarian carcinoma. Gynecol Obstet Invest, 1999, 47 (1):52.
18董春雷.卵巢癌患者血清CA125、SI L-2R联检的临床意义.放射免疫学杂志, 2004, 17(1):74.
19张忠嘉.卵巢肿瘤的CT诊断价值[J] .中国医学影像技术, 1997, 13 :80.
20续晋铭,吴辅仁.卵巢肿瘤的MPI诊断[J].中国临床医学影像杂志, 1999, 10 (1):41.
21 Zimny M, et al. Nukleamearmedizin, 1997, 36 (7):228-233.
22 Romer W, et al. Rofo Fortschr Geb Rontgenstr Neuen Bildgeb Verfahr, 1997, 166 (1):62-68.
23 Smidt VJ, Singh DM, Hurteau JA, et al. Effect of carbon dioxide onhuman ovarian carcinoma cell growth [J]. Am J Obstet G ynecol, 2001, 185 (6):1314-1317.
24 Morice P, Viala J, Pautier P, et al. Port-site metastasis after laparoscopic surgery for gynecologic cancer. A report of six cases [J]. Reprod Med, 2000, 45 (10): 837 - 840.
25 Finn CB, Luesleg DM, Buxton EJ, et al. Is stage I epithelial ovarian cancer overtreated both Surgically and systemically? Results of a five year cancer rigistry review. Brit J obstet Gynecal, 1992, 99:54.
26 Dembo AJ, Davy MLJ, Stenwing AE, et al. Prognostive factors in patients with stage I epithelial ovarian cancer. Obstet Gynecal, 1990, 75:263.
27温宏武,刘书文.Ⅰ期卵巢上皮性癌的预后因素.中华妇产科杂志, 1994, 29:235.
28李孟达,黄欣.中晚期卵巢癌综合治疗疗效及影响因素分析.中华妇产科杂志, 1996, 31:621.
29 Burger CW, Prinssen HM, Beak JPA, et al. The management of borderline epithelial tumors of the ovary [J]. Int J Gynecol Cancer, 2000, 10: 181-197.