卵巢癌病人血游离DNA的临床研究
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摘要
目的:卵巢肿瘤是女性生殖系统常见肿瘤,因卵巢的解剖位置位于女性盆腔深部,临床发病比较隐匿,至今缺乏特异有效早期诊断方法,70%以上的患者诊断时已属晚期。在过去的15～20年间,虽然在诊断和治疗方面作了很大努力,但5年生存率无明显改善,仍徘徊不前。随着宫颈癌及子宫内膜癌的诊断和治疗的进展,卵巢癌已经成为严重威胁妇女生命的肿瘤。因此,寻找卵巢癌高易感性的遗传标志,对卵巢癌的早期诊断、指导临床治疗、早期预防、评估预后具有重要的意义。
循环DNA即存在于人血清或血浆中的游离DNA。近年研究表明,增殖旺盛的肿瘤细胞能持续释放DNA进入血液循环,使肿瘤患者循环DNA含量增高且发生与原发肿瘤组织相一致的分子遗传学改变(如基因突变、抑癌基因启动子高甲基化、微卫星不稳定和杂合性丢失等)。对肿瘤患者循环中DNA的检测可分为定性和定量两种:前者主要检测血清或血浆中肿瘤特异性基因改变,后者则以血清或血浆DNA总量为指标,两者均可反映肿瘤的存在和严重程度,并有希望成为新的肿瘤分子标志物。肿瘤循环DNA的研究在卵巢癌中的报道和研究相对较少,本研究旨在通过对卵巢癌患者外周血游离DNA进行定性研究,探索一种新的可用于早期诊断和疗效监控的方法。
方法:本研究首先收集卵巢癌患者及对照组的血液标本,对卵巢癌患者的临床资料做回顾性分析,提取循环血DNA,设计特异性引物,采用PCR—SSCP、PCR—RFLP分析法检测卵巢癌患者循环血中CYP1A1基因MSPI多态性、GSTT1基因多态性及微卫星不稳定性与卵巢癌易感性的关系,进行测序验证,测序结果与GenBank数据库比对分析后统计处理,分析CYP1A1基因MSPI多态性、GSTT1基因多态性及微卫星不稳定性与卵巢癌患者的病理类型、临床病理分期等相关性。通过对卵巢癌患者外周血游离DNA进行定性研究,探索一种新的可用于早期诊断和疗效监控的方法。
结果:
1.按照FIGO(2000年)分期:CYP1A1基因A基因型组Ⅰ-Ⅱ期14例占28%,Ⅲ-Ⅳ期36例占72%;B基因型组Ⅰ-Ⅱ期14例占48%,Ⅲ-Ⅳ期15例占52%;C基因组Ⅰ-Ⅱ期6例占50%,Ⅲ-Ⅳ期6例占50%。经统计学分析各个基因型在临床分期上无显著性差异。CYP1A1基因A基因型组50例患者,卵巢上皮性癌42例;B基因型组28例患者,卵巢上皮性癌17例;C基因型组13例患者,卵巢上皮性癌11例。对各个基因型患者的病理类型按照卵巢上皮性恶性肿瘤和非上皮性恶性肿瘤进行分组比较,统计分析结果表明各个基因型患者病理类型的构成比有显著性差异(x~2=8.22,P＜0.05)。
2.卵巢癌组和对照组中GSTT1缺失型(null)基因型分布频率为38%(35/91)和12%(6/50),两组中GSTT1缺失型基因型相比较差异有显著性(x~2=10.96,p＜0.05)。GSTT1基因缺失增加患卵巢癌的风险。卵巢上皮性恶性肿瘤和卵巢非上皮性恶性肿瘤中GSTT1缺失型(null)基因型分布频率分别为43.14%(30/70)、14%(3/21),发现GSTT1缺失型(null)基因型在卵巢上皮性恶性肿瘤和对照组中相比较差异有显著性(x~2=9.72,p＜0.05)。GSTT1基因缺失主要增加患卵巢上皮性癌的风险。
3.卵巢癌组中浆液性囊腺癌、粘液性囊腺癌、子宫内膜样癌、库肯勃瘤及其他类型发生微卫星不稳定的频率依次为58.7%(27/46)、41.7%(5/12)、50%(5/10)、0%(0/2)、28.6%(6/21)。相比较差异具有显著性(P＜0.05)。提示微卫星不稳定与卵巢癌的病理类型有关。早期(Ⅰ-Ⅱ期)患者和晚期(Ⅲ-Ⅳ期)患者发生微卫星不稳定的频率分别为。50%(17/34)和45.6%(26/57)。微卫星不稳定在早期和晚期中相比较差异具有显著性(x~2=0.16,P＜0.05)。91例卵巢癌患者中发生微卫星不稳定的频率为47.25%(43/91),良性肿瘤和正常人血中未检测到微卫星不稳定性的发生。
结论:
1.卵巢癌患者外周静脉血循环DNA中存在微卫星不稳定性。微卫星不稳定与卵巢癌病理类型、临床病理分期均有关。微卫星不稳定主要发生在卵巢恶性肿瘤中,良性肿瘤及正常人中不存在微卫星不稳定。
2.卵巢癌患者外周静脉血循环DNA中存在CYP1A1基因MSPI多态性。卵巢上皮性恶性肿瘤发生率A基因型(野生型T/T)高于其他基因型。CYP1A1基因MSPI多态性与卵巢癌病理分期无关。
3.卵巢癌患者外周静脉血循环DNA中存在GSTT1基因遗传易感性。GSTT1基因缺失可能是卵巢癌发病的危险因素之一,GSTT1基因缺失增加患卵巢癌的风险,主要增加患上皮性癌的风险。
4.未来可通过卵巢癌患者循环血中DNA的定性检测为卵巢癌的早期诊断、评估预后提供依据。
Objective:
Malignant ovarian tumors are the highest mortality of malignant tumors of female reproductive system,and its 5-year survival rate is only about 25%due mainly to compare the clinical incidence of occult,early cancer without any symptoms,the lack of specific indicators of early onset,it more than 70%When found,the others belong to patients with advanced,although in the past 15 to 20 years in the diagnosis and treatment have made a great effort,such as a variety of tumor markers in clinical widely used,surgical techniques continue to improve,as well as platinum,taxol,etc.chemotherapeutic drugs have also been used in clinical,but ovarian cancer patients with 5-year survival rate remained stagnant.Therefore,look for high-ovarian cancer susceptibility genetic markers for ovarian cancer diagnosis and guide clinical treatment and early prevention has important significance.
In this study,PCR-SSCP,PCR-RFLP assay in patients with ovarian cancer blood MSPI polymorphism in the CYP1A1 gene,GSTT1 gene polymorphisms and microsatellite instability and susceptibility to ovarian cancer,analysis of CYP1A1 gene MSPI many normality,GSTT1 gene polymorphisms and microsatellite instability in patients with ovarian cancer histological types,such as the relevance of pathological stage.Through the peripheral blood of patients with ovarian cancer circilating DNA for qualitative research to explore a new can be used for early diagnosis and efficacy of the method of monitoring.
Method:
In this study,first of all,the collection of ovarian cancer patients and control group,blood samples of patients with ovarian cancer clinical data to do a retrospective analysis,using conventional phenol-chloroform extract genomic DNA,the design of specific primers,using PCR-SSCP,PCR-RFLP assay in patients with ovarian cancer blood MSPI polymorphism in the CYP1A1 gene,GSTT1 gene polymorphisms and microsatellite instability and susceptibility to ovarian cancer,for sequencing verified the results with the GenBank sequence database analysis than on statistical treatment,MSPI polymorphism analysis of CYP1A1 gene,GSTT1 gene polymorphisms and microsatellite instability in patients with ovarian cancer histological types,such as the relevance of pathological stage. Through the peripheral blood of patients with ovarian cancer free DNA for qualitative research to explore a new can be used for early diagnosis and efficacy of the method of monitoring.
Result:
1.In accordance with the FIGO(2000 years) phases:CYP1A1 gene A genotype groupⅠ-Ⅱaccounted for 14 cases of phase 28%,Ⅲ-Ⅳaccounted for 36 cases of phase 72%;B genotype groupsⅠ-Ⅱperiod 14 cases of 48%By statistical analysis at the various genotypes on the clinical stage was no significant difference.CYP1A1 gene A genotype group of 50 patients with epithelial ovarian cancer in 42 cases;B genotype group of 28 cases of patients with epithelial ovarian cancer in 17 cases;C genotype group of 13 patients with epithelial ovarian cancer in 11 cases.Genotype in patients with various pathological types in accordance with epithelial ovarian cancer and non-epithelial malignant tumor group compared with the results of statistical analysis showed that patients with different genotypes than the composition of pathological types were significantly different(x~2=8.22,P＜0.05).
2.Ovarian cancer group and control group in the GSTT1 deletion(null) genotype distribution frequency of 38%(35/91) and 12%(6/50),the two groups in the GSTT1 deletion genotype compared there was a significant difference(x~2=10.96,p＜0.05).GSTT1 gene deletion increases the risk of ovarian cancer.Epithelial ovarian cancer and non-epithelial ovarian malignancies in the GSTT1 deletion(null) genotype frequencies were 43.14%(30/70),14%(3/21) found that GSTT1 deletion(null) genotype in epithelial ovarian cancer and compared with the control group there was a significant difference(x~2=9.72, p＜0.05).GSTT1 gene deletion increases the risk of major epithelial ovarian cancer risk.
3.Serous ovarian cancer group cystadenocarcinoma,mucinous cystadenocarcinoma,endometrioid carcinoma,Krukenberg tumor and other types happen frequency microsatellite instability was followed by 58.7%(27/46),41.7%(5/12),50%(5/10),0%(0/2),28.6%(6/21). In comparison of the difference was significant(P＜0.05).prompt microsatellite instability and ovarian cancer pathological type. Early(Ⅰ-Ⅱperiod) patients and late(Ⅲ-Ⅳperiod) occurred in patients with microsatellite instability frequencies were 50%(17/34) and 45.6%(26/57).Microsatellite instability in early and late compared in the difference was significant(x~2=0.16,P＜0.05).91 cases of ovarian cancer occur in patients with microsatellite instability frequency of 47.25(43/91),benign and normal human blood was not detected in the microsatellite instability from occurring.
Conclusion:
1.Ovarian cancer in patients with peripheral venous blood circulation DNA exist microsatellite instability.
Microsatellite instability has relationship with pathological types of ovarian cancer,clinical pathological stage.
Microsatellite instability exists only with ovarian cancer,does not occur with benign tumors and normal controls.
2.Ovarian cancer in patients with peripheral venous blood circulation DNA exist the polymorphism MSPI gene CYPIAI.
Malignant epithelial ovarian incidence A genotype(wild-type T/T) higher than that of other genotypes.
CYPIAI gene polymorphism and ovarian cancer MSPI has no relationship with pathological stage.
3.Ovarian cancer circulating DNA in peripheral blood of patients with genetic susceptibility to the existence of GSTT1.
GSTT1 gene deletion in ovarian cancer may be one of the risk factors, GSTT1 gene deletion increases the risk of ovarian cancer,the main increase the risk of epithelial cancer risk.
4.The future through the blood of patients with ovarian cancer in the qualitative detection of DNA for the early diagnosis of ovarian cancer,provide a basis for assessment of prognosis.
循环DNA即存在于人血清或血浆中的游离DNA。近年研究表明,增殖旺盛的肿瘤细胞能持续释放DNA进入血液循环,使肿瘤患者循环DNA含量增高且发生与原发肿瘤组织相一致的分子遗传学改变(如基因突变、抑癌基因启动子高甲基化、微卫星不稳定和杂合性丢失等)。对肿瘤患者循环中DNA的检测可分为定性和定量两种:前者主要检测血清或血浆中肿瘤特异性基因改变,后者则以血清或血浆DNA总量为指标,两者均可反映肿瘤的存在和严重程度,并有希望成为新的肿瘤分子标志物。肿瘤循环DNA的研究在卵巢癌中的报道和研究相对较少,本研究旨在通过对卵巢癌患者外周血游离DNA进行定性研究,探索一种新的可用于早期诊断和疗效监控的方法。
方法:本研究首先收集卵巢癌患者及对照组的血液标本,对卵巢癌患者的临床资料做回顾性分析,提取循环血DNA,设计特异性引物,采用PCR—SSCP、PCR—RFLP分析法检测卵巢癌患者循环血中CYP1A1基因MSPI多态性、GSTT1基因多态性及微卫星不稳定性与卵巢癌易感性的关系,进行测序验证,测序结果与GenBank数据库比对分析后统计处理,分析CYP1A1基因MSPI多态性、GSTT1基因多态性及微卫星不稳定性与卵巢癌患者的病理类型、临床病理分期等相关性。通过对卵巢癌患者外周血游离DNA进行定性研究,探索一种新的可用于早期诊断和疗效监控的方法。
结果:
1.按照FIGO(2000年)分期:CYP1A1基因A基因型组Ⅰ-Ⅱ期14例占28%,Ⅲ-Ⅳ期36例占72%;B基因型组Ⅰ-Ⅱ期14例占48%,Ⅲ-Ⅳ期15例占52%;C基因组Ⅰ-Ⅱ期6例占50%,Ⅲ-Ⅳ期6例占50%。经统计学分析各个基因型在临床分期上无显著性差异。CYP1A1基因A基因型组50例患者,卵巢上皮性癌42例;B基因型组28例患者,卵巢上皮性癌17例;C基因型组13例患者,卵巢上皮性癌11例。对各个基因型患者的病理类型按照卵巢上皮性恶性肿瘤和非上皮性恶性肿瘤进行分组比较,统计分析结果表明各个基因型患者病理类型的构成比有显著性差异(x~2=8.22,P＜0.05)。
2.卵巢癌组和对照组中GSTT1缺失型(null)基因型分布频率为38%(35/91)和12%(6/50),两组中GSTT1缺失型基因型相比较差异有显著性(x~2=10.96,p＜0.05)。GSTT1基因缺失增加患卵巢癌的风险。卵巢上皮性恶性肿瘤和卵巢非上皮性恶性肿瘤中GSTT1缺失型(null)基因型分布频率分别为43.14%(30/70)、14%(3/21),发现GSTT1缺失型(null)基因型在卵巢上皮性恶性肿瘤和对照组中相比较差异有显著性(x~2=9.72,p＜0.05)。GSTT1基因缺失主要增加患卵巢上皮性癌的风险。
3.卵巢癌组中浆液性囊腺癌、粘液性囊腺癌、子宫内膜样癌、库肯勃瘤及其他类型发生微卫星不稳定的频率依次为58.7%(27/46)、41.7%(5/12)、50%(5/10)、0%(0/2)、28.6%(6/21)。相比较差异具有显著性(P＜0.05)。提示微卫星不稳定与卵巢癌的病理类型有关。早期(Ⅰ-Ⅱ期)患者和晚期(Ⅲ-Ⅳ期)患者发生微卫星不稳定的频率分别为。50%(17/34)和45.6%(26/57)。微卫星不稳定在早期和晚期中相比较差异具有显著性(x~2=0.16,P＜0.05)。91例卵巢癌患者中发生微卫星不稳定的频率为47.25%(43/91),良性肿瘤和正常人血中未检测到微卫星不稳定性的发生。
结论:
1.卵巢癌患者外周静脉血循环DNA中存在微卫星不稳定性。微卫星不稳定与卵巢癌病理类型、临床病理分期均有关。微卫星不稳定主要发生在卵巢恶性肿瘤中,良性肿瘤及正常人中不存在微卫星不稳定。
2.卵巢癌患者外周静脉血循环DNA中存在CYP1A1基因MSPI多态性。卵巢上皮性恶性肿瘤发生率A基因型(野生型T/T)高于其他基因型。CYP1A1基因MSPI多态性与卵巢癌病理分期无关。
3.卵巢癌患者外周静脉血循环DNA中存在GSTT1基因遗传易感性。GSTT1基因缺失可能是卵巢癌发病的危险因素之一,GSTT1基因缺失增加患卵巢癌的风险,主要增加患上皮性癌的风险。
4.未来可通过卵巢癌患者循环血中DNA的定性检测为卵巢癌的早期诊断、评估预后提供依据。
Objective:
Malignant ovarian tumors are the highest mortality of malignant tumors of female reproductive system,and its 5-year survival rate is only about 25%due mainly to compare the clinical incidence of occult,early cancer without any symptoms,the lack of specific indicators of early onset,it more than 70%When found,the others belong to patients with advanced,although in the past 15 to 20 years in the diagnosis and treatment have made a great effort,such as a variety of tumor markers in clinical widely used,surgical techniques continue to improve,as well as platinum,taxol,etc.chemotherapeutic drugs have also been used in clinical,but ovarian cancer patients with 5-year survival rate remained stagnant.Therefore,look for high-ovarian cancer susceptibility genetic markers for ovarian cancer diagnosis and guide clinical treatment and early prevention has important significance.
In this study,PCR-SSCP,PCR-RFLP assay in patients with ovarian cancer blood MSPI polymorphism in the CYP1A1 gene,GSTT1 gene polymorphisms and microsatellite instability and susceptibility to ovarian cancer,analysis of CYP1A1 gene MSPI many normality,GSTT1 gene polymorphisms and microsatellite instability in patients with ovarian cancer histological types,such as the relevance of pathological stage.Through the peripheral blood of patients with ovarian cancer circilating DNA for qualitative research to explore a new can be used for early diagnosis and efficacy of the method of monitoring.
Method:
In this study,first of all,the collection of ovarian cancer patients and control group,blood samples of patients with ovarian cancer clinical data to do a retrospective analysis,using conventional phenol-chloroform extract genomic DNA,the design of specific primers,using PCR-SSCP,PCR-RFLP assay in patients with ovarian cancer blood MSPI polymorphism in the CYP1A1 gene,GSTT1 gene polymorphisms and microsatellite instability and susceptibility to ovarian cancer,for sequencing verified the results with the GenBank sequence database analysis than on statistical treatment,MSPI polymorphism analysis of CYP1A1 gene,GSTT1 gene polymorphisms and microsatellite instability in patients with ovarian cancer histological types,such as the relevance of pathological stage. Through the peripheral blood of patients with ovarian cancer free DNA for qualitative research to explore a new can be used for early diagnosis and efficacy of the method of monitoring.
Result:
1.In accordance with the FIGO(2000 years) phases:CYP1A1 gene A genotype groupⅠ-Ⅱaccounted for 14 cases of phase 28%,Ⅲ-Ⅳaccounted for 36 cases of phase 72%;B genotype groupsⅠ-Ⅱperiod 14 cases of 48%By statistical analysis at the various genotypes on the clinical stage was no significant difference.CYP1A1 gene A genotype group of 50 patients with epithelial ovarian cancer in 42 cases;B genotype group of 28 cases of patients with epithelial ovarian cancer in 17 cases;C genotype group of 13 patients with epithelial ovarian cancer in 11 cases.Genotype in patients with various pathological types in accordance with epithelial ovarian cancer and non-epithelial malignant tumor group compared with the results of statistical analysis showed that patients with different genotypes than the composition of pathological types were significantly different(x~2=8.22,P＜0.05).
2.Ovarian cancer group and control group in the GSTT1 deletion(null) genotype distribution frequency of 38%(35/91) and 12%(6/50),the two groups in the GSTT1 deletion genotype compared there was a significant difference(x~2=10.96,p＜0.05).GSTT1 gene deletion increases the risk of ovarian cancer.Epithelial ovarian cancer and non-epithelial ovarian malignancies in the GSTT1 deletion(null) genotype frequencies were 43.14%(30/70),14%(3/21) found that GSTT1 deletion(null) genotype in epithelial ovarian cancer and compared with the control group there was a significant difference(x~2=9.72, p＜0.05).GSTT1 gene deletion increases the risk of major epithelial ovarian cancer risk.
3.Serous ovarian cancer group cystadenocarcinoma,mucinous cystadenocarcinoma,endometrioid carcinoma,Krukenberg tumor and other types happen frequency microsatellite instability was followed by 58.7%(27/46),41.7%(5/12),50%(5/10),0%(0/2),28.6%(6/21). In comparison of the difference was significant(P＜0.05).prompt microsatellite instability and ovarian cancer pathological type. Early(Ⅰ-Ⅱperiod) patients and late(Ⅲ-Ⅳperiod) occurred in patients with microsatellite instability frequencies were 50%(17/34) and 45.6%(26/57).Microsatellite instability in early and late compared in the difference was significant(x~2=0.16,P＜0.05).91 cases of ovarian cancer occur in patients with microsatellite instability frequency of 47.25(43/91),benign and normal human blood was not detected in the microsatellite instability from occurring.
Conclusion:
1.Ovarian cancer in patients with peripheral venous blood circulation DNA exist microsatellite instability.
Microsatellite instability has relationship with pathological types of ovarian cancer,clinical pathological stage.
Microsatellite instability exists only with ovarian cancer,does not occur with benign tumors and normal controls.
2.Ovarian cancer in patients with peripheral venous blood circulation DNA exist the polymorphism MSPI gene CYPIAI.
Malignant epithelial ovarian incidence A genotype(wild-type T/T) higher than that of other genotypes.
CYPIAI gene polymorphism and ovarian cancer MSPI has no relationship with pathological stage.
3.Ovarian cancer circulating DNA in peripheral blood of patients with genetic susceptibility to the existence of GSTT1.
GSTT1 gene deletion in ovarian cancer may be one of the risk factors, GSTT1 gene deletion increases the risk of ovarian cancer,the main increase the risk of epithelial cancer risk.
4.The future through the blood of patients with ovarian cancer in the qualitative detection of DNA for the early diagnosis of ovarian cancer,provide a basis for assessment of prognosis.
引文
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