卵巢癌早期诊断的预警及关键技术的研究
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摘要
研究背景：卵巢癌是妇科肿瘤中病死率最高的恶性肿瘤，近10年流行病学统计显示其发病及死亡人数均呈上升和年轻化趋势。因早期无明显临床症状，60-70%患者发现时已属晚期，尽管手术、放疗、化疗等技术不断改进，5年生存率仅从37%上升至46%；Ⅰ期卵巢癌患者5年生存率大于90%，大部分患者通过手术即可治愈，因此卵巢癌早期诊断是提高患者5年生存率的关键，但只有23%的卵巢癌可做到早期诊断，考虑目前仍不能做到早期诊断的原因为：卵巢癌的病理种类繁多，发展机制及病因学尚未明确，缺乏特异度及敏感度均高的肿瘤标记物，分子生物学发生机制研究尚未完善等。因此对于卵巢癌的早期诊断仍处于研究阶段，目前尚无确切的可应用于临床的理想标志物。
目的：通过本实验，利用质谱分析方法在卵巢癌患者的血清和肿瘤组织中寻找差异多肽/蛋白，并采用免疫组化的方法，对卵巢浆液性癌组织切片进行HE4抗体染色，结合临床资料，探索差异多肽/蛋白以及HE4表达情况与卵巢癌临床特征的相关性，以此为基础建立卵巢癌早期诊断相对特异的预警体系。
方法：1、采用基质辅助激光解析飞行时间质谱分析（MALDI-TOF-MS）结合磁珠的技术对80例卵巢癌、84例卵巢子宫内膜异位囊肿和100例健康人群的血清行质谱分析得到血清多肽图，经Flexanalysis3.0软件对多肽图进行归一化处理标峰后，将其中48例卵巢癌、51例卵巢子宫内膜异位囊肿和60例健康人群血清作为训练集，利用ClinprotoolsTM2.1软件建立相应的分类诊断模型，将剩余32例卵巢癌、33例卵巢子宫内膜异位囊肿和40例健康人群作为测试集验证模型的敏感度和特异度。2.采用双向凝胶电泳技术对3例II期卵巢浆液性癌与3例卵巢子宫内膜异位囊肿囊壁组织进行检测，得到双向电泳图，筛选每组（包括1例卵巢浆液性癌和1例卵巢子宫内膜异位囊肿）差异蛋白质斑点；将三组电泳图进行合并后对已筛选出的差异点进行复筛，选出共同差异蛋白质斑点；采用质谱兼容技术鉴定复筛出的蛋白质种类。3.采用免疫组化法对74例原发性浆液性卵巢癌组织切片进行HE4抗体检测，对表达情况进行评分，结合临床资料，探讨HE4表达与临床特征及病理特征的相关性。
结果:1、卵巢癌与健康女性人群中筛出17个差异多肽峰（P＜0.05），上调13个,下调4个，m/z3373，3342，4791，6948可作为诊断截点，以此建立的诊断模型敏感度100%，特异度92.0%；该模型与CA-125相比，前者准确率100%，后者87.5%。卵巢子宫内膜异位囊肿与健康女性人群中筛查出19个差异多肽峰（P＜0.05），上调15个,下调6个，诊断截点为m/z3342，6689，诊断模型敏感度81.3%，特异度100.0%。利用各期卵巢癌与卵巢子宫内膜异位囊肿血清建立诊断模型的敏感度64.7%，特异度为75%。
2.II期卵巢浆液性癌和卵巢子宫内膜异位囊肿中筛查出共有的蛋白质斑点4个，非共有的蛋白质斑点3个，其中下调蛋白3个，上调蛋白4个，经质谱鉴定后，上调蛋白为：细胞内视黄醇结合蛋白-2（CRBP-2），Nm-23，伴侣蛋白-10（Chaperonin10），胶转蛋白（Transgelin），下调蛋白为肌球蛋白调节亚基-9（Myl-9），视黄醇结合蛋白-1（RBP-1），胶转蛋白-2（Transgelin-2）。
3. HE4在原发性卵巢浆液性癌中高表达，且在无TIC的输卵管中已有表达，阳性表达率在各年龄阶段、病理分级及有无淋巴结转移之间的差异无统计学意义，与手术分期具有一定的相关性，且阳性率随期别升高而增高。I、II期中HE4评分低于III期，且随期别升高（I期-III期），表达量也逐渐上升。
结论：1.采用MALDI-TOF-MS结合磁珠技术以血清为样本的方法，可建立敏感度、特异度较高的卵巢癌、卵巢子宫内膜异位症的分类诊断模型。卵巢癌模型的诊断准确性高于单独应用CA-125的准确性，认为MALDI-TOF-MS结合磁珠技术可作为早期诊断的技术平台。利用此模型可初步鉴别卵巢癌和子宫内膜异位症，说明卵巢子宫内膜异位症的恶性行为与卵巢癌在某些具有一定的相关性。2. Myl-9、Nm-23与肿瘤发生发展相关，Transgelin、Transgelin-2与肿瘤的早期转移相关，CRBP2、RBP1有可能成为靶向治疗的一个靶点，可用于下一步在卵巢癌细胞中进行早期肿瘤发生的分子机制研究。3. HE4在原发性浆液性卵巢癌发生发展过程中发挥了一定的作用，并促其可进一步发展成为晚期癌，因此HE4有望成为早期诊断的指标，但并不完全是肿瘤转移相关因子。
Background：Ovarian cancer is the highest fatality rate in malignant tumors of thegynecologic oncology. Because of no obvious clinical symptoms,60-70%patients are inthe advanced stage in clinic. With surgery, radiotherapy, chemotherapy are improved, the5-year survival rate raise only from37%to46%; it is greater than90%in I stage, so earlydiagnosis is the key to improve patients'5-year survival, but only23%ovarian cancer canbe diagnosed in early stage. Consider the reasons: pathological types of ovarian cancer aremore; the mechanism is not clear; lack tumor markers with high specificity and sensitivity;the occurrence of molecular biology mechanism is not yet perfect. Therefore, there is noideal marker can be applied to clinic to do the early diagnosis in early stage.
Objective: Use of serum peptides and two-dimensional electrophoresis method toscreening a new protein/peptide markers, and use HE4immunohistochemical staining inovarian serous adenocarcinoma paraffin tissue, combined with results of clinicalexamination, to explore the relevance both protein/peptide, expression of HE4and theclinical characters of ovarian serous adenocarcinoma.
Methods:1. Use MALDI-TOF-MS to analyse the serum peptide map, throughFlexananlysis software to deal the map, then analyzed by use of ClinprotoolsTM2.1software to establish diagnosis model, select the validation group to validate the model.2.Use the two-dimensional electrophoresis to screening the different protein andidentification.3. Using HE4antibody by immunohistochemical methods to do detectionthe primary serous ovarian cancer tissue, to explore the correlation of HE4and clinicalfeatures.
Results:1. There are17peptide peaks between ovarian cancer and healthy women, up13, down4, the diagnostic model shows that the sensitivity is100%, specificity is92.0%,and m/z3373,3342,4791,6948can be used as a diagnostic cut-off point. The accurancyof the model is100%.2. There are19peptide peaks between ovarian endometrial cysts and healthy women, up15, down6, the model sensitivity is81.3%, specificity is100.0%,and m/z3342,6689can be used as a diagnostic cut-off point.3. In the model of theovarian cancer and ovarian endometrial cysts, the sensitivity is64.7%, the specificity is75%.4. II stage ovarian serous adenocarcinoma and ovarian endometriotic cysts, screeningout the7protein, two down-regulated, five up-regulated, after mass spectrometry identified,the up-regulated protein are CRBP-2, Nm-23, chaperonin10, Transgelin, down-regulatedproteins are Myl-9, RBP-1, Transgelin-2.5. HE4is high expression in primary ovarianserous carcinoma, there is expression in the tissue of the no TIC oviduct. There is nocorrection of the positive expression rate between the age, pathological grade and themaetastasis of lymph node and HE4expression, but there is relationship between stage andHE4expression.
Conclusion:1. Ovarian cancer and healthy women, ovarian endometriosis cyst andhealthy women can be distinguished by the serum peptide diagnostic model, and show thatthe accuracy of the ovarian cancer diagnosis model is higher than serum CA-125. Thismodel can be used to initial diagnosis the ovarian cancer and endometriosis, the malignantbehavior of ovarian endometriosis and ovarian cancer in some certain degree havecorrelation.2. Myl-9, Nm23have related to the development of tumor, Transgelin,Transgelin-2have related to the early metastasis, CRBP2the RBP1may become a targetfor targeted therapy, can be used to further the molecular mechanism.3. HE4maybe play acertain role in the development of primary serous ovarian cancer, and promote to theadvanced cancer, so HE4is expected to be indicators to do early diagnosis, but not entirelytumor metastasis-related factors.
目的：通过本实验，利用质谱分析方法在卵巢癌患者的血清和肿瘤组织中寻找差异多肽/蛋白，并采用免疫组化的方法，对卵巢浆液性癌组织切片进行HE4抗体染色，结合临床资料，探索差异多肽/蛋白以及HE4表达情况与卵巢癌临床特征的相关性，以此为基础建立卵巢癌早期诊断相对特异的预警体系。
方法：1、采用基质辅助激光解析飞行时间质谱分析（MALDI-TOF-MS）结合磁珠的技术对80例卵巢癌、84例卵巢子宫内膜异位囊肿和100例健康人群的血清行质谱分析得到血清多肽图，经Flexanalysis3.0软件对多肽图进行归一化处理标峰后，将其中48例卵巢癌、51例卵巢子宫内膜异位囊肿和60例健康人群血清作为训练集，利用ClinprotoolsTM2.1软件建立相应的分类诊断模型，将剩余32例卵巢癌、33例卵巢子宫内膜异位囊肿和40例健康人群作为测试集验证模型的敏感度和特异度。2.采用双向凝胶电泳技术对3例II期卵巢浆液性癌与3例卵巢子宫内膜异位囊肿囊壁组织进行检测，得到双向电泳图，筛选每组（包括1例卵巢浆液性癌和1例卵巢子宫内膜异位囊肿）差异蛋白质斑点；将三组电泳图进行合并后对已筛选出的差异点进行复筛，选出共同差异蛋白质斑点；采用质谱兼容技术鉴定复筛出的蛋白质种类。3.采用免疫组化法对74例原发性浆液性卵巢癌组织切片进行HE4抗体检测，对表达情况进行评分，结合临床资料，探讨HE4表达与临床特征及病理特征的相关性。
结果:1、卵巢癌与健康女性人群中筛出17个差异多肽峰（P＜0.05），上调13个,下调4个，m/z3373，3342，4791，6948可作为诊断截点，以此建立的诊断模型敏感度100%，特异度92.0%；该模型与CA-125相比，前者准确率100%，后者87.5%。卵巢子宫内膜异位囊肿与健康女性人群中筛查出19个差异多肽峰（P＜0.05），上调15个,下调6个，诊断截点为m/z3342，6689，诊断模型敏感度81.3%，特异度100.0%。利用各期卵巢癌与卵巢子宫内膜异位囊肿血清建立诊断模型的敏感度64.7%，特异度为75%。
2.II期卵巢浆液性癌和卵巢子宫内膜异位囊肿中筛查出共有的蛋白质斑点4个，非共有的蛋白质斑点3个，其中下调蛋白3个，上调蛋白4个，经质谱鉴定后，上调蛋白为：细胞内视黄醇结合蛋白-2（CRBP-2），Nm-23，伴侣蛋白-10（Chaperonin10），胶转蛋白（Transgelin），下调蛋白为肌球蛋白调节亚基-9（Myl-9），视黄醇结合蛋白-1（RBP-1），胶转蛋白-2（Transgelin-2）。
3. HE4在原发性卵巢浆液性癌中高表达，且在无TIC的输卵管中已有表达，阳性表达率在各年龄阶段、病理分级及有无淋巴结转移之间的差异无统计学意义，与手术分期具有一定的相关性，且阳性率随期别升高而增高。I、II期中HE4评分低于III期，且随期别升高（I期-III期），表达量也逐渐上升。
结论：1.采用MALDI-TOF-MS结合磁珠技术以血清为样本的方法，可建立敏感度、特异度较高的卵巢癌、卵巢子宫内膜异位症的分类诊断模型。卵巢癌模型的诊断准确性高于单独应用CA-125的准确性，认为MALDI-TOF-MS结合磁珠技术可作为早期诊断的技术平台。利用此模型可初步鉴别卵巢癌和子宫内膜异位症，说明卵巢子宫内膜异位症的恶性行为与卵巢癌在某些具有一定的相关性。2. Myl-9、Nm-23与肿瘤发生发展相关，Transgelin、Transgelin-2与肿瘤的早期转移相关，CRBP2、RBP1有可能成为靶向治疗的一个靶点，可用于下一步在卵巢癌细胞中进行早期肿瘤发生的分子机制研究。3. HE4在原发性浆液性卵巢癌发生发展过程中发挥了一定的作用，并促其可进一步发展成为晚期癌，因此HE4有望成为早期诊断的指标，但并不完全是肿瘤转移相关因子。
Background：Ovarian cancer is the highest fatality rate in malignant tumors of thegynecologic oncology. Because of no obvious clinical symptoms,60-70%patients are inthe advanced stage in clinic. With surgery, radiotherapy, chemotherapy are improved, the5-year survival rate raise only from37%to46%; it is greater than90%in I stage, so earlydiagnosis is the key to improve patients'5-year survival, but only23%ovarian cancer canbe diagnosed in early stage. Consider the reasons: pathological types of ovarian cancer aremore; the mechanism is not clear; lack tumor markers with high specificity and sensitivity;the occurrence of molecular biology mechanism is not yet perfect. Therefore, there is noideal marker can be applied to clinic to do the early diagnosis in early stage.
Objective: Use of serum peptides and two-dimensional electrophoresis method toscreening a new protein/peptide markers, and use HE4immunohistochemical staining inovarian serous adenocarcinoma paraffin tissue, combined with results of clinicalexamination, to explore the relevance both protein/peptide, expression of HE4and theclinical characters of ovarian serous adenocarcinoma.
Methods:1. Use MALDI-TOF-MS to analyse the serum peptide map, throughFlexananlysis software to deal the map, then analyzed by use of ClinprotoolsTM2.1software to establish diagnosis model, select the validation group to validate the model.2.Use the two-dimensional electrophoresis to screening the different protein andidentification.3. Using HE4antibody by immunohistochemical methods to do detectionthe primary serous ovarian cancer tissue, to explore the correlation of HE4and clinicalfeatures.
Results:1. There are17peptide peaks between ovarian cancer and healthy women, up13, down4, the diagnostic model shows that the sensitivity is100%, specificity is92.0%,and m/z3373,3342,4791,6948can be used as a diagnostic cut-off point. The accurancyof the model is100%.2. There are19peptide peaks between ovarian endometrial cysts and healthy women, up15, down6, the model sensitivity is81.3%, specificity is100.0%,and m/z3342,6689can be used as a diagnostic cut-off point.3. In the model of theovarian cancer and ovarian endometrial cysts, the sensitivity is64.7%, the specificity is75%.4. II stage ovarian serous adenocarcinoma and ovarian endometriotic cysts, screeningout the7protein, two down-regulated, five up-regulated, after mass spectrometry identified,the up-regulated protein are CRBP-2, Nm-23, chaperonin10, Transgelin, down-regulatedproteins are Myl-9, RBP-1, Transgelin-2.5. HE4is high expression in primary ovarianserous carcinoma, there is expression in the tissue of the no TIC oviduct. There is nocorrection of the positive expression rate between the age, pathological grade and themaetastasis of lymph node and HE4expression, but there is relationship between stage andHE4expression.
Conclusion:1. Ovarian cancer and healthy women, ovarian endometriosis cyst andhealthy women can be distinguished by the serum peptide diagnostic model, and show thatthe accuracy of the ovarian cancer diagnosis model is higher than serum CA-125. Thismodel can be used to initial diagnosis the ovarian cancer and endometriosis, the malignantbehavior of ovarian endometriosis and ovarian cancer in some certain degree havecorrelation.2. Myl-9, Nm23have related to the development of tumor, Transgelin,Transgelin-2have related to the early metastasis, CRBP2the RBP1may become a targetfor targeted therapy, can be used to further the molecular mechanism.3. HE4maybe play acertain role in the development of primary serous ovarian cancer, and promote to theadvanced cancer, so HE4is expected to be indicators to do early diagnosis, but not entirelytumor metastasis-related factors.
引文
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