CN111662985B - 一种microRNA联合CEA用于制备宫颈癌早期诊断试剂盒的用途 - Google Patents
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Abstract
本发明公开了一种microRNA联合CEA用于制备宫颈癌早期诊断试剂盒的用途。以往把CEA作为早期诊断结肠癌和直肠癌的特异性标志物，经大量的临床实践，发现不仅胃肠道的恶性肿瘤CEA值可以升高，在乳腺癌、肺癌及其他恶性肿瘤的血清中也有升高。CEA对宫颈癌诊断虽然具有重要参考价值，但是其单独用于宫颈癌诊断的准确度较低。本发明将血清中一种微小RNAmiR‑3085与血清CEA联合后，对宫颈癌的诊断准确率有了显著提高，二者联合诊断宫颈癌的准确率在90％以上。
Description
技术领域
本发明属于疾病诊断领域，涉及基因诊断试剂，具体涉及一种microRNA联合CEA用于制备宫颈癌早期诊断试剂盒的用途。
背景技术
宫颈癌这种临床常见妇科肿瘤的发病率极高，目前位居妇科肿瘤的第二位已经成为影响世界女性健康的重要问题，临床上对于该病的诊断主要依靠阴道镜、宫颈刮片等方法，但是漏诊率相对较高，因此选取一种有效的诊断方式至关重要。
癌胚抗原(carcinoembryonicantigen，CEA)是1965年由Gold和Freedman首先从结肠癌和胚胎组织中提取的一种肿瘤相关抗原，是一种具有人类胚胎抗原特性的酸性糖蛋白，存在于内胚层细胞分化而来的癌症细胞表面，是细胞膜的结构蛋白。在细胞浆中形成，通过细胞膜分泌到细胞外，然后进入周围体液。因此，可从血清、脑脊液、乳汁、胃液、胸腹水及尿液、粪便等多种体液和排泄物中检出。
以往把CEA作为早期诊断结肠癌和直肠癌的特异性标志物，经大量的临床实践，发现不仅胃肠道的恶性肿瘤CEA值可以升高，在乳腺癌、肺癌及其他恶性肿瘤的血清中也有升高。因此，癌胚抗原是一种广谱肿瘤标志物，虽然不能作为诊断某种恶性肿瘤的特异性指标，但在恶性肿瘤的鉴别诊断、病情监测、疗效评价等方面，仍有重要临床价值。
CEA对宫颈癌诊断具有重要参考价值，但是其单独用于宫颈癌诊断的准确度较低。
发明内容
本发明是为了克服现有技术中存在的不足，提供一种血清微小RNA联合CEA在宫颈癌早期诊断方面的应用。
本发明技术方案如下：
一种血清微小RNA联合血清CEA在宫颈癌早期诊断方面的应用，所述微小RNA为miR-3085。
一种血清微小RNA联合血清CEA在制备宫颈癌早期诊断试剂盒方面的应用，所述微小RNA为miR-3085。
有益技术效果：
以往把CEA作为早期诊断结肠癌和直肠癌的特异性标志物，经大量的临床实践，发现不仅胃肠道的恶性肿瘤CEA值可以升高，在乳腺癌、肺癌及其他恶性肿瘤的血清中也有升高。CEA对宫颈癌诊断虽然具有重要参考价值，但是其单独用于宫颈癌诊断的准确度较低。本发明将血清中一种微小RNAmiR-3085与血清CEA联合后，对宫颈癌的诊断准确率有了显著提高，二者联合诊断宫颈癌的准确率在90％以上。
附图说明
图1为训练集中血清CEA单独诊断区分宫颈癌和非宫颈癌的ROC曲线；
图2为训练集中血清CEA联合血清miR-3085诊断区分宫颈癌和非宫颈癌的ROC曲线。
具体实施方式
下面通过具体的实施例详细介绍本发明实质性内容，但不能以此限定本发明的保护范围。
实施例1：
一、试验材料
总RNA提取试剂盒购自美国Invitrogen公司。
反转录试剂盒购自ThermoFisherScientific。
RT-PCR测量仪购自德国Qiagen公司。
miR-3085以及内参GAPDH引物由北京博奥森公司设计合成。
二、试验方法
1、一般资料
宫颈癌样本：选取南京医科大学第一附属医院2015～2017年病理确诊为宫颈癌的患者145例；宫颈良性疾病样本：选取南京医科大学第一附属医院2015～2017年CT或病理确诊为宫颈良性疾病的患者87例；健康人群样本：选取南京医科大学第一附属医院2015～2017年体检的健康女性95例。三组样本的年龄分布具有高度相似性，P＞0.05，无统计学意义。
入组标准：①经计算机体层摄影(computedtomography，CT)等影像学检查或病理学检查证实；②检测前未行放疗、化疗等抗肿瘤治疗；③年龄≥18岁。排除标准：①合并其他部位恶性肿瘤；②妊娠期或哺乳期妇女；③合并免疫系统疾病、血液系统疾病等。
2、样本分组
训练集：分别从宫颈癌样本、宫颈良性疾病样本和健康人群样本中随机选取45、27、25例样本组成训练集，总样本数为97例；验证集：剩余的宫颈癌样本、宫颈良性疾病样本和健康人群样本组成验证集，总样本数为230例。如表1所示。
表1训练集和验证集样本组成
3、血清CEA测定
空腹情况下抽取5mL静脉血，以2500r/min的转速进行离心处理5min，分离血清，使用罗氏电化学发光免疫分析仪以及配套的原装试剂，严格按照说明书测定CEA浓度。
4、血清miR-3085相对表达量测定
空腹情况下抽取5mL静脉血，以2500r/min的转速进行离心处理5min，分离血清，用总RNA提取试剂盒提取总RNA。取2μg总RNA于反转录试剂盒中合成cDNA。取cDNA置于PCR扩增仪中扩增，反应条件为94℃15min预变性，60℃30s退火，72℃30s延伸，40个循环。采用相对定量法，测定目的基因、GAPDH的PCR产物的Ct值，以2-ΔΔCt计算目的基因相对表达量，各设3个复孔，实验重复3次。
miR-3085基因上游引物序列(SequenceNO.1)：5’-GAGTACATGTATAGCAGCCTTA-3’；
miR-3085基因下游引物序列(SequenceNO.2)：5’-GTCCGAGGTTTGGAACGAGGCT-3’；
GAPDH基因上游引物序列(SequenceNO.3)：5’-GGAGCGAGATCCCTCCAAAAT-3；
GAPDH基因下游引物序列(SequenceNO.4)：5’-GGCTGTTGTCATACTTCTCATGG-3’。
5、统计学处理
采用SPSS19.0处理数据，所有计量资料均进行正态和方差齐性检验，符合正态分布的数据用均值±偏差表示，不符合正态和方差齐性检验的计量资料采用非参数检验，组间两两比较采用t检验。采用SPSS19.0绘制血清CEA单独和联合血清miR-3085诊断区分宫颈癌和非宫颈癌的受试者工作特征(ROC)曲线，并计算曲线下面积(AUC)，并利用AUC评估血清CEA或血清CEA和血清miR-3085对宫颈癌和非宫颈癌的诊断价值；AUC≤0.5为无诊断价值，0.5＜AUC≤0.7为诊断准确性较低，0.7＜AUC≤0.9为诊断准确性较好，AUC≥0.9为诊断准确性最高，P＜0.05为差异有统计学意义。
三、试验结果
1、血清CEA和血清miR-3085在宫颈癌和非宫颈癌人群中含量比较
血清CEA和血清miR-3085在宫颈癌和非宫颈癌人群中含量如表2所示，与非宫颈癌相比，血清CEA和血清miR-3085在宫颈癌人群中的含量均显著升高。
表2血清CEA和血清miR-3085在宫颈癌和非宫颈癌人群中含量
| 血清CEA(ng/mL) | 血清miR-3085 | |
| 宫颈癌 | 32.45±8.27 | 44.17±6.39 |
| 非宫颈癌 | 7.66±3.39 | 10.95±4.68 |
2、训练集中ROC曲线分析
训练集中，以各样本CEA含量为自变量X，以组别宫颈癌和非宫颈癌为应变量，使用SPSS软件对CEA在宫颈癌和非宫颈癌样本中的含量进行二元逻辑回归，得到二元逻辑回归方程：Ln[p/(1-p)]＝3.364X-5.509，再将各样本中CEA含量代入该二元逻辑回归方程，得到各血清样本的p值，以可能p值作为诊断点，计算灵敏度和特异性，绘制ROC曲线，如图1所示，AUC＝0.685，灵敏度为69.8％，特异性为70.5％。根据ROC曲线计算维登指数＝特异性+灵敏度-1，维登指数最大值对应的p值为诊断区分宫颈癌和非宫颈癌的最佳cut-off值0.505。
训练集中，以各样本CEA含量为自变量X1，miR-3085相对含量为自变量X2，以组别宫颈癌和非宫颈癌为应变量，使用SPSS软件对CEA和miR-3085在宫颈癌和非宫颈癌样本中的含量进行二元逻辑回归，得到二元逻辑回归方程：Ln[p/(1-p)]＝2.871X1+4.025X2-7.585，再将各样本中CEA、miR-3085含量代入该二元逻辑回归方程，得到各血清样本的p值，以可能p值作为诊断点，计算灵敏度和特异性，绘制ROC曲线，如图2所示，AUC＝0.935，灵敏度为86.7％，特异性为92.8％。根据ROC曲线计算维登指数＝特异性+灵敏度-1，维登指数最大值对应的p值为诊断区分宫颈癌和非宫颈癌的最佳cut-off值0.574。
本领域技术人员知道，AUC≤0.5为无诊断价值，0.5＜AUC≤0.7为诊断准确性较低，0.7＜AUC≤0.9为诊断准确性较好，AUC≥0.9为诊断准确性最高，上述AUC结果可知，CEA单独用于区分宫颈癌和非宫颈癌的诊断准确性较低，CEA和miR-3085联合用于区分宫颈癌和非宫颈癌的诊断准确性最高。
3、验证集中诊断准确率验证
验证集中，将各样本中CEA含量(X)代入上述二元逻辑回归方程Ln[p/(1-p)]＝3.364X-5.509，得到各血清样本的回归预测概率p，高于最佳cut-off值0.505的预测为宫颈癌，反之预测为非宫颈癌，结果诊断准确率为54.8％(126/230)。
验证集中，将各样本中CEA含量(X1)、miR-3085相对含量(X2)代入上述二元逻辑回归方程Ln[p/(1-p)]＝2.871X1+4.025X2-7.585，得到各血清样本的回归预测概率p，高于最佳cut-off值0.574的预测为宫颈癌，反之预测为非宫颈癌，结果诊断准确率为94.3％(217/230)。
很显然，血清miR-3085与血清CEA联合后，对宫颈癌的诊断准确率有了显著提高，二者联合诊断宫颈癌的准确率在90％以上。
实施例2：
一种宫颈癌诊断试剂盒，包括血清CEA测定试剂和血清miR-3085测定试剂。
序列表
<110> 南京凡亦达生物科技有限公司
<120> 一种microRNA联合CEA用于制备宫颈癌早期诊断试剂盒的用途
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<170> SIPOSequenceListing 1.0
<210> 1
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<213> 人工序列(Artificial Sequence)
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<213> 人工序列(Artificial Sequence)
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Claims (1)
1.一种血清微小RNA联合血清CEA在制备宫颈癌早期诊断试剂盒方面的应用，所述微小RNA为miR-3085。
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| CN110579611A (zh) * | 2019-09-18 | 2019-12-17 | 郑州大学 | 一种用于肺癌早期筛查和诊断的联合检测血清标志物、试剂盒及检测方法 |
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| CN110579611A (zh) * | 2019-09-18 | 2019-12-17 | 郑州大学 | 一种用于肺癌早期筛查和诊断的联合检测血清标志物、试剂盒及检测方法 |
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