CN113777309A - 自身抗体在制备胰腺导管腺癌诊断试剂盒中的应用 - Google Patents
自身抗体在制备胰腺导管腺癌诊断试剂盒中的应用 Download PDFInfo
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Abstract
本发明涉及医学生物检测技术领域,提供了10种自身抗体:抗TSPAN18,ENTPD1,IZUMO4,DHRS7C,ATP5G1,SECTM1,CPT1A,SLC39A14,SLC7A4,LDLRAD4抗体的新用途,具体是在制备胰腺导管腺癌诊断试剂或诊断试剂盒中的应用,本发明进一步提供了利用针对上述10种自身抗体检测来进行胰腺导管腺癌诊断的试剂盒。本发明的试剂盒和检测方法简便,可靠,周期短,特异性高,易于临床推广。
Description
技术领域
本发明涉及医学生物检测技术领域,涉及10种自身抗体在胰腺导管腺癌诊断中的应用。
背景技术
胰腺导管腺癌(Pancreatic ductal adenocarcinoma,PDAC)是我国最常见的恶性肿瘤之一,约90%的胰腺癌为起源于腺管上皮的导管腺癌,具有发病率高、早期诊断困难、转移复发早、预后差等特点,5年生存率仅9%[1,2]。手术切除是早期PDAC首选及唯一的根治性治疗方法,但约85%的PDAC诊断时已属于局部晚期或伴有远处转移,不能手术切除,化疗是这部分患者的主要治疗措施,但易耐药,疗效差[3]。因此,寻找高敏感性、高特异性的诊断标志物,提高早期诊断率仍是目前亟待解决的问题。
CA19-9是目前广泛应用的PDAC诊断标志物。系列研究结果显示,CA19-9诊断PDAC的中位敏感性和特异性分别为79%、82%[4,5]。CA19-9诊断肿瘤大小≤2cm PDAC的敏感性更差,仅为48.4%[6]。此外,CA19-9升高也常见于胆道恶性肿瘤、胰腺炎、黄疸等,出现假阳性,超15%的PDAC因Lewis抗原阴性等原因出现假阴性[7-8]。因此需要联合或寻找新的诊断标志物。
肿瘤免疫微环境是肿瘤的十大特征之一,机体的免疫***在识别肿瘤这一“异物”时会产生针对肿瘤抗原的自身抗体。当肿瘤抗原水平很低,利用常规蛋白检测方法无法检测到时,免疫***就能监测到该蛋白的存在,引发免疫反应,产生大量抗体,对抗原信号起到一定的放大作用。因此,自身抗体的检测比肿瘤抗原更加敏感,有可能为肿瘤早期诊断开辟新途径。研究发现,多个自身抗体(如抗Ezrin、p53、p16、p62、survivin、Koc、IMP1等)与PDAC的发生发展有关[9-10],但这些自身抗体及其组合用于PDAC诊断的敏感性、特异性尚无***研究,目前仍无对PDAC相关自身抗体的高通量筛查研究。
发明内容
本发明为解决上述技术问题进行,目的在于提供胰腺癌特别是胰腺导管腺癌的诊断标志物,本发明的目的也在于提供抗TSPAN18,ENTPD1,IZUMO4,DHRS7C,ATP5G1,SECTM1,CPT1A,SLC39A14,SLC7A4,LDLRAD4抗体的新用途,即在制备胰腺导管腺癌诊断试剂盒中的应用。
本发明的10种自身抗体采用HuProtTM人类蛋白质组芯片筛选得到,HuProtTM人类蛋白质组芯片最早由美国约翰霍普金斯大学开发,经过不断升级,目前含超过20000个人重组蛋白,是迄今为止最高通量人重组蛋白质组芯片。我们首次将这个高通量的蛋白芯片用于PDAC的诊断。
先进行初筛,采集30例PDAC患者及30例健康人的血清样本,每一个样品使用1张HuProtTM蛋白质芯片进行检测,并以同一标准分析,如下:针对每一个蛋白,计算差异倍数(Fold change,FC)(PDAC组均值/健康组均值)以及P值(t检验),筛选出符合条件的自身抗体:P值<0.05,FC>1.2,符合上述条件的蛋白,共计165个,其中响应抗体类型为IgG的83个,响应抗体为IgM的82个。
而后继续进行筛选,定制含上述165个蛋白的胰腺癌专属芯片,并在266例PDAC,248例健康人,98例胰腺炎的患者中进行检测验证。筛选出符合条件的自身抗体:FC>1.2,Pvalue<0.05;阳性率>10%;ROC曲线:AUC>0.7,特异性>70%,敏感性>70%。符合上述条件的抗体共计10个,均为IgG抗体:抗TSPAN18,ENTPD1,IZUMO4,DHRS7C,ATP5G1,SECTM1,CPT1A,SLC39A14,SLC7A4,LDLRAD4抗体,这10个自身抗体可作为胰腺癌诊断的血清标志物。
本发明的第一方面,提供了自身抗体在制备胰腺导管腺癌诊断试剂或诊断试剂盒中的应用,该自身抗体为抗TSPAN18,ENTPD1,IZUMO4,DHRS7C,ATP5G1,SECTM1,CPT1A,SLC39A14,SLC7A4,LDLRAD4抗体中的任意一种或多种组合。
优选的,诊断试剂为检测生物血清样品中抗TSPAN18,ENTPD1,IZUMO4,DHRS7C,ATP5G1,SECTM1,CPT1A,SLC39A14,SLC7A4,LDLRAD4抗体含量的试剂。
优选的,诊断试剂盒包含了检测生物血清样品中抗TSPAN18,ENTPD1,IZUMO4,DHRS7C,ATP5G1,SECTM1,CPT1A,SLC39A14,SLC7A4,LDLRAD4抗体含量的试剂。
优选的,生物样品获自对象的外周血,血液样本采集后离心获取血清样品。
本发明中,抗体含量或浓度采用常规方法检测得到,如传统的沉淀试验、凝集试验、补体结合试验等,近年来发展的酶联免疫吸附、荧光免疫、放射免疫或免疫印迹的方法均适用。
本发明的第二方面,提供了一种胰腺导管腺癌诊断试剂盒,该试剂盒包含了检测生物血清样品中抗TSPAN18,ENTPD1,IZUMO4,DHRS7C,ATP5G1,SECTM1,CPT1A,SLC39A14,SLC7A4,LDLRAD4抗体含量的试剂,即包含了与检测方法对应的相关试剂。
本发明的第三方面,提供了采用上述试剂盒进行胰腺导管腺癌诊断的方法,如下:
A.将待检血液样本常温离心,获取血清;
B.采用抗体检测的常规方法对血清中上述10种自身抗体水平进行检测,并针对检测结果判断是否罹患胰腺导管腺癌。
使用LSD法进行组间两两比较后发现,胰腺导管腺癌分别与慢性胰腺炎和正常人抗体水平表达差异显著。ROC分析结果提示,将其用于区分胰腺导管腺癌与慢性胰腺炎和正常人混合体时,AUC下面积均高于0.75,特异性和敏感性均高于70%;将其用于区分胰腺导管腺癌分别与慢性胰腺炎时,AUC下面积均高于0.82,诊断准确性更高,有助于降低癌症筛选的假阳性率。
本发明的有益保障及效果如下:
就技术而言,10种自身抗体的检测本质上是血清样本中抗体水平或浓度检测,临床检测方法成熟,具有操作简便、检测灵敏、特异性好、重复性高等特点,临床推广性高。
此外,本发明所涉及的10种自身抗体指标的AUC下面积均高于0.75,诊断准确性至少为中等,多数抗体的敏感性维持在71%以上,特异性高达80%以上,相比于CA19-9,其临床参考价值和可信度较高,相较于病理切片诊断,检测者所受痛苦和危害小。所以,此种检测试剂盒不仅能够提高胰腺导管腺癌的检出率和准确率,而且只需要采集检测者的血液即可获得检测结果,患者依从性高。
本发明提供了一种以抗体水平检测为基础的胰腺导管腺癌检测试剂盒,可以通过检测病人血清样本中的抗体水平对胰腺癌作出诊断,其检测方法简便、周期短、灵敏度高,是现行检测方法的有效补充。
附图说明
图1为HuProtTM人类蛋白质组芯片的检测原理图;
图2为本发明10个自身抗体的筛选流程图;
图3为本发明10个自身抗体诊断胰腺癌的ROC曲线:A.胰腺癌vs(健康人+胰腺炎),B.胰腺癌vs健康人,C.胰腺癌vs胰腺炎;
图4为本发明10个自身抗体在胰腺癌、胰腺炎、健康人血清中的表达水平差异(*P<0.05,**P<0.01,***P<0.001,****P<0.0001,ns无统计学差异)
图5为本发明10个自身抗体诊断CA199阴性胰腺癌的ROC曲线:A.CA199-胰腺癌vs.(健康人+胰腺炎),B.CA199-胰腺癌vs健康人,C.CA199-胰腺癌vs胰腺炎。
具体实施方式
现结合实施例和附图,对本发明作详细描述,但本发明的实施不仅限于此。
实施例一十个自身抗体筛选及验证
本实施例中的筛选及验证流程如图2所示,具体如下:
1、初筛阶段
采集30例PDAC患者及30例健康人的血清样本,每一个样品使用1张HuProtTM蛋白质芯片进行检测,检测原理如图1所示:芯片特异性的抗体(包括IgG、IgM或其它类型抗体)与固定于芯片上的蛋白进行结合,清洗去除未结合的抗体和其它蛋白质,再用抗人IgM荧光标记二抗(cy5标记,呈现红色)和抗人IgG荧光二抗(cy3标记,呈现绿色)检测,通过荧光扫描仪读取信号,信号的强弱与抗体的亲和力和数量呈正相关。数据提取并归一化处理后进行分析。
将IgG和IgM的数据整合,并以同一标准分析,如下:针对每一个蛋白,计算差异倍数(Fold change,FC)(PDAC组均值/健康组均值)以及P值(t检验),筛选出符合条件的自身抗体:P值<0.05,FC>1.2,符合上述条件的蛋白,共计165个,其中响应抗体类型为IgG的83个,响应抗体为IgM的82个。
2、验证阶段
定制含上述165个蛋白的胰腺癌专属芯片,并在266例PDAC,248例健康人,98例胰腺炎的患者中进行检测验证。数据提取并归一化处理后进行分析。
将IgG和IgM的数据整合,并以同一标准分析,如下:针对每一个蛋白,计算差异倍数(Fold change,FC)(PDAC组均值/健康+胰腺炎组均值)、P值(t检验)、阳性率即在一定阈值下,统计每一组样本的自身抗体出现的频次。首先,为每个蛋白的响应设定阈值,即该蛋白的对照组样本的平均值+2SD;其次,定义高于此阈值的样本为自身抗体阳性)、ROC曲线(AUC、敏感性、特异性)。
筛选出符合条件的自身抗体:FC>1.2,P value<0.05;阳性率>10%;ROC曲线:AUC>0.7,特异性>70%,敏感性>70%。符合上述条件的蛋白共计10个,均为IgG抗体:抗TSPAN18,ENTPD1,IZUMO4,DHRS7C,ATP5G1,SECTM1,CPT1A,SLC39A14,SLC7A4,LDLRAD4抗体。这10个自身抗体可作为胰腺癌早期诊断的血清标志物。
按上述步骤筛选出来的10个自身抗体:抗TSPAN18,ENTPD1,IZUMO4,DHRS7C,ATP5G1,SECTM1,CPT1A,SLC39A14,SLC7A4,LDLRAD4抗体,诊断PDAC的AUC、敏感性、特异性如下表1所示,10个自身抗体诊断PDAC的ROC曲线参见图3。
表1 10个自身抗体诊断PDAC的临界值、敏感性、特异性、阳性预测值、阴性预测值汇总
ROC分析结果提示,PDAC vs.健康人组,AUC下面积介于0.77-0.80之间,诊断准确性为中等,特异性结果介于66%~82%之间,敏感性介于62%~78%之间;PDAC vs.胰腺炎组,AUC下面积介于0.82~0.89之间,特异性结果介于72%~89%之间,敏感性介于64%~80%之间,能够有效将PDAC患者与健康人及胰腺炎患者区别开。
根据图4,使用LSD法进行组间两两比较,发现10个自身抗体在胰腺导管腺癌患者血清中的表达显著高于慢性胰腺炎和健康人(P<0.001),初步判定10个自身抗体可以用作诊断胰腺癌。
3、CA199阴性胰腺癌患者诊断效果
CA199是目前广泛应用的胰腺癌诊断标志物,进一步分析了在CA199阴性胰腺癌患者中,这10个自身抗体的诊断效能。
表2 10个自身抗体诊断CA199阴性PDAC的临界值、敏感性、特异性、阳性预测值、阴性预测值汇总
根据图5的ROC分析结果提示,CA199阴性PDAC vs.健康人组,AUC下面积介于0.70-0.78之间,诊断准确性为中等,特异性结果介于65%~83%之间,敏感性介于58%~79%之间;CA199阴性PDAC vs.胰腺炎组,AUC下面积介于0.77~0.86之间,特异性结果介于72%~90%之间,敏感性介于67%~79%之间,能够有效将CA199阴性PDAC患者与健康人及胰腺炎患者区别开。
参考文献:
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以上已对本发明创造的较佳实施例进行了具体说明,但本发明创造并不限于所述实施例,熟悉本领域的技术人员在不违背本发明创造精神的前提下还可作出种种的等同的变型或替换,这些等同的变型或替换均包含在本申请权利要求所限定的范围内。
Claims (6)
1.自身抗体在制备胰腺导管腺癌诊断试剂或诊断试剂盒中的应用,其特征在于,抗TSPAN18,ENTPD1,IZUMO4,DHRS7C,ATP5G1,SECTM1,CPT1A,SLC39A14,SLC7A4,LDLRAD4抗体中的任意一种或多种组合。
2.根据权利要求1所述的应用,其特征在于,所述的诊断试剂为检测生物血清样品中抗TSPAN18,ENTPD1,IZUMO4,DHRS7C,ATP5G1,SECTM1,CPT1A,SLC39A14,SLC7A4,LDLRAD4抗体含量的试剂。
3.根据权利要求1所述的应用,其特征在于,所述的诊断试剂盒包含了检测生物血清样品中抗TSPAN18,ENTPD1,IZUMO4,DHRS7C,ATP5G1,SECTM1,CPT1A,SLC39A14,SLC7A4,LDLRAD4抗体含量的试剂。
4.根据权利要求2或3所述的应用,其特征在于,所述的生物样品获自对象的外周血。
5.一种胰腺导管腺癌诊断试剂盒,该试剂盒包含了检测生物血清样品中抗TSPAN18,ENTPD1,IZUMO4,DHRS7C,ATP5G1,SECTM1,CPT1A,SLC39A14,SLC7A4,LDLRAD4抗体含量的试剂。
6.根据权利要求5所述的胰腺导管腺癌诊断试剂盒,其特征在于:
其中,所述试剂为采用沉淀试验、凝集试验、补体结合试验、酶联免疫吸附、荧光免疫、放射免疫或免疫印迹方法检测的试剂。
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