CN114672554A - 一种检测肿瘤相关基因谱表达量的方法及其用途 - Google Patents
一种检测肿瘤相关基因谱表达量的方法及其用途 Download PDFInfo
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Abstract
本发明属生物和医学检验技术领域，涉及检测肿瘤相关基因产物表达量的一种分子生物学方法，该方法可用于提供鉴别结直肠癌变、结直肠癌分类/型、预后评估等的参考。所涉及的基因包括：KRT23,KRT80,CA9,FOXQ1,CDH3,KIAA1199，CLDN2,KLK10,CLDN1,GRIN2D,NKD1,C6ORF223，MMP3,MMP11,TRIM29,TESC,GYLTL1B,NKD2,PRSS22,VWA2,REG1A,DPEP1,FABP6,CEL,CELP,CPNE7,RPL13AP20,TNFRSF6B,CYP19A1,RPLP0P2，GUCA2B,AQP8,CA1,GUCA2A,CA2,CLCA4，H19,FAP,NAT1等。上述基因(单个或任意组合)的联合应用有助于提供对结直肠癌的鉴定、分类/型、预后评估等参考；联合应用上述基因鉴别结直肠癌和正常结直肠组织，在特异性100％时，灵敏度可达97％。
Description
技术领域
本发明属生物和医学检验技术领域，涉及检测肿瘤相关基因谱表达量的方法及其用途。具体涉及检测肿瘤相关基因谱(单个或任意组合)表达量(蛋白质、RNA)的一种分子生物学方法，通过检测的相关基因谱的改变提供鉴别结直肠癌变、结直肠癌分类/型、预后评估等的参考。所涉及的基因包括：KRT23,KRT80,CA9,FOXQ1,CDH3,KIAA1199，CLDN2,KLK10,CLDN1,GRIN2D,NKD1,C6ORF223，MMP3,MMP11,TRIM29,TESC,GYLTL1B,NKD2,PRSS22,VWA2,REG1A,DPEP1,FABP6,CEL,CELP,CPNE7,RPL13AP20,TNFRSF6B,CYP19A1,RPLP0P2，GUCA2B,AQP8,CA1,GUCA2A,CA2,CLCA4,H19,FAP,NAT1等。
背景技术
临床实践显示，结直肠癌是常见消化道肿瘤，其已成为重要的健康和生命的杀手。迄今为止，结直肠的早期诊断、分子分型、预后评估是尽早发现结直肠癌、根据分子分型采取相应的个性化精准治疗是目前对抗结直肠癌的有力手段。病理形态学是诊断结直肠癌的金标准，然而近年来病理医生紧缺而且病理诊断耗时长、主观性强；而且病理上的改变往往滞后于在分子生物学上的改变。因此，寻找早期、快速鉴别结直肠癌的分子生物学方法迫在眉睫。
基于现有技术的研究基础与现状，本申请的发明人拟提供检测肿瘤相关基因谱表达量的方法及其用途。具体涉及检测肿瘤相关基因谱(单个或任意组合)表达量(蛋白质、RNA)的一种分子生物学方法，通过检测的相关基因谱的改变提供鉴别结直肠癌变、结直肠癌分类/型、预后评估等的参考。
发明内容
本发明的目的在于为“快速、高效的鉴别结直肠癌、组织分型、分子分型及预后评估等”问题，提供一种检测肿瘤相关基因谱表达量的方法及其用途。本发明利用肿瘤相关基因表达谱改变，为辅助结直肠癌的鉴别、分类、分子分型及预后评估的提供参考。
本发明基于大规模结直肠癌相关癌基因/抑癌基因表达谱的分析，筛查出与正常结直肠组织相比基因表达差异显著的、与结直肠癌组织分类及预后等相关的一组基因，包括：KRT23,KRT80,CA9,FOXQ1,CDH3,KIAA1199，CLDN2,KLK10,CLDN1,GRIN2D,NKD1,C6ORF223，MMP3,MMP11,TRIM29,TESC,GYLTL1B,NKD2,PRSS22,VWA2,REG1A,DPEP1,FABP6,CEL,CELP,CPNE7,RPL13AP20,TNFRSF6B,CYP19A1,RPLP0P2，GUCA2B,AQP8,CA1,GUCA2A,CA2,CLCA4，H19,FAP,NAT1等基因。经实验证实，所述的结直肠癌鉴别、分类、分子分型及预后评估与上述基因组在结直肠组织癌变前后出现表达量改变具有相关，本发明方法的检测结果为预测结直肠癌是否发生癌变、癌症分类、分子分型、耐药性、药物筛选、病人预后评估等提供了有价值的参考。
进一步的，本发明通过上述基因组(单个或二种及以上任意组合)在结直肠癌变组织中的表达量改变，提供辅助结直肠癌鉴别、分类、分子分型及预后评估等的参考。尤其是通过多种基因联合形成阵列，再与提取、检测结直肠病变组织中蛋白质(如免疫比浊、胶体金、免疫化学发光等)或RNA(如RT-PCR、荧光定量PCR、RNA array、RNA Sequencing等)相结合，可以为结直肠癌的预测、分类、分子分型及预后评估等提供一种快速、高通量、有效、客观的参考方法。
本发明中，进行了实验对比，结果表明，上述与结直肠相关的基因肿瘤标志物与正常结直肠组织相比，上述基因在癌变结直肠组织中的表达量极度改变，并与结直肠癌的类型、预后等具有紧密联系；上述基因的联合应用有助于辅助结直肠癌的鉴定、分型和预后评估，尤其是在结直肠癌组织与正常结肠组织的鉴别上，在特异性为100％时，灵敏度可达97％。
本发明中，
S1单独利用上述基因表达量改变来预测结直肠癌变、癌症分类、分子分型、肿瘤恶性程度、病人预后等；
S2联合上述基因(2个及2个以上的任意组合)表达量改变来预测结直肠癌变、癌症分类、分子分型、肿瘤恶性程度、病人预后等；
S3上述单个基因或任意组合后再与其它指标相结合后，来预测结直肠癌变、癌症分类、分子分型、肿瘤恶性程度、病人预后等；本发明中研究显示：与其对应的正常组织相比，在结直肠癌组织中GUCA2B,AQP8,CA1,GUCA2A,CA2,CLCA4,NAT1等基因的总体表达量显著性降低；而KRT23,KRT80,CA9,FOXQ1,CDH3,KIAA1199,CLDN2,KLK10,CLDN1,GRIN2D,NKD1,C6ORF223,MMP3,MMP11,TRIM29,TESC,GYLTL1B,NKD2,PRSS22,VWA2,REG1A,DPEP1,FABP6,CEL,CELP,CPNE7,RPL13AP20,TNFRSF6B,CYP19A1,RPLP0P2,H19,FAP等基因的总体表达量显著性增高；
本发明研究显示：CYP19A1,FAP,H19,RPLP0P2,CELP等基因的表达量增加提示肿瘤恶性程度高、病人预后较差；而AQP8,NAT,CDH3,CA2,CLCA4,GUCA2A,PRSS22,MMP3等基因表达量较高者肿瘤恶性程度低、病人预后较好。
本发明涉及到检测上述基因表达产物包括：蛋白质和RNA。
本发明涉及到检测的上述基因产物，既包括肿瘤细胞中的，也包括各种原因进入体液中的mRNA、蛋白质以及外泌体中的，包括是完整和片段。
本发明所涉及的用于分析的生物样品包括结直肠癌组织、体液(包括血液、尿液、穿刺液等)、穿刺组织、大便、肠道分泌物等，上述基因表达量改变的检测，作为预测结直肠癌变、肿瘤恶性程度、靶向药物筛选、转移能力、分子分型、生存期等预后评估指标。
本发明所涉及的体液包括血液、尿液、胸腔积液、腹腔积液、肿瘤穿刺液、淋巴液等。
本发明所涉及的血液包括全血、血清、血浆、分离有核细胞、血液中的循环肿瘤细胞、外泌体等。
本发明所涉及的上述基因蛋白检测包括直接提取结直肠病变组织蛋白经化学或免疫学方法进行检测和免疫组化分析。
本发明所涉及的上述基因RNA检测包括经直接提取结直肠病变组织RNA后结合RT-PCR技术、荧光定量PCR技术、RNA Sequencing、RNA array等进行检测。
本发明涉及基因产物的检测包括蛋白水平和RNA水平，检测方法涉及：免疫组化、免疫荧光、Westernblot、ELISA、流式细胞术检测、RT-PCR、胶体金、免疫学检测、化学法检测、荧光定量PCR、RNA Sequencing、RNA array等检测技术(但不仅限于这些技术)等。
本发明所涉及所述的RT-PCR检测上述基因的RNA产物，逆转录后，涉及到PCR包括：普通PCR、荧光定量PCR、巢式PCR、多重PCR、数字PCR等。
本发明的有益效果是：
病理形态学是诊断结直肠癌的金标准，然而近年来病理医生紧缺而且病理诊断耗时长、主观性强；而且病理上的改变往往滞后于在分子生物学上的改变。本发明提供了一种基于肿瘤基因组表达谱改变辅助参考鉴别结直肠癌、分类、分子分型、药物筛选、预后评估等。应用上述基因的组合表达谱鉴别结直肠癌与正常结直肠癌组织时，当特异性为100％时，灵敏度超过97％。另一方面，根据不同需求通过多种肿瘤标志物联合形成阵列，再与提取、检测结直肠癌病变组织中蛋白质(如免疫比浊、胶体金、免疫化学发光等)或RNA(如RT-PCR、荧光定量PCR、RNA array、RNA Sequencing等)等相结合，可以为结直肠癌的预测、组织分型及预后评估提供一种快速、高通量、有效、客观的参考方法。
本发明涉及的肿瘤标志物也可用于结直肠癌的疗效评估、药物筛选、耐药监测等。
附图说明
图1.mRNA Sequencing结果的热图显示：本发明涉及的基因KRT23,KRT80,CA9,FOXQ1,CDH3,KIAA1199，CLDN2,KLK10,CLDN1,GRIN2D,NKD1,C6ORF223，MMP3,MMP11,TRIM29,TESC,GYLTL1B,NKD2,PRSS22,VWA2,REG1A,DPEP1,FABP6,CEL,CELP,CPNE7,RPL13AP20,TNFRSF6B,CYP19A1,RPLP0P2，GUCA2B,AQP8,CA1,GUCA2A,CA2,CLCA4，H19,FAP,NAT1等的mRNA在正常结肠组织和结肠癌(COAD)组织中总体表达情况。
图2.mRNA Sequencing结果的热图显示：本发明涉及的基因KRT23,KRT80,CA9,FOXQ1,CDH3,KIAA1199，CLDN2,KLK10,CLDN1,GRIN2D,NKD1,C6ORF223，MMP3,MMP11,TRIM29,TESC,GYLTL1B,NKD2,PRSS22,VWA2,REG1A,DPEP1,FABP6,CEL,CELP,CPNE7,RPL13AP20,TNFRSF6B,CYP19A1,RPLP0P2，GUCA2B,AQP8,CA1,GUCA2A,CA2,CLCA4，H19,FAP,NAT1等的mRNA在正常结肠组织和结肠癌(COAD)组织中总体表达情况。
图3.mRNA Sequencing结果显示：与正常结肠组织相比，结肠癌(COAD)组织中总体及各亚型中KRT23,KRT80,CA9,FOXQ1,CDH3,KIAA1199等基因的mRNA表达量的改变。****p<0.0001,***p<0.001，**P<0.01，*P<0.05。
图4.mRNA Sequencing结果显示：与正常结肠组织相比，结肠癌(COAD)组织中总体及各亚型中CLDN2,KLK10,CLDN1,GRIN2D,NKD1,C6ORF223等基因的mRNA表达量的改变。
图5.mRNA Sequencing结果显示：与正常结肠组织相比，结肠癌(COAD)组织中总体及各亚型中MMP3,MMP11,TRIM29,TESC,GYLTL1B,NKD2等基因的mRNA表达量的改变。
图6.mRNA Sequencing结果显示：与正常结肠组织相比，结肠癌(COAD)组织中总体及各亚型中PRSS22,VWA2,REG1A,DPEP1,FABP6,CEL等基因的mRNA表达量的改变。
图7.mRNA Sequencing结果显示：与正常结肠组织相比，结肠癌(COAD)组织中总体及各亚型中CELP,CPNE7,RPL13AP20,TNFRSF6B,CYP19A1,RPLP0P2等基因的mRNA表达量的改变。
图8.mRNA Sequencing结果显示：与正常结肠组织相比，结肠癌(COAD)组织中总体及各亚型中GUCA2B,AQP8,CA1,GUCA2A,CA2,CLCA4等基因的mRNA表达量的改变。
图9.mRNA Sequencing结果显示：与正常直肠组织相比，直肠癌(READ)组织中总体及各亚型中KRT23,KRT80,CA9,FOXQ1,CDH3,KIAA1199等基因的mRNA表达量的改变。
图10.mRNA Sequencing结果显示：与正常直肠组织相比，直肠癌(READ)组织中总体及各亚型中CLDN2,KLK10,CLDN1,GRIN2D,NKD1,C6ORF223等基因的mRNA表达量的改变。
图11.mRNA Sequencing结果显示：与正常直肠组织相比，直肠癌(READ)组织中总体及各亚型中MMP3,MMP11,TRIM29,TESC,GYLTL1B,NKD2等基因的mRNA表达量的改变。
图12.mRNA Sequencing结果显示：与正常直肠组织相比，直肠癌(READ)组织中总体及各亚型中PRSS22,VWA2,REG1A,DPEP1,FABP6,CEL等基因的mRNA表达量的改变。
图13.mRNA Sequencing结果显示：与正常直肠组织相比，直肠癌(READ)组织中总体及各亚型中CELP,CPNE7,RPL13AP20,TNFRSF6B,CYP19A1,RPLP0P2等基因的mRNA表达量的改变。
图14.mRNA Sequencing结果显示：与正常直肠组织相比，直肠癌(READ)组织中总体及各亚型中GUCA2B,AQP8,CA1,GUCA2A,CA2,CLCA4等基因的mRNA表达量的改变。
图15.mRNA Sequencing结果显示：与正常结直肠组织相比，结肠癌(COAD)组织和直肠癌(READ)组织中总体及各亚型中H19,FAP,NAT1等基因的mRNA表达量的改变。
图16.生存曲线结果显示：AQP8,CYP19A1,FAP,NAT,H19等基因的mRNA表达量与病人总体生存时间间的关系。CYP19A1,FAP,H19等基因的mRNA表达量高的病人总体生存时间短、预后较差。AQP8,NAT等基因的mRNA表达量高的病人总体生存时间长、预后较好。
图17.生存曲线结果显示：CDH3,CA2,CLCA4,GUCA2A,PRSS22,RPLP0P2,CELP,MMP3等基因的mRNA表达量与病人总体生存时间间的关系。RPLP0P2,CELP等基因的mRNA表达量高的病人总体生存时间短、预后较差；CDH3,CA2,CLCA4,GUCA2A,PRSS22,MMP3等基因的mRNA表达量高的病人总体生存时间长、预后较好。
具体实施方式
实施例1
在本发明中，以原发性结直肠癌为实施对象。
以RNA Sequencing技术分析结直肠癌与正常结直肠组织中mRNA表达量的差异；以及这些差异与结直肠癌的鉴别、分类及预后等之间的关系为例。所述结肠癌(Colonadenocarcinoma，COAD)和结肠癌(Rectum adenocarcinoma,READ)的组织学分类均包括Adenocarcinoma和Mucinous adenocarcinoma。基于The Cancer GenomeAtlas(TCGA)数据库研究，分析大量结直肠癌相关癌基因/抑癌基因在正常结直肠组织和结直肠癌间表达量的差异、表达谱与结直肠癌组织类型之间的关系、基因表达量与结肠癌预后之间的关系，筛选出与结肠癌的鉴别、分类、预后等密切相关的一组基因；包括:KRT23,KRT80,CA9,FOXQ1,CDH3,KIAA1199，CLDN2,KLK10,CLDN1,GRIN2D,NKD1,C6ORF223，MMP3,MMP11,TRIM29,TESC,GYLTL1B,NKD2,PRSS22,VWA2,REG1A,DPEP1,FABP6,CEL,CELP,CPNE7,RPL13AP20,TNFRSF6B,CYP19A1,RPLP0P2，GUCA2B,AQP8,CA1,GUCA2A,CA2,CLCA4，H19,FAP,NAT1等基因。
通过分析TCGA数据库中mRNA Sequencing结果，结果显示：与其对应的正常组织相比，在结直肠癌组织中GUCA2B,AQP8,CA1,GUCA2A,CA2,CLCA4,NAT1等基因的总体表达量显著性降低；而KRT23,KRT80,CA9,FOXQ1,CDH3,KIAA1199,CLDN2,KLK10,CLDN1,GRIN2D,NKD1,C6ORF223,MMP3,MMP11,TRIM29,TESC,GYLTL1B,NKD2,PRSS22,VWA2,REG1A,DPEP1,FABP6,CEL,CELP,CPNE7,RPL13AP20,TNFRSF6B,CYP19A1,RPLP0P2,H19,FAP等基因的总体表达量显著性增高(如图1-15所示)；所述基因可根据需要进行不同组合形成阵列，进行联合应用。
通过对TCGA数据库中mRNA Sequencing结果与病人总体生存曲线间关系的研究，结果显示：CYP19A1,FAP,H19,RPLP0P2,CELP等基因的表达量增加提示总体上肿瘤恶性程度较高、病人预后较差；而AQP8,NAT,CDH3,CA2,CLCA4,GUCA2A,PRSS22,MMP3等基因表达量较高者肿瘤恶性程度较低、病人预后较好(如图16，17所示)。
通过上述基因的组合，可以提高结肠癌鉴定的灵敏度和特异性，显著性提高结肠癌的鉴定效率。例如，用KRT23,CA9,FOXQ1,H19,MMP11,TRIM29,TESC,NKD1,CEL,KLK10基因组合的mRNA表达量差异谱，区分正常结肠组织和结肠癌(COAD)时，特异性为100％时，灵敏度超过97％(如图1所示)；用REG1A,DPEP1,CEL,RPL13AP20,H19,TNFRSF6B,KRT23,CLDN2,MMP3,MMP11，区分正常直肠组织和直肠癌(READ)时，特异性为100％时，灵敏度超过97％(如图2所示)；
本发明通过对TCGA数据库中mRNA Sequencing结果与结直肠癌组织类型的关系分析，结果显示：上述基因在不同类型的结直肠癌具有不同的表达谱(图3-8，15)；包括：Adenocarcinoma和Mucinous adenocarcinoma等类型。例如：KRT23，CLDN1，NKD1，REG1A,CA9，CELP等基因mRNA表达量差异，可用以区分Adenocarcinoma和Mucinousadenocarcinoma组织型(图3-15)；
本发明通过对TCGA数据库中mRNA Sequencing结果显示：即使同一病理类型的结肠癌中，也存在着上述基因表达谱的差异；可以依据不同上述基因表达谱的差异对结直肠癌进行分子分型；例如：KRT23+，CLDN1+，NKD1+型；KRT23-，CLDN1-型等，将结直肠癌分为不同分子亚型(图1，2)。
结果表明：KRT23,KRT80,CA9,FOXQ1,CDH3,KIAA1199，CLDN2,KLK10,CLDN1,GRIN2D,NKD1,C6ORF223，MMP3,MMP11,TRIM29,TESC,GYLTL1B,NKD2,PRSS22,VWA2,REG1A,DPEP1,FABP6,CEL,CELP,CPNE7,RPL13AP20,TNFRSF6B,CYP19A1,RPLP0P2，GUCA2B,AQP8,CA1,GUCA2A,CA2,CLCA4，H19,FAP,NAT1等基因与结直肠癌之间具有紧密联系，上述基因组mRNA表达量的改变可进一步为结直肠癌的鉴别、分类、分子分型、预后评估等提供较重要的参考价值；而且联合应用KRT23,CA9,FOXQ1,H19,MMP11,TRIM29,TESC,NKD1,CEL,KLK10基因组合的mRNA表达量差异谱，区分正常结肠组织和原发性结肠癌(COAD)时，特异性为100％时，灵敏度超过97％。用REG1A,DPEP1,CEL,RPL13AP20,H19,TNFRSF6B,KRT23,CLDN2,MMP3,MMP11等基因组合来区分正常直肠组织和原发性直肠癌(READ)时，特异性为100％时，灵敏度超过97％(图2)；结果表明：本发明提供的方法能为结直肠癌的快速鉴定、分型及预后评估等提供有价值的参考。
Claims (12)
1.一种检测肿瘤相关基因谱表达量的方法，其特征在于，检测结直肠癌相关基因组癌基因/抑癌基因的基因表达产物得表达量的改变，分析所述基因组与结直肠癌变的相关性；
所述基因组，包括：KRT23,KRT80,CA9,FOXQ1,CDH3,KIAA1199，CLDN2,KLK10,CLDN1,GRIN2D,NKD1,C6ORF223，MMP3,MMP11,TRIM29,TESC,GYLTL1B,NKD2,PRSS22,VWA2,REG1A,DPEP1,FABP6,CEL,CELP,CPNE7,RPL13AP20,TNFRSF6B,CYP19A1,RPLP0P2，GUCA2B,AQP8,CA1,GUCA2A,CA2,CLCA4，H19,FAP,NAT1中的单个或二种及以上任意组合基因。
2.按权利要求1所述的方法，其特征在于，所述的基因表达产物包括：蛋白质和RNA。
3.按权利要求1所述的方法，其特征在于，所述的基因表达产物包括：肿瘤细胞中的，和进入体液中的游离的RNA、蛋白及外泌体中的RNA、蛋白，包括完整和片段RNA、蛋白；蛋白质和RNA。
4.权利要求1所述的方法，其特征在于，所述方法中，通过多种基因联合形成阵列，再与提取、检测结直肠病变组织中蛋白质如，免疫比浊、胶体金、免疫化学发光，或RNA如，RT-PCR、荧光定量PCR、RNA array、RNA Sequencing相结合，检测肿瘤相关基因谱的表达量。
5.权利要求1的检测肿瘤相关基因谱表达量的方法在制备用于预测结直肠是否发生癌变、癌症分类、分子分型、耐药性、药物筛选、肿瘤恶性程度、病人预后评估制品中的用途。
6.按权利要求5所述的用途，其特征在于，所述的制品中，通过检测相关基因谱的表达量的改变，分析预测结直肠是否发生癌变、癌症分类、分子分型、耐药性、药物筛选、肿瘤恶性程度、病人预后评估；其中，
单独利用所述基因表达量改变预测结直肠癌变、癌症分类、分子分型、肿瘤恶性程度或病人预后；或，
联合所述基因中2个及2个以上的任意组合表达量改变预测结直肠癌变、癌症分类、分子分型、肿瘤恶性程度、病人预后；或，
所述单个基因或任意组合后再与其它指标相结合，预测结直肠癌变、癌症分类、分子分型、肿瘤恶性程度或病人预后。
7.按权利要求6所述的用途，其特征在于，所述结肠癌(Colon adenocarcinoma，COAD)和结肠癌(Rectum adenocarcinoma,READ)的组织学分类包括Adenocarcinoma和Mucinousadenocarcinoma。
8.按权利要求6所述的用途，其特征在于，所述检测对象包括：结直肠病变组织包括癌变、增生、癌前病变、体液包括血液、尿液、穿刺液、穿刺组织、大便、肠道分泌物。
9.按权利要求5或6所述的用途，其特征在于，所述恶性分级及预后判断包括：肿瘤类型、分子分型、恶性程度、转移能力、耐药性、靶向药物的选择、生存期评估。
10.权利要求5或6所述的用途，其特征在于，所述的基因的表达量包括：与自身内参的比较、和自身内参的比较后再与癌旁组织、和自身内参的比较后再与正常组织相比较。
11.按权利要求10所述的用途，其特征在于：与其对应的正常组织相比，在结直肠癌组织中GUCA2B,AQP8,CA1,GUCA2A,CA2,CLCA4,NAT1基因的总体表达量显著性降低；而KRT23,KRT80,CA9,FOXQ1,CDH3,KIAA1199,CLDN2,KLK10,CLDN1,GRIN2D,NKD1,C6ORF223,MMP3,MMP11,TRIM29,TESC,GYLTL1B,NKD2,PRSS22,VWA2,REG1A,DPEP1,FABP6,CEL,CELP,CPNE7,RPL13AP20,TNFRSF6B,CYP19A1,RPLP0P2,H19,FAP基因的总体表达量显著性增高。
12.权利要求5或6所述的用途，其特征在于，CYP19A1,FAP,H19,RPLP0P2,CELP基因的表达量增加表明肿瘤恶性程度高、病人预后差；而AQP8,NAT,CDH3,CA2,CLCA4,GUCA2A,PRSS22,MMP3基因表达量较高表明肿瘤恶性程度低、预后好。
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