一组胃癌RNA分子标志物及其应用的制作方法

本发明属于生物医药领域，具体涉及多种RNA及其不同组合的肿瘤标志物及其在制备诊断胃癌试剂中的应用。
背景技术：
：胃癌是最常见的恶性肿瘤之一，因缺乏有效的早期诊断手段,早期筛查发现肿瘤较困难.目前胃癌的主要诊断方式有胃镜、CT或PET/CT等,这些检查手段成本高且有创,无法有效地筛查出早期的胃癌患者。而经典的肿瘤标志物如CEA、CA724、CA19-9等,由于缺乏较强的敏感性及特异性而局限。越来越多的研究发现多种非编码RNA参与调控肿瘤细胞的增殖、凋亡等生物学过程，直接或间接发挥着癌基因或抑癌基因的功能，在肿瘤的发生、发展中起至关重要作用。长链非编码RNA（lncRNA）是一类长度大于200个核苷酸左右的非编码RNA分子,其主要通过直接或间接影响相关基因或蛋白质的表达水平或结构等来发挥其肿瘤基因的功能，lncRNA在肿瘤中的表达异常,与肿瘤形成、进展有密切联系,可以作为肿瘤诊断及治疗的靶分子。由于肿瘤标本来源的限制，使得临床上应用组织RNA存在一定局限性，而外周血标本获得方便，如果能在血液中检出癌症特异性的microRNA、lncRNA及mRNA并将其作为癌症的生物学标志，对于癌症的早期诊断具有重要意义。进一步的研究发现RNA分子在外周血中的表达同样具有肿瘤相关性和组织特异性，外周血RNA可能成为理想的肿瘤标志物，并且血浆可以作为一种有效、无创的筛查手段，因此血浆等体液中的RNA分子适合作为诊断早期胃癌的潜在肿瘤标志物。本发明提供一组RNA分子,用于胃癌患者的诊断及胃癌的早期诊断,具有高的敏感性及特异性。技术实现要素：本发明的目的在于对现有胃癌检测标志物的补充，提供胃癌患者血浆中循环RNA标志物及检测分析方法，为临床上胃癌患者的早期发现及诊断治疗提供支持。本发明公开了用于通过分析RNA分子标志物来表征表型的方法和组合物。本发明提供了一组胃癌RNA标志物，其特征在于，所述RNA分子选自:1)序列表中所示的RNA分子及其组合，AK001058序列如SEQIDNO.1所示；INHBA-AS1(NR_027118)序列如SEQIDNO.2所示，MIR4435-2HG(NR_015395)序列如SEQIDNO.3所示，CEBPA-AS1(NR_026887)序列如SEQIDNO.4所示。2)序列表中所示与SEQIDNO.2核酸序列具有同源性的INHBA-AS1(NR_027119)序列SEQIDNO.5，与SEQIDNO.3核酸序列具有同源性的MIR4435-2HG(NR_024373)序列SEQIDNO.6、MIR4435-2HG(NR_136161)序列SEQIDNO.7、MIR4435-2HG(NR_136162)序列SEQIDNO.8、MIR4435-2HG(NR_136163)序列SEQIDNO.9、MIR4435-2HG(NR_136164)序列SEQIDNO.10、MIR4435-2HG(NR_136165)序列SEQIDNO.11、MIR4435-2HG(NR_136166)序列SEQIDNO.12所示。在染色体上的同一基因由于转录方式以及转录后剪切加工等方式的不同可以生成高度同源的不同长度的RNA分子。本发明的的RNA分子SEQIDNO.5是SEQIDNO.2的同原序列，SEQIDNO.6、SEQIDNO.7、SEQIDNO.8、SEQIDNO.9、SEQIDNO.10、SEQIDNO.11、SEQIDNO.12是SEQIDNO.3同源序列。本发明所述的RNA分子作为肿瘤标志物的应用，其特征在于，所述肿瘤为胃癌。在研究过程中发明人发现，序列表中四种RNA分子SEQIDNO.1、SEQIDNO.2、SEQIDNO.3、SEQIDNO.4在胃癌组织中的表达比癌旁组织的表达高，同时发现这四个基因表达的RNA在胃癌患者血浆中的含量比健康人血浆中的含量高。由此可见，患者在患病期间这四种RNA表达的增加与胃癌存在着密切的相关性。本发明首次发现血浆/血清及组织中4个RNA基因，在胃癌临床早期诊断、鉴别诊断的作用，具有重大的理论意义和实用价值。在上述发现的基础上，本发明提供了一组胃癌的RNA分子标志物，以及该分子标志物在制备诊断胃癌试剂中的应用。使用该分子标志物及含有该分子标志物的诊断试剂盒诊断胃癌，具有操作简单、取材方便的优点，且具有高特异性、高灵敏性和易于大量筛查的特点。本发明提供的RNA分子标志物检测的方法，其包括测定离体样品中一种或多种RNA标志物的含量，其中所述一种或多种RNA标志物包括一种或多种选自序列表中的RNA标志物。在实际检测过程中，可以检测其中任一种RNA分子，也可以检测不同RNA分子的组合，确定胃癌患者样本中RNA分子含量是否相对于对照健康人群有所改变，由此进行胃癌的筛查和诊断。本发明RNA分子检测方法所使用的样本可以是组织标本，同样也适用于体液样本，包括血浆、血清和尿液等。针对体液样本的无创诊断方式更具有临床应用价值。本发明采用反转录实时定量PCR方法检测样本中的RNA分子。不同样本中RNA的制备均采用常规的RNA制备方法。诊断胃癌的检测RNA分子系统中包括了常规的RNA反转录试剂、实时定量PCR试剂。其中包括了扩增RNA分子标志物的上、下游寡核苷酸引物。PCR扩增引物本领域人员均可以依照引物设计原则进行设计。本发明在实施例中优选了表1所示引物用于样本的检测分析，其中18srRNA是作为内参分子。表1.实时定量PCR所用的引物序列RNA序列上游引物（5′-3′）下游引物（5′-3′）SEQIDNO.1CTGCTTTGCCATTTCCCCTTGTTGATGCCACACAGAGGGASEQIDNO.2CCTACTACACACAGGGGCTCTTCCAGAAGCTCCTCATGGGSEQIDNO.3AATTTGCCACCACCCTGTGAATGCCGTTTTAGGGGGACAGSEQIDNO.4TGCGTCCCTCGCATTCTTTAGACAGGAGACACTTGAGGGC18SrRNAGTAACCCGTTGAACCCCATTCCATCCAATCGGTAGTAGCG为使本发明更易理解，下面结合具体实施例进一步阐述本发明，但下述实施例仅用于说明本发明而不用于限制本发明的范围，下列实施例中未提及的具体实验方法，通常按照常规实验方法进行。结合附图说明本发明的具体实施方法。附图说明图1.NR_027119(A),NR_015395(B),NR_026887(C)和AK001058(D)在胃癌组织中的相对表达量。纵坐标是lncRNA的相对表达量（-△△Ct值）,横坐标是样本例数。图2.胃癌患者及健康人群血浆中NR_027119(A),NR_015395(B),NR_026887(C)和AK001058(D)的相对表达量。纵坐标是lncRNA的相对表达量（△Ct值）,横坐标是不同类型样本。图3.4条lncRNA检测数据结果的ROC曲线分析及曲线下面积（AUC）（A），4条lncRNA联合ROC曲线分析及去除任何一条lncRNA后剩余3条lncRNA联合ROC曲线分析及曲线下面积（B）。横坐标是1-特异性（specificity），纵坐标是敏感度（sensitivity）。实施例实施例一胃癌组织RNA检测1.组织样本RNA提取49例配对的胃癌及癌旁组织手术切除标本用TRI试剂提取总RNA，用琼脂糖凝胶电泳检验组织中RNA的完整性。2.RNA反转录用ImPromIIReverseTranscriptase反应试剂盒进行逆转录反应。取1μg组织总RNA，作为反转录模板，加入1μL随机引物、1μLdNTP（10mM）、5×RTbuffer4μL、0.5μLRNase抑制剂、1μLImPromII反转录酶，用无RNase水补齐至20μL。反应条件为：42℃60min，72℃15min，20℃5min。选择18SrRNA作为内参基因，组织反转录得到的cDNA，取1μL加9μL无RNase水稀释10倍，混匀后，取1μL稀释物加9μL无RNase水稀释10倍，第二次的稀释物作为胃癌及癌旁组织检测18SrRNA的模板。未稀释的cDNA作为检测AK001058、INHBA-AS1、MIR4435-2HG及CEBPA-AS1的模板。3.组织样本RNA分子检测用SYBRPremixExTaq试剂进行实时定量PCR，检测目的RNA分子在胃癌组织和癌旁组织中的相对表达量。以上述cDNA作为模板，分别使用表1中优选的PCR引物，用SYBRPremixExTaq试剂在MX3000P实时定量PCR仪上进行实时定量PCR，检测AK001058、INHBA-AS1、MIR4435-2HG及CEBPA-AS1等4个基因的相对表达量。实时定量PCR反应体系组分及用量：0.5μLcDNA模板、2×SYBR10μL、PCR上游引物（20mM）0.4μL、PCR下游引物（20mM）0.4μL、ROX0.4μL，加水补至20μL。反应条件为:先95℃30s预变性，95℃10s变性，60℃延伸20s，45个循环。检测结果见图1，INHBA-AS1（A）、MIR4435-2HG（B）、CEBPA-AS1（C）及AK001058（D）等4个基因在胃癌组织中的表达水平与配对胃癌旁组织中表达水平相比,显著上调,且p〈0.0001，有显著性差异。实施例二胃癌患者血浆RNA检测1.血浆RNA提取51例胃癌患者血浆及53例性别、年龄匹配的正常人血浆用Qiagen血浆提取试剂盒提取200μL血浆中的总RNA，并溶于40μL无RNase水中。2.RNA反转录用ImPromIIReverseTranscriptase反应试剂盒进行逆转录反应。取10μL血浆总RNA分别作为反转录模板，加入1μL随机引物、1μLdNTP（10mM）、5×RTbuffer4μL、0.5μLRNase抑制剂、1μLImPromII反转录酶，用无RNase水补齐至20μL。反应条件为：42℃60min，72℃15min，20℃5min。选择18SrRNA作为内参基因。血浆提取的RNA反转录得到的cDNA作为检测AK001058、INHBA-AS1、MIR4435-2HG、CEBPA-AS1及18SrRNA内参基因的模板。3.血浆样本RNA分子检测用SYBRPremixExTaq试剂进行实时定量PCR，检测目的RNA分子在胃癌组织和癌旁组织中的相对表达量。以上述cDNA作为模板，分别使用表1中优选的PCR引物，用SYBRPremixExTaq试剂在MX3000P实时定量PCR仪上进行实时定量PCR，检测AK001058、INHBA-AS1、MIR4435-2HG及CEBPA-AS1等4个基因的相对表达量。实时定量PCR反应体系组分及用量：0.8μLcDNA模板、2×SYBR10μL、PCR上游引物（20mM）0.4μL、PCR下游引物（20mM）0.4μL、ROX0.4μL、加水补至20μL。反应条件为:先95℃30s预变性，95℃10s变性，60℃延伸20s，45个循环。检测结果见图2，INHBA-AS1（A）、MIR4435-2HG（B）、CEBPA-AS1（C）及AK001058（D）等4个基因在胃癌患者血浆中的表达水平与在正常血浆中表达水平相比,显著上调,且p〈0.0001，有显著性差异。4.ROC曲线分析用SPSS17.0作ROC曲线并计算其AUC值、诊断指标的敏感度值及特异性值。将检测结果分成正常组及患病组，并将每组对应的数据录入SPSS17.0中。作ROC曲线，求对应的AUC值。根据计算出的每组敏感度值及（1-特异性）值求出cutoff值，cutoff值=敏感度+特异性-1，根据最大cutoff值即可计算出该诊断指标的敏感度值及特异性值。联合ROC分析：用二元logistic回归分析求出联合诊断指标的预测p值，然后根据预测p值作ROC曲线，并求出其AUC值及联合诊断指标的敏感度值及特异性值。分析结果见图3，INHBA-AS1、MIR4435-2HG、CEBPA-AS1及AK001058等4个基因在胃癌患者血浆及正常人血浆中的相对表达量作ROC曲线，其曲线底下面积（AUC）分别0.855，0.882，0.785，0.852；上述4条基因联合ROC曲线分析得到的曲线底下面积（AUC）为0.921，分别剔除其中任意一条lncRNA，如INHBA-AS1、MIR4435-2HG、CEBPA-AS1或AK001058后，剩下3条lncRNA联合ROC曲线得到的曲线底下面积（AUC）分别为0.910、0.880、0.917及0.908。上述结果表明单一RNA分子和组合使用RNA分子均能作为胃癌诊断的RNA分子标志物。序列表<110>中国人民解放军军事医学科学院放射与辐射医学研究所<120>一组胃癌RNA分子标志物及其应用<160>12<170>PatentInversion3.5<210>SEQIDNO.1<211>1631<212>RNA<213>人<400>SEQIDNO.1auuuacuaaugaggcaguuugcaaagacugucccugaaguguaguguagucuuucagggg60gauucauuuaguaagcuagauugauuuaaccugguacuguacuagcauagggucaaauac120gugucaucagagaccuggguaugaccaggcuuacaaaacucaggaacaaacucagauucc180uacugaccucaaccaacuaaacuaggccaaauuucuccguguacaaaauggaccacguua240uuuacaauccacgugguggagaagaugguagacauguggagagaguuuggccaggugcuc300cauucuaggucuuuuuccaguuucucaaaggcagaacauuggcuccuaauuauuugccau360ggauauuugcuuccuguucuggagcuauguuguaagacagcugugugauguccaucauuc420uugacuccagaaugaagacagggcuugcuguuuucuguccuguugguaucaucuguugcc480uuggcgaucacucagugaugagucgucaguauuuugacaugucccagugcuugcuguaca540agaggggacucagaucaacaggaagacucugaagacaggaaccugcaugguaucuuacau600cuuugauacuugggugcugauaugaagcagaguuguugauuuacuuuaucuaggcccuuc660uuucaucucaccuggaucaagcaacugagaaguguaucaggagacacuggauacauaucu720cuaugaaauagagagggccaucgcagggccugguacuuaacuacauuaacguucuaaaac780ccaguuugguuuacguugucuuucacaguaguauauuuagcucuucucuggaaaguugug840gguuaauauaauucuuaaacaugaaaauguaauuaaacacaccacgagagaacaauauuc900caggagacuuaauagugauuacuuucuucaaucaggaaaucguuucagugccuccuuugu960aggaaugcuuuguuuugugauggguuuucuuaaagaagagcacaccuccguccaaucucc1020ugagacagccacgucuccgcugacaucccacugugaugcuuucagauagucagugaaugu1080uucugauaaccuucauccaguaucugaaacacaaugugagagauuauauuguuuuagaua1140auaacaucccauuuaguugacuaaaaucuuccaaacucugaaagcugcacacugcuacuc1200cagagagugcaggucuuagcucuucuccuuucugacuucaagaugaaucuuugggacgau1260guuucuggugcuugguccacagugauucacuuuugaaggagaggccacaugacaugaacu1320gccugguguuacaaccuagcuaacauauuugaugcuacuccuguugucuguacugcuuau1380ucaaguaguauucuaaguuauguuacuaaaaaacaugguggguaaagcacaauccuaccc1440aucauuguccuccaaaauaauuguaugacauacacggcccagcccauugcccucccugca1500ucucugugcugcuuugccauuuccccuucuacccagccuccucaagggguaccuuggugg1560auauuucaguacuuaaaaccagacuguaaucauaaccucccucuguguggcaucaauaaa1620uagccaaacuc1631<210>SEQIDNO.2<211>2995<212>RNA<213>人<400>SEQIDNO.2gccuccuucuccugguguccauuucuggaacugcuauuuguauauugcaugauauuuuau60caggaaaaaauauaaaacagaucuaauuucaugaaaaugcuguugccauaaugcucagga120gaacagggggaagagagagauucaagucuuccuaaugucuaccuuauaugcagagccuug180gaaagaugggcaaaugcucugugacaagccaccaggguagacugguacugaaaagacccu240acuacacacaggggcucugucccuggcuggaaaguuacaagucagccuaccucucuguga300ucugguuuccacaccuacuacucuuuaucccaugaggagcuucuggaaacuaaaauaggu360acuucgaauuucauuguugcaucgagccagcugauuugggaguugaguuccuggauaggc420auacuauccacaguguuuuaccagagugaaaucacaggauaggcucagcuguaacaaacu480auaucaaaucucagaagcuucaaaagacuaagguuuauuucucacucaugccacccgucu540acugagggucaugcggaguucugcugagugauguucuccauccaggaucccagccaggau600cccagcugguagagcagccuccaccuggaacauugccuaagauauuggaaggguacacca660aggcaauggugaagcucaaaguggcuccuaauggcuggccagaaucagccuuuguaucuc720cuuggccaaagcaagucucaugaccacagcuaauucccagcaggugaagaugugauuucu780uccauccagaaagacagaaagccagaacaucuugaacagcucuggugacuaucauauccu840uuucuucuaagccaaauaugagauucuuuuauagcagcuaugacauucaaggagcucuua900cagauguccccaauacugucacaguggaguuuaucuuacagaauugggccacucuaagug960acuaccuguugccucaaaggguaacaggucuaacagaaagaacuguacuccagaauugua1020agucuucuagauucugcaacuggaagaguaaguggauaagaauagccaagaacaugugaa1080agaagaauuuguggaaguuaauuuguaaugaggacaaucauaaauucuuccugaguuagg1140ucuccuuaucugcaaaguucccaucugccaaggggacaagauacaacaugggaaucccaa1200uggaugcagaagggaaguagagguaaauuugccucuucuagccacacaauaucugguaga1260agaaacggagaaaaaggcaggggcagacaaccagagggagggguagugauucuggggaaa1320acagaaggcagaguauauucauuacaauuuaauaaaacuauaggaggugacccucuugaa1380ggcugccuccacacccaccagucaaggcuccaucaauguaaacuagcaauccaacauggu1440agugcccagagagccaagauuauuuaucauguuauggacagauuggcauaggcccugagg1500gguacucaaaggccagugggacugcuucaaggcccuuguguuggggugguauccagcaua1560gcagacuccucuagguugauauccugggccagaggggacagcuggacagugucacauugg1620uucugacaggugcauggcacuugcaugagccagacuggggcuaagucagccaggcaggcu1680gucaggcccuaaucacaucaaggauggccaaaucauguuccacuagggaccagcuugagc1740ugcaaaugaccaauaggacaaaugaugucauccagaggacccaaccacccggaucugaga1800cacaguaagccuccaucauccacccagacauacguuaggaaacugaaagaggaagacagg1860agccuccaaagauuggguuuuuguguagaaggaacugaauaauuuaaagaauguucaguu1920uaugaggucagacugagaugaaugaauggagauaaggugucacgaggaagaucagcucac1980ugagagcaguaguucucaacccuggcuguacauugcccaaugcccagagcuuucagaaaa2040uacucccccccaccccaaaccacaacuauuauguugcaauugcugguggugggcuuagau2100cugggcguaggugcauauguaugcaaggacacauauguacguaauuucuccaauguuuau2160aauguacaaauaugaauuaucuaauagaaauaaacagugucacuaaagggcaugcccugg2220cagauccucagggcugguggaauuggcuccagaacuuuugcucuuggcucccauucccca2280cugggagaagccugauaccugacucccugaaccuggccuuuggcuucagacucugaaguc2340aaaucccuuccuucucccucuggcucagucuccaucgacucaacuaguccugccaccucu2400uuucugcuuggcccagcccuagcacccuacucacugguguagccauuauaggcagcucaa2460uguagaccagucagcguuuuggcuggaaaauagacagauguagcugaaagaagcugaugg2520aucuuucucaggacuggcaguuacccgccaugaggaugaaggccacaugggguauaguca2580aggggugagcacacguccagugaacuggcugauuccugcuguggcaggugcaaccugcag2640gcccacggaugucagaucuucuacagaagggaagccagaauucuagauuuuuaucugaaa2700uuuaccaauauuuaaauaccag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