CN111850115B - 用于预测晚期肾癌应用tki类药物敏感性的分子诊断模型 - Google Patents
用于预测晚期肾癌应用tki类药物敏感性的分子诊断模型 Download PDFInfo
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Abstract
本发明公开了一种用于预测转移性肾癌患者应用TKI类靶向药物敏感性的DNA甲基化位点分子标记物及其应用。所述DNA甲基化位点分子标记物包括：cg00396667、cg18815943、cg03890877、cg07611000和cg14391855。通过检测上述5个DNA甲基化位点在转移性肾癌患者组织中的甲基化水平，并通过相应的预测模型，达到预测转移性肾癌患者应用TKI类靶向药物敏感性的目的，提高了转移性肾癌患者应用TKI类靶向药物人群界定的准确性，对患者的进一步诊治方案和延长患者生存期具有重大意义。
Description
技术领域
本发明涉及用于预测转移性肾癌患者应用TKI类靶向药物敏感性的DNA甲基化位点分子标记物及其应用，涉及用于预测转移性肾癌患者术后对TKI类靶向药物敏感人群的界定。
背景技术
在全球范围内，每年约有300000人被诊断为肾癌，每年约有129000人死于肾癌[1,2]。肾癌的主要组织学亚型为透明细胞癌（clearcell renal cell carcinoma,ccRCC），ccRCC约占所有肾癌病例的80%，为方便叙述，以下简称肾癌[1]。大约20%-30%的肾癌患者在确诊时肿瘤已发生远处转移而不能接受手术根治[3]。此类转移性肾癌患者的预后差，中位生存期仅为6-12个月，5年生存率小于10%，局限性肾癌患者术后仍有20%-40%的患者出现远处转移[3, 4]。近年来，美国食品药品管理局（FDA）先后审批通过了一系列TKI类靶向药物，如舒尼替尼、索拉菲尼及帕唑帕尼等。这些药物当前已广泛用于转移性肾癌的一线和二线治疗。其疗效一直是人们关注的焦点，但研究发现不同的个体对药物的反应存在较大差异[5-7]。近年来，多项研究利用分子标记物，对病人进行个体化治疗，回顾性和前瞻性研究已经报道了TKI类靶向药物治疗获益的预后和预测指标，包括血清标志物[8, 9]、肿瘤组织内标志物[10-12]和基因变异标记物[13-15]，然而至今仍没有用于晚期转移性肾癌患者接受TKI类靶向药物治疗是否获益的预后/预测指标应用于临床。
DNA甲基化（DNA methylation）为DNA化学修饰的一种形式，在不改变DNA序列的前提下，在基因组CpG二核苷酸的胞嘧啶5'碳位共价键结合一个甲基基团，引起染色质结构、DNA构象、DNA稳定性及DNA与蛋白质相互作用方式的改变，从而控制基因表达。DNA甲基化是癌症发生发展的关键因素之一，其作为诊断和预后的生物标记物迅速引起了临床的关注[16-18]。随着全基因组技术的不断发展，对包括肾癌在内的人类癌症相关的DNA甲基化的认识逐渐深入[19-21]。我们前期通过DNA甲基化芯片筛选发现5个DNA甲基化位点分子标记物cg00396667、cg18815943、cg03890877、cg07611000和cg14391855与肾癌患者总体生存密切相关[22]。本发明进一步应用该5个DNA甲基化分子标记物构建新的分子预测模型，用于转移性肾癌患者应用TKI类靶向药物敏感性的评估。
专利CN200680012835.2探索MTOR抑制剂疗法的敏感性的生物标记物，但局限于MTOR抑制剂，而且局限于单个分子标记物，其检测方法受蛋白、mRNA稳定性的影响大等问题。目前，还未见有基于多个DNA甲基化位点模型对转移性肾癌患者应用TKI类靶向药物敏感性预测的报道。
发明内容
本发明所要解决的技术问题是克服临床晚期转移性肾癌应用TKI类靶向药物敏感性预测方面存在的缺陷和不足，提供一组用于预测转移性肾癌患者应用TKI类靶向药物敏感性的DNA甲基化位点分子标记物cg00396667、cg18815943、cg03890877、cg07611000和cg14391855，通过综合分析上述5个DNA甲基化位点在转移性肾癌患者组织中甲基化水平，通过建立分子预后模型，达到预测转移性肾癌患者应用TKI类靶向药物敏感性的目的。
本发明的目的是提供一种用于预测转移性肾癌患者应用TKI类靶向药物敏感性的DNA甲基化位点的分子标记物。
本发明的另一个目的是提供所述DNA甲基化位点的分子标记物的应用。
本发明的上述目的是通过以下技术方案给予实现的：预测转移性肾癌患者应用TKI类靶向药物敏感性的DNA甲基化位点的分子标记物，包括cg00396667、cg18815943、cg03890877、cg07611000和cg14391855。
本发明还请求保护上述DNA甲基化位点分子标记物在制备预测转移性肾癌患者应用TKI类靶向药物敏感性的试剂盒或构建预测转移性肾癌患者应用TKI类靶向药物敏感性的模型中的应用。
一种用于检测权利要求1所述DNA甲基化位点分子标记物的焦磷酸测序技术扩增及延伸引物组，其特征在于，包括分别检测cg00396667、cg18815943、cg03890877、cg07611000和cg14391855位点甲基化水平的扩增引物及延伸引物，其序列依次如表1所示。
本发明还提供一种用于预测转移性肾癌患者应用TKI类靶向药物敏感性的模型，其特征在于，所述模型为通过检测cg00396667、cg18815943、cg03890877、cg07611000和cg14391855这5个DNA甲基化位点的甲基化水平来计算转移性肾癌患者应用TKI类靶向药物敏感性的预后评分指数，预后评分指数=(–0.745×cg00396667) + (0.068×cg18815943)+ (70.421×cg03890877) + ( –0.608×cg07611000) + (–10.236×cg14391855)。
本发明还提供一种用于预测转移性肾癌患者应用TKI类靶向药物敏感性的试剂盒，其特征在于，包含权利要求3所述的焦磷酸测序扩增及测序引物组。
本发明还提供利用上述试剂盒进行转移性肾癌患者应用TKI类靶向药物敏感性的方法为：
S1、提取肾癌组织样品DNA；
S2、利用上述引物组对S1的样本DNA进行焦磷酸测序检测，确定DNA甲基化位点甲基化水平；
S3、根据转移性肾癌患者应用TKI类靶向药物敏感性预后评分指数=(–0.745×cg00396667) + (0.068×cg18815943) + (70.421×cg03890877) + ( –0.608×cg07611000) + (–10.236×cg14391855)计算出晚期转移性组织样本的预后评分指数，以预测转移性肾癌患者应用TKI类靶向药物敏感性。
与现有技术相比，本发明具有以下有益效果：
本发明公开了一组用于预测转移性肾癌患者应用TKI类靶向药物敏感性的DNA甲基化位点分子标记物，所述位点包括cg00396667、cg18815943、cg03890877、cg07611000和cg14391855。通过检测上述5个DNA甲基化位点在转移性肾癌患者组织中的甲基化水平，并通过相应的预测模型，达到预测转移性肾癌患者应用TKI类靶向药物敏感性的目的，对患者的进一步诊治方案和延长患者生存期具有重大意义。
表1：5个DNA甲基化位点焦磷酸测序扩增引物及测序引物
具体实施方式
以下结合说明书附图和具体实施例来进一步说明本发明，但实施例并不对本发明做任何形式的限定。除非特别说明，本发明采用的试剂、方法和设备为本技术领域常规试剂、方法和设备。
实施例1 用于预测转移性肾癌患者应用TKI类靶向药物敏感性的DNA甲基化位点及预后风险模型建立。
1、肾癌预后相关5个DNA甲基化位点构建预后风险模型
（1）在TCGA 数据库中33例应用TKI类靶向药物转移性肾癌患者，从甲基化芯片数据（Infinium HumanMethylation 450 BeadChip）提取5个DNA甲基化位点分子标记物（cg00396667、cg18815943、cg03890877、cg07611000和cg14391855）的数据，同时提取这33例患者临床病理资料、随访数据及TKI类靶向药物使用情况资料；
（2）采用COX回归模型方法，构建用于预测转移性肾癌患者应用TKI类靶向药物敏感性的分子模型，其线性方程表示如下：预后评分指数=(–0.745×cg00396667) + (0.068×cg18815943) + (70.421×cg03890877) + ( –0.608×cg07611000) + (–10.236×cg14391855)。
2、TCGA数据组评估5个DNA甲基化模型预测准确度
根据5个DNA甲基化水平，计算TCGA数据库33例应用TKI类靶向药物患者的预后评分指数，分数范围从-2.17至1.29。通过风险模型计算出每个样本的预后评分指数，我们使用x-tile软件选取0.815为最佳截点（Cut-off）值，将TCGA数据库中应用TKI类靶向药物转移性肾癌患者分为低风险组和高风险组，低风险组患者与高风险组患者生存时间显著差异（log rank P=0.002，图1）。
3、中山大学数据组验证预后风险模型
（1）设计5个DNA甲基化位点分子标记物（cg00396667、cg18815943、cg03890877、cg07611000和cg14391855）的焦磷酸测序扩增引物和测序引物；
（2）提取35例中山大学附属第一医院肾癌石蜡标本组织DNA，采用步骤(1)的特异性引物，通过焦磷酸测序的方法，检测5个DNA甲基化位点分子标记物（cg00396667、cg18815943、cg03890877、cg07611000和cg14391855）甲基化水平；
（3）通过风险模型计算出每个样本的预后评分指数，选取与TCGA组相同的Cut-off值（0.815），将中山大学组应用TKI类靶向药物的35例转移性肾癌患者患者分为低风险组和高风险组，低风险组患者与高风险组患者生存时间显著差异（log rank P=0.029，图2）。基于上述技术方案，本发明所述的DNA甲基化位点及检测方法可有效的用于预测转移性肾癌患者应用TKI类靶向药物敏感性。通过检测患者肿瘤组织中cg00396667、cg18815943、cg03890877、cg07611000和cg14391855共5个DNA甲基化水平的变化，用于预测转移性肾癌患者应用TKI类靶向药物敏感性，提高了转移性肾癌患者应用TKI类靶向药物人群界定的准确性，对患者的进一步诊治方案和延长患者生存期具有重大意义。
实施例2 用于预测转移性肾癌患者应用TKI类靶向药物敏感性的试剂盒。
用于预测转移性肾癌患者应用TKI类靶向药物敏感性的试剂盒，所述试剂盒包含下列所示检测5个DNA甲基化位点焦磷酸延伸引物及测序引物：
具体地，利用上述试剂盒进行转移性肾癌患者应用TKI类靶向药物敏感性的方法为：
S1、提取转移性肾癌组织样品DNA；
S2、利用上述引物组对S1的样本DNA进行焦磷酸测序技术检测，确定5个DNA甲基化分子标记物甲基化水平；
S3、根据预后风险模型-预后评分指数=(–0.745×cg00396667) + (0.068×cg18815943) + (70.421×cg03890877) + ( –0.608×cg07611000) + (–10.236×cg14391855)计算出转移性肾癌患者应用TKI类靶向药物敏感性的评分指数。
以上对本发明公开的一种用于预测转移性肾癌患者应用TKI类靶向药物敏感性的DNA甲基化位点以及检测方法进行了详细介绍，本文中应用了具体个例对本发明的原理及实施方式进行了阐述，以上实施例的说明只是用于帮助理解本发明的方法及其核心思想；同时，对于本领域的一般技术人员，依据本发明的思想，在具体实施方式及应用范围上均会有改变之处，综上所述，本说明书内容不应理解为对本发明的限制。
参考文献
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Claims (2)
1.一组用于预测晚期肾癌患者应用TKI类靶向药物敏感性的DNA甲基化位点分子标记物，其特征在于，包括cg00396667、cg18815943、cg03890877、cg07611000和cg14391855。
2.一种用于检测权利要求1所述DNA甲基化位点分子标记物的焦磷酸测序引物组，其特征在于，包括分别检测cg00396667、cg18815943、cg03890877、cg07611000和cg14391855位点甲基化水平的扩增引物及延伸引物，其序列依次如表1所示。
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