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桐树科研 硕果累累 | 大样本研究表明TME能有效预测食管癌患者预后

首页  ꄲ  桐树科研  ꄲ  桐树科研 硕果累累 | 大样本研究表明TME能有效预测食管癌患者预后

本文发表于《Journal of Gastrointestinal Oncology》 

 

 

 

导语

 
 

肿瘤微环境（TME）细胞是肿瘤组织的重要组成部分。越来越多的证据表明 TME 在肿瘤预后中起着至关重要的作用，并且与各种恶性肿瘤的患者生存相关。 然而，目前关于如何有效地使用 TME 来更好地评估食管癌 (EC) 患者预后的研究很少。本研究引入“TMEscore”的概念，探讨TME是否可以作为生物标志物来评估患者的预后。

 

本研究收集TCGA中160例食管癌患者的数据，包括RNA-seq数据、SNP、CNV、miRNA微阵列数据、甲基化微阵列数据及其带有生存信息的相应临床数据。构建了TMEscore模型，将样本分为TMEscore-high和TMEscore-low两个亚型，并且对两个亚型的遗传特征、TMEscore与食管癌预后的相关性进行分析。

 

 
 

结果总结

 
 

1. 根据免疫细胞类型分型定义了两种TME亚型， TMEscore-high亚型和TMEscore-low亚型。

2. 不同的TMEscore亚型与EC的预后显著相关， TMEscore-high亚型的患者比具有TMEscore-low亚型的患者具有更好的预后。

3. TMEscore可预测免疫检查点抑制剂(ICIs)的疗效。

4. 基因组不稳定性在肿瘤微环境中普遍存在，并且TMEscore-low亚型患者相较于TMEscore-high亚型患者的染色体状态更不稳定。

 

 
 

结果展示

 
 

TMEscore亚型可以作为预测食管癌预后的生物标志物

基于160个食管癌样本数据与生存信息，采用单变量Cox回归分析TMEscore与患者生存并对预后进行评估。22种免疫细胞特征与TMEscore亚型的关联分析如图1A所示。肿瘤-免疫细胞间相互作用及其与生存的相关性如图1B所示。基于Cox回归模型计算TMEscores, 进一步分析TMEscore与生存关系，发现TMEscore-high的患者相较于TMEscore-low的患者预后更好（图1D）。

 

图1. 肿瘤微环境与食管癌预后相关性

 

在临床特征方面，对202个相关基因进行聚类，并将160例食管癌患者有显著预后影响的免疫亚型分为TMEscore-high和TMEscore-low亚型。基于Cox回归模型，鉴定出2个差异表达的miRNAs和8个差异表达的mRNAs对EC的预后有显著影响。2个miRNA分别为hsa-mir-1248和hsa-mir-5000，排名前4位的基因分别为WDR93、CARNS1、CFAP52, HSPD1P5。has-mir-1248 或 has-mir-5000 表达水平高的患者OS 明显短于表达水平较低的患者（图 2C、2D）。同样，WDR93、CFAP52 和 HSPD1P5 的高表达水平是 EC 的阴性预测因子（见图 2E-2G），而 CARNS1 的高表达水平是 EC 的良好预后因子（见图 2H）

 

图2. 食管癌TMEscore两种亚型差异表达基因的生存曲线

 

不同TMEscore亚型基因组特征

TMEscore亚型中突变最频繁的基因均为TP53。不同TMEscore亚型间突变频率差异基因前10位为TP53、TTN、CSMD3、SYNE1、FLG、RIMS2、KMT2D、MUC16、MUC4、RYR2、LRP1B、DNAH5、PCLO(见图3A、B、C)。这些高频突变基因在EC肿瘤的预后中起着关键作用。

 

图3. 食管癌TMEscore两种亚型的基因组变异

 

突变特征分析显示，TMEscore-high亚型与Signature 1、Signature 13、Signature 17和Signature29（图4A）相关，而TMEscore-low亚型与Signature 1、Signature 3和Signature17相关(图4B)。Signature1与5-甲基胞嘧啶自发脱氨相关，Signature 3与DNA双链断裂修复有关，而Signature 29与接触烟草诱变剂有关。

 

对基因组不稳定性进行分析，基于GISTIC对CNVs分析发现TMEscore-low的患者染色体状态更不稳定。根据CNV结果，利用ABSOLUTE软件进行肿瘤纯度和倍性分析显示，基因组紊乱是肿瘤发生过程中常见的现象（图4C、4D）。不同TMEscore亚型在肿瘤纯度和倍性方面无显著差异。

 

图4. 食管癌TMEscore两种亚型的突变特征

 

TMEscore与治疗效果分析

应用TIDE模型评价不同TMEscore亚型免疫治疗的临床疗效。通过Kaplan-Meier分析，EC中TIDE评分高的亚型与TIDE评分低的亚型相比，无进展生存期要短得多。然而低 TIDE 评分亚型和高TIDE评分亚型的生存预测效率无显著差异（图5A）。基于ROC曲线 的TMB评分的预测效果与TMEscore无显著差异（图5B）。TMEscore和TMB均可用于预测EC患者的生存，且结果一致。

 

图5. TMEscore是预测免疫治疗效果的预后生物标志物

 

 
 

结语

 
 

我们开发了TME signarure来综合评估TME，并且TMEscore分类有效地预测了 EC 患者的预后，这可能对识别EC 患者处于生存风险高、低亚组具有重要意义。

 

 

 

桐树基因3D科研模型

 

设计执行丨数据挖掘丨撰写投稿

提供一站式转化性研究服务

 

桐树基因作为一家深耕肿瘤精准医疗领域多年的创新型企业，始终紧跟国际研究前沿，在科研上倾注了大量的精力与资金。

 

搭建了以肿瘤进化论与肿瘤基因组学标本库为基础的转化性研究中心，从课题设计、研究执行（基因检测）、数据整理及挖掘、文章撰写、投稿修改，提供一站式转化性研究服务。

 

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END

 

桐树基因成立于2016年11月，是一家同时具备LDT+IVD双重能力的分子诊断企业。

 

桐树基因专注于肿瘤分子诊断的研发、生产、销售一体化，依托“多平台布局”的策略，先后开发了肿瘤微卫星不稳定MSI、ctDNA等多款重磅IVD诊断试剂盒。以NGS微量建库技术为核心壁垒的基因检测服务、以肿瘤基因组学标本库为基础的大数据转化研究中心构筑了其在行业中的竞争优势，并致力于成为千亿级的精准医学肿瘤市场的领导者之一。

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