Assistance Publique-Hôpitaux de Paris, Department of Biochemistry, Pharmacogenetics and Molecular Oncology, European Georges Pompidou Hospital, Paris Cancer Institute CARPEM, 20 Rue Leblanc, 75015, Paris, France.
Centre de Recherche des Cordeliers, INSERM, Team Personalized Medicine, Pharmacogenomics and Therapeutic Optimization (MEPPOT), Université de Paris, Sorbonne Université, Paris, France.
J Transl Med. 2023 May 15;21(1):324. doi: 10.1186/s12967-023-04086-7.
In Lung adenocarcinoma (LUAD), targeted therapies and immunotherapies have moved from metastatic to early stage and stratification of the relapse risk becomes mandatory. Here we identified a miR-200 based RNA signature that delineates Epithelial-to-mesenchymal transition (EMT) heterogeneity and predicts survival beyond current classification systems.
A miR-200 signature was identified using RNA sequencing. We scored the miR-200 signature by WISP (Weighted In Silico Pathology), used GSEA to identify pathway enrichments and MCP-counter to characterize immune cell infiltrates. We evaluate the clinical value of this signature in our series of LUAD and using TCGA and 7 published datasets.
We identified 3 clusters based on supervised classification: I is miR-200-sign-down and enriched in TP53 mutations IIA and IIB are miR-200-sign-up: IIA is enriched in EGFR (p < 0.001), IIB is enriched in KRAS mutation (p < 0.001). WISP stratified patients into miR-200-sign-down (n = 65) and miR-200-sign-up (n = 42). Several biological processes were enriched in MiR-200-sign-down tumors, focal adhesion, actin cytoskeleton, cytokine/receptor interaction, TP53 signaling and cell cycle pathways. Fibroblast, immune cell infiltration and PDL1 expression were also significantly higher suggesting immune exhaustion. This signature stratified patients into high-vs low-risk groups, miR-200-sign-up had higher DFS, median not reached at 60 vs 41 months and within subpopulations with stage I, IA, IB, or II. Results were validated on TCGA data on 7 public datasets.
This EMT and miR-200-related prognostic signature refines prognosis evaluation independently of tumor stage and paves the way towards assessing the predictive value of this LUAD clustering to optimize perioperative treatment.
在肺腺癌 (LUAD) 中，靶向治疗和免疫疗法已经从转移性疾病转移到早期阶段，并且分层复发风险变得势在必行。在这里，我们确定了一个基于 miR-200 的 RNA 特征，该特征描绘了上皮间质转化 (EMT) 异质性，并预测了当前分类系统之外的生存。
使用 RNA 测序确定 miR-200 特征。我们通过 WISP（加权虚拟病理学）对 miR-200 特征进行评分，使用 GSEA 识别途径富集，使用 MCP-counter 对免疫细胞浸润进行特征描述。我们评估了该特征在我们的 LUAD 系列以及 TCGA 和 7 个已发表数据集的临床价值。
我们基于监督分类确定了 3 个聚类：I 是 miR-200 信号下调，并且富集了 TP53 突变 IIA 和 IIB 是 miR-200 信号上调：IIA 富集了 EGFR(p<0.001)，IIB 富集了 KRAS 突变 (p<0.001)。WISP 将患者分为 miR-200 信号下调 (n=65) 和 miR-200 信号上调 (n=42)。几个生物学过程在 miR-200 信号下调的肿瘤中富集，包括粘着斑、肌动蛋白细胞骨架、细胞因子/受体相互作用、TP53 信号通路和细胞周期途径。成纤维细胞、免疫细胞浸润和 PDL1 表达也显著升高，提示免疫衰竭。该特征将患者分为高风险组和低风险组，miR-200 信号上调的患者的 DFS 更高，中位未达到 60 个月 vs 41 个月，并且在 I 期、IA 期、IB 期或 II 期的亚组中。在 TCGA 数据和 7 个公共数据集上验证了结果。
这种 EMT 和 miR-200 相关的预后特征独立于肿瘤分期，细化了预后评估，为评估这种 LUAD 聚类对优化围手术期治疗的预测价值铺平了道路。
