Ravegnini Gloria, De Leo Antonio, Coada Camelia, Gorini Francesca, de Biase Dario, Ceccarelli Claudio, Dondi Giulia, Tesei Marco, De Crescenzo Eugenia, Santini Donatella, Corradini Angelo Gianluca, Tallini Giovanni, Hrelia Patrizia, De Iaco Pierandrea, Angelini Sabrina, Perrone Anna Myriam
Department of Pharmacy and Biotechnology (FaBiT), University of Bologna, Bologna, Italy.
Centro di Studio e Ricerca delle Neoplasie Ginecologiche (CSR), University of Bologna, Bologna, Italy.
Front Oncol. 2021 Oct 29;11:757678. doi: 10.3389/fonc.2021.757678. eCollection 2021.
The Cancer Genome Atlas (TCGA) project identified four distinct prognostic groups in endometrial cancer (EC), among which two are correlated with an intermediate prognosis: the MisMatch Repair-deficient (MMRd) and the No Specific Molecular Profile (NSMP) groups. The two groups represent a heterogeneous subset of patients frequently harboring CTNNB1 alterations with distinctive clinicopathologic features. The study aimed to evaluate the miRNA expression in ECs to identify potential biomarkers of prognosis.
We analyzed miRNA expression in 72 ECs classified as MMRd or NSMP including 15 ECs with CTNNB1 mutations. In the discovery step, miRNA expression was evaluated in 30 cases through TaqMan miRNA arrays. Subsequently, four miRNAs were validated in the total cohort of ECs. The data were further tested in the TCGA cohort, and correlations with overall survival (OS) and progression-free interval (PFI) were evaluated.
miR-499a-3p and miR-499a-5p resulted to be overexpressed in CTNNB1 mutant EC patients at intermediate risk. Similarly, in the TCGA cohort, miR-499a-3p and miR-499a-5p were differentially expressed between CTNNB1 mutant and wild-type patients (p < 0.0001). NSMP patients with low miR-499a-5p expression showed longer OS (p = 0.03, log-rank test). By combining miR-499a-3p or -5p expression levels with the CTNNB1 status, ECs with CTNNB1 mutation and lower miR-499a-5p expression showed better OS compared with the other subgroups (p = 0.03, log-rank test), among the NSMP patients. Moreover, in a multivariate analysis, combination of wild type CTNNB1 status and high miR-499a-5p expression was indipendently associated with high risk of death [HR (95%CI): 3.53 (1.1-10.5), p = 0.02].
Our results suggest that the combination of CTNNB1 status and miR-499a-5p allows a better stratification of NSMP patients and could promote a personalization of the treatment in intermediate-risk patients.
癌症基因组图谱（TCGA）项目在子宫内膜癌（EC）中确定了四个不同的预后组，其中两个与中等预后相关：错配修复缺陷（MMRd）组和无特定分子特征（NSMP）组。这两组代表了一个异质性的患者亚组，经常携带具有独特临床病理特征的CTNNB1改变。该研究旨在评估EC中miRNA的表达，以确定潜在的预后生物标志物。
我们分析了72例被分类为MMRd或NSMP的EC中的miRNA表达，其中包括15例具有CTNNB1突变的EC。在发现阶段，通过TaqMan miRNA阵列评估了30例病例中的miRNA表达。随后，在EC的整个队列中验证了四种miRNA。数据在TCGA队列中进一步测试，并评估了与总生存期（OS）和无进展生存期（PFI）的相关性。
miR-499a-3p和miR-499a-5p在中等风险的CTNNB1突变EC患者中过度表达。同样，在TCGA队列中，miR-499a-3p和miR-499a-5p在CTNNB1突变患者和野生型患者之间存在差异表达（p < 0.0001）。miR-499a-5p低表达的NSMP患者显示出更长的OS（p = 0.03，对数秩检验）。通过将miR-499a-3p或-5p表达水平与CTNNB1状态相结合，与其他亚组相比，CTNNB1突变且miR-499a-5p表达较低的EC在NSMP患者中显示出更好的OS（p = 0.03，对数秩检验）。此外，在多变量分析中，野生型CTNNB1状态和高miR-499a-5p表达的组合与高死亡风险独立相关[HR（95%CI）：3.53（1.1 - 10.5），p = 0.02]。
我们的结果表明，CTNNB1状态和miR-499a-5p的组合可以更好地对NSMP患者进行分层，并可能促进中等风险患者治疗的个性化。
