Abstract
IntroductionThe 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.MethodsWe 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.ResultsmiR-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].ConclusionOur 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.
Highlights
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
Given the similar intermediate prognosis usually observed in MMRd ECs, we included seven consecutive additional MMRd cases, all CTNNB1wt, in our discovery step
MiRNA expression profiling was evaluated on a total of 30 cases with intermediate risk, of which 12 were NSMP CTNNB1mut, 11 NSMP CTNNB1wt, and 7 MMRd
Summary
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. Histopathological parameters used alone to identify risk factors are not always reproducible, in highgrade carcinomas and those with intratumoral heterogeneity [4,5,6,7,8] To overcome this kind of problems, recently, The Cancer Genome Atlas (TCGA) endometrial collaborative project identified four distinct prognostic EC groups based on molecular alterations: (i) the ultramutated subtype that encompassed POLE exonuclease domain mutated (POLE) cases (excellent prognosis); (ii) the hypermutated subtype, characterized by MisMatch Repair deficiency (MMRd) (intermediate prognosis); (iii) the copynumber high subtype, with p53 abnormal/mutated features (p53abn) (poor prognosis); and (iv) the copy-number low subtype, known as No Specific Molecular Profile (NSMP) (intermediate prognosis) [9]. In 2021, the European Society of Gynecological Oncology (ESGO), the European Society for Radiotherapy and Oncology (ESTRO), and the European Society of Pathology (ESP) published updated guidelines for the determination of the risk group in EC, integrating both molecular and clinicopathological diagnostic variables, with the aim of improving patients’ treatment [13]
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