Abstract
Simple SummaryIn the precision medicine era, epithelial ovarian cancer (EOC) is characterized by a high death-to-incidence rate and poor 5-year survival. The identification of novel molecular markers is of utmost importance to guide personalized prognosis. The objective of the present study has been to evaluate, for the first time, the prognostic utility of tRNA-derived fragments (tRFs) in ovarian carcinomas. In this context, we have performed in silico analysis and expression profiling, utilizing a TCGA-OV database, GEO datasets and our two institutionally-independent cohorts. The analysis highlighted the internal tRF derived from tRNAGlyGCC (i-tRF-GlyGCC) as a novel molecular predictor of EOC prognosis. More precisely, elevated i-tRF-GlyGCC levels were correlated with an aggressive phenotype of ovarian tumor and linked to adverse survival outcomes and early progression following debulking surgery and platinum-based chemotherapy. Interestingly, i-tRF-GlyGCC integration in multivariate strategies benefits prognostication and achieves superior patient risk-stratification, supporting precision medicine decisions.Epithelial ovarian cancer (EOC) remains a highly-lethal gynecological malignancy, characterized by frequent recurrence, chemotherapy resistance and poor 5-year survival. Identifying novel predictive molecular markers remains an overdue challenge in the disease’s clinical management. Herein, in silico analysis of TCGA-OV highlighted the tRNA-derived internal fragment (i-tRF-GlyGCC) among the most abundant tRFs in ovarian tumors, while target prediction and gene ontology (GO) enrichment analysis predicted its implication in key biological processes. Thereafter, i-tRF-GlyGCC levels were quantified in a screening EOC (n = 98) and an institutionally-independent serous ovarian cancer (SOC) validation cohort (n = 100, OVCAD multicenter study). Disease progression and patient death were used as clinical endpoints for the survival analysis. Internal validation was performed by bootstrap analysis and the clinical net benefit was estimated by decision curve analysis. The analysis highlighted the significant association of i-tRF-GlyGCC with advanced FIGO stages, suboptimal debulking and most importantly, with early progression and poor overall survival of EOC patients. The OVCAD validation cohort corroborated the unfavorable predictive value of i-tRF-GlyGCC in EOC. Ultimately, evaluation of i-tRF-GlyGCC with the established/clinically used prognostic markers offered superior patient risk-stratification and enhanced clinical benefit in EOC prognosis. In conclusion, i-tRF-GlyGCC assessment could aid towards personalized prognosis and support precision medicine decisions in EOC.
Highlights
Ovarian cancer (OC) is the most lethal female reproductive system-related malignancy in developed countries, responsible for more than 300,000 incidences and 200,000 deaths worldwide per year [1,2]
The analysis revealed the significantly icantly elevated serum i-tRF-GlyGCC levels in patients with Epithelial ovarian cancer (EOC) and benign ovarian leelevated serum i-tRF-GlyGCC levels in patients with EOC and benign ovarian lesions comsions compared to normal controls (p = 0.001; Figure 2A), as well as the association of ipared to normal controls (p = 0.001; Figure 2A), as well as the association of i-tRF-GlyGCC
The elevated i-tRF-GlyGCC levels could efficiently define patients with favorable response to first-line platinum-based chemotherapy (CR/Partial response (PR)/Stable disease (SD)) at higher risk for poor overall survival (OS) (p < 0.001 Figure 6C) and short-term progression (p < 0.001 Figure 6D), similar to Progressive disease (PD) patients, highlighting the superior risk-stratification that integration of i-tRF-GlyGCC can provide in EOC clinical management
Summary
Ovarian cancer (OC) is the most lethal female reproductive system-related malignancy in developed countries, responsible for more than 300,000 incidences and 200,000 deaths worldwide per year [1,2]. Survival in many human malignancies; only a modest improvement was observed in EOC, while emerging novel strategies remain suboptimal. EOC patients are treated with the one-size-fits-all approach of cytoreductive surgery and adjuvant platinum-based first-line chemotherapy, while disease prognosis relies mainly on FIGO stage and residual tumor size following debulking surgery [6,7]. The majority of women will progress after first-line chemotherapy and maintenance therapy, which constitutes the main reason for the poor prognosis of EOC patients [8,9]. The development of a biomarkers-based approach [11] towards the improvement of prognostic accuracy and risk-stratification of EOC patients will certainly support personalized treatment decisions and modern precision medicine
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