Abstract
BackgroundHigh-grade serous ovarian carcinoma (HGSOC) is generally associated with a very dismal prognosis. Nevertheless, patients with similar clinicopathological characteristics can have markedly different clinical outcomes. Our aim was the identification of novel molecular determinants influencing survival.MethodsGene expression profiles of extreme HGSOC survivors (training set) were obtained by microarray. Differentially expressed genes (DEGs) and enriched signalling pathways were determined. A prognostic signature was generated and validated on curatedOvarianData database through a meta-analysis approach. The best prognostic biomarker from the signature was confirmed by RT-qPCR and by immunohistochemistry on an independent validation set. Cox regression model was chosen for survival analysis.ResultsEighty DEGs and the extracellular matrix-receptor (ECM-receptor) interaction pathway were associated to extreme survival. A 10-gene prognostic signature able to correctly classify patients with 98% of accuracy was identified. By an ‘in-silico’ meta-analysis, overexpression of FXYD domain-containing ion transport regulator 5 (FXYD5), also known as dysadherin, was confirmed in HGSOC short-term survivors compared to long-term ones. Its prognostic and predictive power was then successfully validated, both at mRNA and protein level, first on training than on validation sample set.ConclusionWe demonstrated the possible involvement of FXYD5 and ECM-receptor interaction signal pathway in HCSOC survival and prognosis.
Highlights
High-grade serous ovarian carcinoma (HGSOC) is generally associated with a very dismal prognosis
Identification of prognostic gene signature in patients with HGSOC Eighty mRNAs were found differentially expressed (FDR < 0.1) between the two extreme survivor groups in the training set (27 short-term and 12 long-term survivors): 28 genes (35%) were under-expressed and 52 (65%) were over-expressed in long-overall survival (OS) patients compared to short-OS ones (Supplementary Table S2)
While the first approach tests if the amount of Differentially expressed genes (DEGs) in a pathway is higher than the proportion that would have been obtained by chance, the second checks the position of DEGs within pathway-map, giving high priority to the upstream genes of the pathway
Summary
High-grade serous ovarian carcinoma (HGSOC) is generally associated with a very dismal prognosis. Epithelial ovarian cancer is a heterogeneous disease accounting for multiple histological variants and clinical behaviours.[2] Patients harbouring high-grade serous ovarian carcinoma (HGSOC), the most prevalent histotype, are at major risk of cancer related death, since their disease displays an aggressive nature and is usually advanced in stage at diagnosis.[2] Five-year survival rates for HGSOC patients are around 30–40% world-wide,[3] long-term survivorship is ~15%.4. Disparity in prognosis is largely a function of patient age, disease stage and amount of residual tumour after cytoreductive surgery, which are the most important clinical prognostic factors for survival.[5] tumours with similar clinicopathological characteristics can have markedly different clinical outcomes. Since prognosis cannot rely exclusively on clinical factors observed at diagnosis, great effort has been made to discover the molecular features of the tumour influencing survival
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