Molecular Diagnostics

FXYD5 (Dysadherin) upregulation predicts shorter survival and reveals platinum resistance in high-grade serous ovarian cancer patients

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Abstract

Background

High-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.

Methods

Gene 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.

Results

Eighty 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.

Conclusion

We demonstrated the possible involvement of FXYD5 and ECM-receptor interaction signal pathway in HCSOC survival and prognosis.

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Acknowledgements

We would like to thank Dr Francesco Gebbia for the support in collecting clinical data and Mrs Adele Bellandi for her excellent support to the project. We are also grateful to Dr Laura Tassone for technical help in biopsy validation. Finally, we wish to thank all the physicians and the nurses working in the Department of Obstetrics and Gynecology, ASST Spedali Civili of Brescia, University of Brescia.

Author information

R.A.T. participated in the study design, performed the experiments, interpreted the data, drafted and wrote the report. C.R. and L.Z. helped in collecting patients’ tissue samples, P.T. helped in the creation of patients’ database, E.B. performed microarray experiments. G.T. helped in the collection of data from patients’ medical records and in the selection of patients’ training set. L.A. and M.B. performed immunohistochemical experiments and their evaluation. A.G., E.S. and F.O. participated in the study design. D.K. and F.B. selected and provided tissue samples of the validation set. C.R. preformed all the statistical analyses, helped in data interpretation and critically reviewed the paper. A.R. coordinated the study, interpreted the data and critically reviewed the paper. All of the authors read and approved the final paper.

Correspondence to Antonella Ravaggi.

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Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards, and approved by the Research Review Board—the Ethic Committee—of the ASST Spedali Civili, Brescia, Italy (study reference number: NP1676). Informed consent was obtained from all individual participants included in the study.

Funding

The study was supported in part by grants from: EULO Foundation and Donazione Pizzini Maria Luisa to F. Odicino, Italian Association for Cancer Research (IG17185) to C. Romualdi, and Fondazione Umberto Veronesi post-doctoral fellowship to C. Romani and P. Todeschini.

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