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Molecular Diagnostics

Discovery of a biomarker candidate for surgical stratification in high-grade serous ovarian cancer

Abstract

Background

Maximal effort cytoreductive surgery is associated with improved outcomes in advanced high-grade serous ovarian cancer (HGSOC). However, despite complete gross resection (CGR), there is a percentage of patients who will relapse and die early. The aim of this study is to identify potential candidate biomarkers to help personalise surgical radicality.

Methods

136 advanced HGSOC cases who underwent CGR were identified from three public transcriptomic datasets. Candidate prognostic biomarkers were discovered in this cohort by Cox regression analysis, and further validated by targeted RNA-sequencing in HGSOC cases from Imperial College Healthcare NHS Trust (n = 59), and a public dataset. Gene set enrichment analysis was performed to understand the biological significance of the candidate biomarker.

Results

We identified ALG5 as a prognostic biomarker for early tumour progression in advanced HGSOC despite CGR (HR = 2.42, 95% CI (1.57–3.75), p < 0.0001). The prognostic value of this new candidate biomarker was additionally confirmed in two independent datasets (HR = 1.60, 95% CI (1.03–2.49), p = 0.0368; HR = 3.08, 95% CI (1.07–8.81), p = 0.0365). Mechanistically, the oxidative phosphorylation was demonstrated as a potential biological pathway of ALG5-high expression in patients with early relapse (p < 0.001).

Conclusion

ALG5 has been identified as an independent prognostic biomarker for poor prognosis in advanced HGSOC patients despite CGR. This sets a promising platform for biomarker combinations and further validations towards future personalised surgical care.

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Fig. 1: Complete gross tumour resection is associated with improved prognosis in advanced stage high-grade serous ovarian cancer patients.
Fig. 2: Biomarker discovery workflow.
Fig. 3: The prognostic associations of ALG5 expression in CGR-operated HGSOC patients.
Fig. 4: ALG5 correlates with oxidative phosphorylation pathway.
Fig. 5: ALG5 expression may not directly predict primary chemotherapy response.

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Acknowledgements

Tissue samples were provided by the Imperial College Healthcare NHS Trust Tissue Bank. Other investigators may have received samples from these same tissues. We acknowledge Ms Naina Patel, Ms Nona Rama and Dr. Ed Curry for help and suggestions on tumour collection, study design and data analysis.

Author information

Authors and Affiliations

Authors

Contributions

C.F. and H.L. conceived and designed this study. K.N. and N.R. collected the clinical annotations. P.C. prepared the tumour samples. H.L. collected the RNA-sequencing data and performed bioinformatics analysis. H.L., P.C., K.N., N.R., E.A. and C.F. contributed to the interpretation of data. H.L., P.C. and C.F. wrote the manuscript. All authors revised the manuscript.

Corresponding author

Correspondence to Christina Fotopoulou.

Ethics declarations

Ethics approval and consent to participate

Frozen tumour specimens were provided by the Imperial College Healthcare NHS Trust Tissue Bank after full informed patient consent. The ethical approval was obtained from the Hammersmith and Queen Charlotte’s & Chelsea Research Ethics Committee approval 05/QO406/178. The procedures involved human participants were done in accordance with the ethical standards of the institutional and/or national research committee and with the principles of the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Consent to publish

This manuscript does not contain any individual patient data.

Data availability

The RNA-sequencing data and clinical annotations are accessible in Mendeley Data with the identifier https://doi.org/10.17632/kw736vjpsd.1.

Competing interests

The authors declare no competing interests.

Funding information

This study is supported by the National Institute for Health Research (NIHR), Imperial Biomedical Research Centre (BRC), the Imperial College Experimental Cancer Medicine Centre (ECMC), and Cancer Research UK. C.F., P.C., K.N. and N.R. acknowledge funding from Imperial Health Charity, Myrovlytis Trust and Imperial Private Healthcare. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.

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Lu, H., Cunnea, P., Nixon, K. et al. Discovery of a biomarker candidate for surgical stratification in high-grade serous ovarian cancer. Br J Cancer 124, 1286–1293 (2021). https://doi.org/10.1038/s41416-020-01252-2

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