title: Accumulated Metabolites of Hydroxybutyric Acid Serve as Diagnostic and Prognostic Biomarkers of Ovarian High-Grade Serous Carcinomas.
abstract: Ovarian cancer is a heterogeneous disease of low prevalence, but poor survival. Early diagnosis is critical for survival, but it is often challenging because the symptoms of ovarian cancer are subtle and become apparent only during advanced stages of the disease. Therefore, the identification of robust biomarkers of early disease is a clinical priority. Metabolomic profiling is an emerging diagnostic tool enabling the detection of biomarkers reflecting alterations in tumor metabolism, a hallmark of cancer. In this study, we performed metabolomic profiling of serum and tumor tissue from 158 patients with high-grade serous ovarian cancer (HGSOC) and 100 control patients with benign or non-neoplastic lesions. We report metabolites of hydroxybutyric acid (HBA) as novel diagnostic and prognostic biomarkers associated with tumor burden and patient survival. The accumulation of HBA metabolites caused by HGSOC was also associated with reduced expression of succinic semialdehyde dehydrogenase (encoded by ALDH5A1), and with the presence of an epithelial-to-mesenchymal transition gene signature, implying a role for these metabolic alterations in cancer cell migration and invasion. In conclusion, our findings represent the first comprehensive metabolomics analysis in HGSOC and propose a new set of metabolites as biomarkers of disease with diagnostic and prognostic capabilities.
authors.affiliation: VTT Technical Research Centre of Finland, P.O. Box 1000, FI-02044 VTT, Espoo, Finland.
authors.forename: Mika
authors.initials: M
authors.lastname: Hilvo
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, UK.
authors.forename: Ines
authors.initials: I
authors.lastname: de Santiago
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
authors.forename: Peddinti
authors.initials: P
authors.lastname: Gopalacharyulu
authors.affiliation: Institute of Pathology, Charité University Hospital, 10117 Berlin, Germany.
authors.forename: Wolfgang D
authors.initials: WD
authors.lastname: Schmitt
authors.affiliation: Institute of Pathology, Charité University Hospital, 10117 Berlin, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Budczies
authors.affiliation: Department for Gynecology, Campus Virchow Clinic, Charité Medical University, Berlin.
authors.forename: Marc
authors.initials: M
authors.lastname: Kuhberg
authors.affiliation: Institute of Pathology, Charité University Hospital, 10117 Berlin, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Dietel
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
authors.forename: Tero
authors.initials: T
authors.lastname: Aittokallio
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, UK.
authors.forename: Florian
authors.initials: F
authors.lastname: Markowetz
authors.affiliation: Institute of Pathology, Charité University Hospital, 10117 Berlin, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Denkert
authors.affiliation: Department for Gynecology, Campus Virchow Clinic, Charité Medical University, Berlin.|On behalf of the Tumor Bank Ovarian Cancer Network (www.toc-network.de).
authors.forename: Jalid
authors.initials: J
authors.lastname: Sehouli
authors.affiliation: MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, UK.
authors.forename: Christian
authors.initials: C
authors.lastname: Frezza
authors.affiliation: Institute of Pathology, Charité University Hospital, 10117 Berlin, Germany.
authors.forename: Silvia
authors.initials: S
authors.lastname: Darb-Esfahani
authors.affiliation: Department for Gynecology, Campus Virchow Clinic, Charité Medical University, Berlin.|On behalf of the Tumor Bank Ovarian Cancer Network (www.toc-network.de).
authors.forename: Elena Ioana
authors.initials: EI
authors.lastname: Braicu
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D000077216:Carcinoma, Ovarian Epithelial; D018284:Cystadenocarcinoma, Serous / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D005260:Female; D006801:Humans; D006885:Hydroxybutyrates / Q000378:metabolism*; D060787:Neoplasm Grading; D009375:Neoplasms, Glandular and Epithelial / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D010051:Ovarian Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D011379:Prognosis; D016019:Survival Analysis; D014157:Transcription Factors
chemical_list: D014408:Biomarkers, Tumor; D006885:Hydroxybutyrates; D014157:Transcription Factors