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.

Metabolomics of biomarker discovery in ovarian cancer: a systematic review of the current literature

“…Increased levels of long chain fatty acids were a commonly reported finding in serum and tissue of OC. Elevated palmitate, myristate and oleate concentrations were commonly reported in serum, ascitic fluid, and metastatic OC tissue (Guan et al 2009; Fong et al 2011; Shender et al 2014; Hilvo et al 2015). Further, a recent study by Buas et al used lipidomics profiling and identified 17 metabolites including glycerolipids and glycerophospholipids that were decreased in OC cases relative to controls (Buas et al 2016).…”

“…Increased lysophosphatidic acid (LPA) levels were reported in urine and ascitic fluid in OC patients (Shender et al 2014; Zhang et al 2013). Ceramides and gangliosides were also increased in the serum and ascitic fluid of OC patients (Fan et al 2012; Shender et al 2014; Ke et al 2015; Hilvo et al 2015). Increased levels of long chain fatty acids were a commonly reported finding in serum and tissue of OC.…”

“…Biological samples utilized for metabolomic analysis included serum/plasma in 13 studies, urine in 4 studies, cyst fluid in 3 studies, tissue in 2 studies, and ascitic fluid in one study. Validation of the results of serum profiling using tissue was conducted in two studies (Chen et al 2011a; Hilvo et al 2015). The analytical platforms used for metabolite detection included LC–MS in 12 studies, GC–MS in 6 studies, NMR in 5 studies, and direct analysis in real time–time of flight mass spectrometry (DART/TOF–MS) in one study.…”

“…The majority of reported metabolites related to these pathways show contradictory results across the different studies. Lactate, a product of anaerobic glycolysis, was found to be elevated in malignant cyst fluid, primary and metastatic OC tissue (Fong et al 2011; Kyriakides et al 2016; Boss et al 2000) while serum and urine profiling showed a reduction (Slupsky et al 2010; Hilvo et al 2015). Levels of lactate in tissue were down-regulated in OC when compared to borderline ovarian tumors (Denkert et al 2006).…”

Metabolomic characterization of experimental ovarian cancer ascitic fluid

“…3-hydroxybutyrate was one of the metabolites responsible for the differences in spectral patterns. These results were recently confirmed by mass spectrometry that detected accumulation of hydroxybutyric acid metabolites in ovarian cancer patient serum and tumor tissues (Hilvo et al 2016). Studies using 1 H NMR to explore ovarian cancer MA have been previously published (Bala et al 2008; Vettukattil et al 2013).…”