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Accumulated Metabolites of Hydroxybutyric Acid Serve As Published OnlineFirst December 18, 2015; DOI: 10.1158/0008-5472.CAN-15-2298 Cancer Integrated Systems and Technologies Research Accumulated Metabolites of Hydroxybutyric Acid Serve as Diagnostic and Prognostic Biomarkers of Ovarian High-Grade Serous Carcinomas Mika Hilvo1, Ines de Santiago2, Peddinti Gopalacharyulu3, Wolfgang D. Schmitt4, Jan Budczies4, Marc Kuhberg5, Manfred Dietel4, Tero Aittokallio3, Florian Markowetz2, Carsten Denkert4, Jalid Sehouli5, Christian Frezza6, Silvia Darb-Esfahani4, and Elena Ioana Braicu5 Abstract Ovarian cancer is a heterogeneous disease of low prevalence, hydroxybutyric acid (HBA) as novel diagnostic and prognostic but poor survival. Early diagnosis is critical for survival, but it is biomarkers associated with tumor burden and patient survival. often challenging because the symptoms of ovarian cancer are The accumulation of HBA metabolites caused by HGSOC subtle and become apparent only during advanced stages of the was also associated with reduced expression of succinic semi- disease. Therefore, the identification of robust biomarkers of aldehyde dehydrogenase (encoded by ALDH5A1), and with early disease is a clinical priority. Metabolomic profiling is an the presence of an epithelial-to-mesenchymal transition gene emerging diagnostic tool enablingthedetectionofbiomarkers signature, implying a role for these metabolic alterations reflecting alterations in tumor metabolism, a hallmark of in cancer cell migration and invasion. In conclusion, our cancer. In this study, we performed metabolomic profiling of findings represent the first comprehensive metabolomics anal- serum and tumor tissue from 158 patients with high-grade ysis in HGSOC and propose a new set of metabolites as serous ovarian cancer (HGSOC) and 100 control patients with biomarkers of disease with diagnostic and prognostic capabilities. benign or non-neoplastic lesions. We report metabolites of Cancer Res; 76(4); 796–804. Ó2015 AACR. Introduction stage III and IV patients, it is only around 20% (3). However, the diagnosis of ovarian cancer is challenging because symptoms Ovarian cancer is the eighth most frequent cause of cancer often tend to mimic those of other diseases and appear only in death among women and is associated with poor overall survival. advanced stages of cancer. According to the World Health Organization statistics worldwide, The main diagnostic methods for ovarian cancer at the moment there were estimated to be 239,000 new cases and 152,000 deaths include pelvic examination, CA-125 blood test, and transvaginal due to ovarian cancer in 2012 (1). High-grade serous carcinoma ultrasound. CA-125 and HE4 proteins are the only two FDA- (HGSOC) is the most common type of ovarian epithelial carci- approved biomarkers for monitoring disease recurrence or pro- noma, accounting approximately 70% of the cases (2). Early gression, but not for screening purposes (4). CA-125 levels are diagnosis is critical for the survival of the patients, as for the stage raised in approximately 90% of patients with advanced epithelial I patients, the 5-year survival rate is around 90%, whereas for the ovarian cancer, but only in 50% of patients with stage I disease (3). Many studies have suggested CA-125 to be a prognostic factor for overall and progression-free survival in ovarian cancer, but also 1VTT Technical Research Centre of Finland, Espoo, Finland. 2Cancer studies showing contradictory results exist (3). Thus, CA-125, the Research UK Cambridge Institute, University of Cambridge, Li Ka golden standard for ovarian cancer diagnostics, is relatively good Shing Centre, Robinson Way, Cambridge, United Kingdom. 3Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, in detecting patients with advanced disease, but its expression is Finland. 4Institute of Pathology, Charite University Hospital, Berlin, elevated in benign conditions, such as endometriosis, and fluc- 5 Germany. Department for Gynecology, Campus Virchow Clinic, tuations associated with menstrual cycle and pregnancy (5). Charite Medical University, Berlin, Germany. 6MRC Cancer Unit, Hutch- ison/MRC Research Centre, University of Cambridge, Cambridge, Therefore, new biomarkers, either alone or in combination of United Kingdom. the aforementioned proteins, are warranted for more specific and Note: Supplementary data for this article are available at Cancer Research sensitive ovarian cancer diagnostics and prognostics. Online (http://cancerres.aacrjournals.org/). Several lines indicate that cancer cells undergo profound met- J. Sehouli and E. Ioana Braicu: On behalf of the Tumor Bank Ovarian Cancer abolic reprogramming to sustain increased energy demand for Network (www.toc-network.de) growth and proliferation (6). This metabolic reprogramming leads to the accumulation of small-molecule metabolites in the S. Darb-Esfahani and E. Ioana Braicu contributed equally to this article. tumor tissue that can also be secreted in the blood stream, Corresponding Author: Mika Hilvo, Zora Biosciences, Biologinkuja 1, FI-02150 becoming potential biomarkers for cancer detection and disease Espoo, Finland. Phone: 358-50-5347782; E-mail: mika.hilvo@zora.fi progression. Of note, metabolic differences in the blood of doi: 10.1158/0008-5472.CAN-15-2298 ovarian cancer patients have already been described (7–9), but Ó2015 American Association for Cancer Research. the clinical utility of these biomarkers has remained limited due to 796 Cancer Res; 76(4) February 15, 2016 Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst December 18, 2015; DOI: 10.1158/0008-5472.CAN-15-2298 Metabolic Biomarkers for Ovarian High-Grade Serous Ovarian Carcinomas small study populations, lack of validation by other studies or canoic acid (186.5 mg/L), succinic acid-d4 (62.9 mg/L)] were orthogonal methodologies, as well as lack of clinicopathologic added to 70 mL of the homogenate. For the serum samples, 400 mL data to elucidate the most relevant pathways for progression of the methanol and 10 mL standard mixture [valine-d8 (37.6 mg/L), disease. To overcome these challenges, we performed global heptadecanoic acid (186.5 mg/L), succinic acid-d4 (62.9 mg/L), metabolomics profiling in a large and well-characterized cohort glutamic acid-d5 (103.5 mg/L)] were added to 30 mL of the of HGSOC patients. This analysis revealed profound deregulation sample. The samples were vortexed for 2 minutes. After 30 of hydroxybutyric acid (HBA) metabolism in the blood and minutes at room temperature, the samples were centrifuged for tumor tissue of these patients, which can be used as diagnostic 5 minutes at 10,000 rpm. Supernatant (200 mL) was moved to a and prognostic biomarkers of the disease. We also found that gas chromatography (GC) vial and evaporated to dryness under these metabolic alterations were associated with the emergence of nitrogen. The samples were derivatized with 25 mL methoxyamine epithelial-to-mesenchymal transition (EMT), a feature of most (45C, 60 minutes) and 25 mL N-methyltrimethylsilyltrifluoroa- invasive and aggressive tumor, suggesting a potential role of HBA cetamide (45C, 60 minutes), and 50 mL of hexane with retention metabolism in EMT. Finally, we validated the prognostic signature index compounds, and injection standard (4,40-dibromoocta- by analyzing independent, publicly available, gene expression fluorobiphenyl) was added to samples. datasets. For the analysis, a Leco Pegasus 4D GCÂGC-TOFMS instru- ment (Leco Corp.) equipped with a cryogenic modulator was Materials and Methods used. The gas chromatography part of the instrument was an Agilent 6890 gas chromatograph (Agilent Technologies), Patients and samples equipped with split/splitless injector. The first-dimension chro- The data from a global metabolomic profiling were obtained matographic column was a 10-m Rxi-5MS capillary column with from serum samples of 100 subjects without malignant disease an internal diameter of 0.18 mm and a stationary-phase film (control group) as well as from 158 ovarian HGSOC patient thickness of 0.18 mm, and the second-dimension chromatograph- serum samples. Clinicopathologic characteristics of the study ic column was a 1.5-m BPX-50 capillary column with an internal cohort are summarized in Supplementary Table S1. Before meta- diameter of 100 mm and a film thickness of 0.1 mm. A methyl- bolomic analyses, the case and control group samples were deactivated retention gap (1.5 m  0.53 mm i.d.) was used in the combined into one set and randomized. In addition, the data front of the first column. High-purity helium was used as the from tumor tissues were obtained for 124 ovarian cancer patients, carrier gas at a constant pressure mode (40 psig). A 4-second of which 112 had matching serum samples in the study. separation time was used in the second dimension. The MS Serum samples were collected from preoperative and pre- spectra were measured at 45 to 700 atomic mass units with treated primary ovarian cancer patients as well as from patients 100 spectra/sec. For the injection, a splitless injection (1.0 mL) without ovarian cancer. All tissue and serum samples were col- at 240C was utilized. The temperature program was as follows: lected at the Tumor Bank Ovarian Cancer (www.toc-network.de) the first-dimension column oven ramp began at 50C with a 2- at the Charite Medical University (Berlin, Germany) between minute hold, after which the temperature was programmed to September 2000 and February 2011. The Ethics Committee 240C at
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