Abstract
In this study, we characterized the metabolome of the human ovary and identified metabolic alternations that coincide with primary epithelial ovarian cancer (EOC) and metastatic tumors resulting from primary ovarian cancer (MOC) using three analytical platforms: gas chromatography mass spectrometry (GC/MS) and liquid chromatography tandem mass spectrometry (LC/MS/MS) using buffer systems and instrument settings to catalog positive or negative ions. The human ovarian metabolome was found to contain 364 biochemicals and upon transformation of the ovary caused changes in energy utilization, altering metabolites associated with glycolysis and β-oxidation of fatty acids—such as carnitine (1.79 fold in EOC, p<0.001; 1.88 fold in MOC, p<0.001), acetylcarnitine (1.75 fold in EOC, p<0.001; 2.39 fold in MOC, p<0.001), and butyrylcarnitine (3.62 fold, p<0.0094 in EOC; 7.88 fold, p<0.001 in MOC). There were also significant changes in phenylalanine catabolism marked by increases in phenylpyruvate (4.21 fold; p = 0.0098) and phenyllactate (195.45 fold; p<0.0023) in EOC. Ovarian cancer also displayed an enhanced oxidative stress response as indicated by increases in 2-aminobutyrate in EOC (1.46 fold, p = 0.0316) and in MOC (2.25 fold, p<0.001) and several isoforms of tocopherols. We have also identified novel metabolites in the ovary, specifically N-acetylasparate and N-acetyl-aspartyl-glutamate, whose role in ovarian physiology has yet to be determined. These data enhance our understanding of the diverse biochemistry of the human ovary and demonstrate metabolic alterations upon transformation. Furthermore, metabolites with significant changes between groups provide insight into biochemical consequences of transformation and are candidate biomarkers of ovarian oncogenesis. Validation studies are warranted to determine whether these compounds have clinical utility in the diagnosis or clinical management of ovarian cancer patients.
Highlights
Ovarian cancer is the most lethal malignancy of the female reproductive system and the 5th cause of cancer death in women
For the first time we report the metabolic profile of the normal human ovary and compare it to the metabolic profile of primary epithelial ovarian cancer (EOC) and metastatic tumors resulting from initial EOC (MOC) using gas chromatography mass spectrometry (GC/mass spectrometry (MS)) and LC/ MS/MS
Woo et al [33] found urinary biomarkers for ovarian cancer using GC/MS related to DNA oxidative damage and DNA methylation: 1-methyladenosine, 3-methyluridine, and 4androstene-3,17-dione
Summary
Ovarian cancer is the most lethal malignancy of the female reproductive system and the 5th cause of cancer death in women. It is estimated that 21,880 women will be diagnosed and 13,850 will die from this disease this year. The five-year survival rate at Stage I is 93.5% but drops to 27.6% at Stage IV, where a majority of cases are diagnosed due to a lack of symptoms at the earlier stages [1]. Current detection strategies include transvaginal ultrasound and blood CA-125 levels. Cancer could be mistaken for functional cysts in pre-menopausal women due to the dynamic nature of the ovarian surface [2]. CA-125 has a high false positive rate [2] that can arise from a variety of conditions including endometriosis, fibroids, hemorrhagic ovarian cysts, acute pelvic inflammatory disease, menstruation, first trimester pregnancy, and several other cancer types [3]. Alternative methods are being developed for patients who have normal CA-
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