Identification of Metabolomic Biomarkers for Endometrial Cancer and Its Recurrence after Surgery in Postmenopausal Women

Abstract

Endometrial cancer (EC) is the most frequent gynecological cancer in developed countries. Most EC occurs after menopause and is diagnosed as endometrioid (type I) carcinomas, which exhibit a favorable prognosis. In contrast, non-endometrioid (type II) carcinomas such as serous tumors have a poor prognosis. Our goal was to identify novel blood-based markers associated with EC subtypes and recurrence after surgery in postmenopausal women. Using mass spectrometry-based untargeted metabolomics, we examined preoperative serum metabolites among control women (n = 18) and those with non-recurrent (NR) and recurrent (R) cases of type I endometrioid (n = 24) and type II serous (n = 12) carcinomas. R and NR cases were similar with respect to pathological characteristics, body mass index, and age. A total of 1,592 compounds were analyzed including 14 different lipid classes. When we compared EC cases with controls, 137 metabolites were significantly different. A combination of spermine and isovalerate resulted in an age-adjusted area under the receiver-operating characteristic curve (AUCadj) of 0.914 (P < 0.001) for EC detection. The combination of 2-oleoylglycerol and TAG42:2-FA12:0 allowed the distinction of R cases from NR cases with an AUCadj of 0.901 (P < 0.001). Type I R cases were also characterized by much lower levels of bile acids and elevated concentrations of phosphorylated fibrinogen cleavage peptide, whereas type II R cases displayed higher levels of ceramides. The findings from our pilot study provide a detailed metabolomics study of EC and identify putative serum biomarkers for defining clinically relevant risk groups.

Blood Metabolites Associate with Prognosis in Endometrial Cancer

“…A population-based case-control study also identified potential biomarkers in relation to EC which were independent of risk factors like obesity and previously known blood samples, and the authors suggest that metabolic profiling may be important in its early detection and risk assessment [28]. Moreover, metabolomics have demonstrated certain metabolites to be associated with histological subtypes [29,30], with recurrence following surgery [29], and with tumor blood flow in EC patients [31]. A recent study has also evaluated plasma sphingomyelins and phosphatidylcholines as biomarkers in EC [32], proposing ratios between specific metabolites as diagnostic and prognostic models.…”

Metabolomic Biomarkers for Detection, Prognosis and Identifying Recurrence in Endometrial Cancer

“…These glycerides are ultimately metabolised (by the action of monoacylglycerol lipase) to free fatty acids, the group of lipid metabolites that are known to be downregulated in EC. The downregulation of the lipase enzyme in EC may, in theory, account for the observed findings [71,83]. Using plasma samples from women with EC (n = 342), atypical hyperplasia (n = 68) and healthy controls (n = 242) in a cross-sectional diagnostic accuracy study, our group was able to show that spectroscopy has the potential to detect EC with 87% sensitivity and 78% specificity [84].…”

“…Audet-Delage and colleagues, using mass spectrometry-based untargeted metabolomics on pre-operative serum samples of 36 EC cases and 18 controls, reported an upregulation of conjugated lipids including acylcholines, monoacylglycerols and acylcarnitines in EC cases and downregulation of free fatty acids, suggesting the potential remodelling of lipid metabolic pathways in EC [71]. Further, they found C5 acylcarnitine 2-methyl butyryl carnitine was elevated in EC cases [71]. These findings align with those of Bahado-Singh, who also reported an upregulation of acylcholines in EC [77].…”

“…Acyl-carnitines, on the other hand, are 14-carbon fatty acids attached to a carboxylate through an ester-bond and play crucial roles in mitochondrial fatty acid oxidation [76]. They are reportedly enriched in hypoxic tissues and have previously been linked to breast cancer biochemistry [71,72,82]. Other upregulated lipid metabolites in EC include monoacylglycerols, which are products of the enzymatic hydrolysis of triacylglycerols, and diacylglycerols [71,72,76].…”

“…They are reportedly enriched in hypoxic tissues and have previously been linked to breast cancer biochemistry [71,72,82]. Other upregulated lipid metabolites in EC include monoacylglycerols, which are products of the enzymatic hydrolysis of triacylglycerols, and diacylglycerols [71,72,76]. These glycerides are ultimately metabolised (by the action of monoacylglycerol lipase) to free fatty acids, the group of lipid metabolites that are known to be downregulated in EC.…”