Metabolomic Biomarkers for the Detection of Obesity-Driven Endometrial Cancer

Abstract

Endometrial cancer is the most common malignancy of the female genital tract and a major cause of morbidity and mortality in women. Early detection is key to ensuring good outcomes but a lack of minimally invasive screening tools is a significant barrier. Most endometrial cancers are obesity-driven and develop in the context of severe metabolomic dysfunction. Blood-derived metabolites may therefore provide clinically relevant biomarkers for endometrial cancer detection. In this study, we analysed plasma samples of women with body mass index (BMI) ≥30kg/m2 and endometrioid endometrial cancer (cases, n = 67) or histologically normal endometrium (controls, n = 69), using a mass spectrometry-based metabolomics approach. Eighty percent of the samples were randomly selected to serve as a training set and the remaining 20% were used to qualify test performance. Robust predictive models (AUC > 0.9) for endometrial cancer detection based on artificial intelligence algorithms were developed and validated. Phospholipids were of significance as biomarkers of endometrial cancer, with sphingolipids (sphingomyelins) discriminatory in post-menopausal women. An algorithm combining the top ten performing metabolites showed 92.6% prediction accuracy (AUC of 0.95) for endometrial cancer detection. These results suggest that a simple blood test could enable the early detection of endometrial cancer and provide the basis for a minimally invasive screening tool for women with a BMI ≥ 30 kg/m2.

Molecular Basis of Endometriosis and Endometrial Cancer: Current Knowledge and Future Perspectives

“…According to the US statistics, 57% of all ECs are attributable to obesity [76,80,86]. In the United Kingdom (UK) almost half of all ECs are attributed to overweight (BMI ≥ 25 kg/m 2 ) and obesity (BMI ≥ 30 kg/m 2 ) [93]. If compared with all other cancers, EC has the strongest association with obesity [78,88,93].…”

“…In the United Kingdom (UK) almost half of all ECs are attributed to overweight (BMI ≥ 25 kg/m 2 ) and obesity (BMI ≥ 30 kg/m 2 ) [93]. If compared with all other cancers, EC has the strongest association with obesity [78,88,93]. Women with a normal BMI have a much lower lifetime risk of EC (up to 3%), but for every 5-unit increase in BMI, the risk of EC increases by more than 50% [88,93,94].…”

“…If compared with all other cancers, EC has the strongest association with obesity [78,88,93]. Women with a normal BMI have a much lower lifetime risk of EC (up to 3%), but for every 5-unit increase in BMI, the risk of EC increases by more than 50% [88,93,94]. Although the average age at diagnosis is 63 years, EC incidence is increasing among young obese women [88].…”

“…Although the average age at diagnosis is 63 years, EC incidence is increasing among young obese women [88]. Specific lipid metabolites, including phospholipids and sphingolipids (sphingomyelins), demonstrated good accuracy for the detection of EC [93]. The underling mechanisms of the association of obesity with EC are not fully understood; however, they likely include higher estrogen levels in postmenopausal women due to aromatase activity and adipose tissue conversion of androgens into estrogens, hyperinsulinemia, and chronic inflammation [78,95,96].…”

Comprehensive Library Generation for Identification and Quantification of Endometrial Cancer Protein Biomarkers in Cervico-Vaginal Fluid

“…In recent years, there has been growing interest in the use of high-throughput technologies for cancer biomarker discovery [14,17]. Platforms such as mass spectrometry (MS) based proteomics, for instance, have shown promise for facilitating the comprehensive analysis of complex biological specimens to better understand both physiological and pathological states [18].…”