Abstract
Simple SummaryEndometrial cancer is the commonest cancer of the female genital tract and obesity is its main modifiable risk factor. Over 80% of endometrial cancers develop in the context of obesity-induced metabolic changes. This study focuses on the potential of plasma-based metabolites to enable the early detection of endometrial cancer in a cohort of women with body mass index (BMI) ≥ 30 kg/m2. Specific lipid metabolites including phospholipids and sphingolipids (sphingomyelins) demonstrated good accuracy for the detection of endometrial cancer, especially when combined in a diagnostic model. This study advances our knowledge of the role of metabolomics in endometrial cancer and provides a basis for the minimally invasive screening of women with elevated BMI.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) ≥ 30 kg/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.
Highlights
Endometrial cancer is the most common gynaecological malignancy in the United Kingdom, where its incidence is rising in parallel with the obesity epidemic [1]
Almost half of all endometrial cancers are attributed to overweight (BMI ≥ 25 kg/m2) and obesity (BMI ≥ 30 kg/m2) [3]
This study included women with body mass index (BMI) ≥ 30 kg/m2 participating in clinical research, who donated blood samples and gave written, informed consent for their pseudo-anonymised data to be used for future research
Summary
Endometrial cancer is the most common gynaecological malignancy in the United Kingdom, where its incidence is rising in parallel with the obesity epidemic [1]. Almost half of all endometrial cancers are attributed to overweight (BMI ≥ 25 kg/m2) and obesity (BMI ≥ 30 kg/m2) [3]. The strong dose–response relationship portends a 10–15% lifetime risk of endometrial cancer in women with class III obesity (BMI ≥ 40 kg/m2) compared with a population average of 2% [4]. Whilst its aetiological importance is clear, the biology underpinning obesity-driven endometrial carcinogenesis is incompletely understood [5]. Unhealthy obesity, rather than excess bodyweight per se, is of particular aetiological significance, with impaired glucose tolerance and chronic insulin resistance acting synergistically to increase endometrial cancer risk [7]. Type 2 diabetes mellitus is associated with a 62% upsurge [8], and uncontrolled diabetes mellitus a nearly five-fold greater susceptibility to endometrial cancer [9]
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