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

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Summary

Introduction

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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