51 DNA methylation markers for endometrial cancer INTRODUCTION Endometrial cancer (EC) is the most commonly diagnosed gynecological cancer in developed countries (1). Incidence is rising worldwide with around 382,000 new cases and 89,929 deaths reported in 2018 (2). This is partly driven by the increased global prevalence of risk factors, such as obesity and aging (3). Conventionally, ECs are categorized into two groups based on tumor grade. Lowgrade estrogen-related endometrioid carcinomas (also called type I tumors) are most common. The more aggressive high-grade tumors, like serous or clear cell carcinomas (also called type II tumors), are less common (3, 4). Various risk factors, such as obesity, prolonged estrogen exposure, and Lynch syndrome, contribute to the heterogeneous presentation of ECs (5). Over the last decade, molecular efforts revealed an objective molecular stratification of ECs that reflect their biological and clinical heterogeneity (6). The four prognostic molecular subtypes include ultramutated DNA polymerase epsilon, hypermutated microsatellite instable, copy number low and copy number high carcinomas. Though not yet clinically implemented, this genomic classification emphasizes the additional value of molecular markers during diagnostics (7). Although the majority of EC cases are preceded by postmenopausal bleeding symptoms, women presenting with these symptoms pose a diagnostic dilemma since only 9% has an underlying malignancy like EC (8). Diagnostic evaluation of women with suspected EC involves the measurement of endometrial thickness by transvaginal ultrasonography (TVS) (9). In case thickened endometrium is observed by TVS, endometrial pipelle sampling is performed to aspirate endometrial tissue and diagnose endometrial pathology (10). Absence of endometrial thickening does not exclude EC, since especially high-grade ECs can be present without endometrial thickening (11, 12). Since the gold standard for EC diagnosis remains histological examination, invasive procedures to obtain endometrial tissue are still essential to determine the presence of an endometrial malignancy (13). Considering the low disease prevalence and the fact that TVS might miss EC, many women without cancer undergo unnecessary painful biopsy procedures (14). Detecting and excluding EC in high-risk women, like women with Lynch syndrome for which screening is recommended (15), and women presenting with abnormal bleeding using minimally invasive tools could prevent redundant clinical interventions. 3
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