80 Chapter 4 INTRODUCTION Endometrial cancer is the most frequently diagnosed cancer of the female genital tract and the sixth most common cancer in women globally (1). With its rising incidence worldwide, endometrial cancer accounted for 417,000 new diagnoses and over 97,000 deaths in 2020 (2, 3). Early detection is crucial since advanced stage disease has a poor prognosis and a high risk of relapse (4). In about 90% of cases, postmenopausal bleeding precedes endometrial cancer (5). Consequently, diagnostic procedures that require a referral for specialized care are indicated for all patients presenting with postmenopausal bleeding, causing discomfort and high healthcare costs (6-8). Yet only 5% to 10% of patients with this common alarming symptom have an underlying malignancy (9). Another small subset of asymptomatic endometrial cancer patients is detected via a Pap smear obtained during cytology-based cervical cancer screening or other indications (10-12). As cervical cancer screening programs have shifted from cytology to primary testing for human papillomavirus (HPV) in many countries today, the detection of asymptomatic endometrial cancers via Pap testing is declining (13). Besides the detection of endometrial cancer in Pap smears, recent cytology research demonstrates that endometrial cancer cells are detectable in vaginal samples (14) and urine (15) by shedding through the cervix into the vaginal debris. An added benefit of using minimally invasive types of diagnostic samples, including urine and cervicovaginal self-samples, is that they can be collected at home, which is rather inexpensive and reduces the burden of health care. As an alternative to cytology, objective biomarker testing on minimally invasive sample types has demonstrated great potential and would be ideal to triage patients with postmenopausal bleeding. DNA methylation signatures in promoter regions of tumor suppressor genes represent a valuable biomarker for the detection of early-stage disease. In the early stages of cancer development, promoter hypermethylation can lead to gene silencing and loss of their tumor suppressive function (16). Methylation testing does not necessarily require the presence of intact tumor cells for interpretation and is also measurable using tumor-shedded circulating DNA. Based on our previous studies and literature, nine markers (ADCYAP1, BHLHE22, CDH13, CDO1, GALR1, GHSR, HAND2, SST, and ZIC1) are considered to be suitable for detection of endometrial cancer in minimally invasive sample types (17-25). Our study was initiated to evaluate the diagnostic performance of endometrial cancer detection using DNA
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