64 Chapter 3 Although the identified DNA methylation markers appear promising for EC detection in minimally invasive specimens, individual studies show various discordances, making it difficult to compare study outcomes. The studies selected in this review vary substantially in population selection, characteristics of case and control groups, sample type, sample preparation, DNA methylation detection techniques, and the cut-off values used to handle DNA methylation levels. Included studies investigated small sample sizes of varying types of cases and controls. Besides normal endometrium, control groups contained different types of benign endometrial and ovarian lesions, and in some cases atypical endometrial hyperplasia (EH) and low-grade cervical intraepithelial neoplasia (CIN1). This varying selection of controls may have influenced the resulting AUC for distinguishing EC from benign endometrium of the corresponding marker, and therefore also our ultimate marker selection. None of the studies included a separate EH group and case or control groups contained only limited numbers of women with EH. DNA methylation markers that enable detection of EH with a high risk of cancer progression could, therefore, have been overlooked. The source populations of which the study participants were enrolled also showed major differences among the selected studies. For instance, De Strooper et al. (30) recruited participants from a population-based cervical screening cohort, whereas others included participants that presented with abnormal (13, 25) or postmenopausal (28, 29) bleeding symptoms. Interestingly, Nair et al. (44) performed a genomic analysis of cancer-specific somatic mutations in uterine lavage samples to detect EC and found that the women with cancer-specific somatic mutations were more likely to be older and postmenopausal. Likewise, the performance of the selected DNA methylations markers may have been affected by the age and postmenopausal status of the study participants. The majority of cancers in the included studies comprised low-grade endometrioid carcinomas, which is coherent to the fact that this subtype involves more than 80% of EC cases (4). High-grade ECs are known to be more aggressive, as they have a higher risk to metastasize and a worse prognosis (3). DNA methylation of the three-gene panel BHLHE22/CDO1/CELF4, described by Huang et al. (24), allowed accurate detection of both groups. When used in a screening setting, it is important to ensure that the DNA methylation markers allow the detection of all subtypes. Our review has several limitations. The final selection of studies in our review is small and originates from only four research groups, underlining the scarcity of publications on this particular topic. Moreover, none of the DNA methylation markers has independently been validated by investigators outside those groups. The lack of
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