53 DNA methylation markers for endometrial cancer Search strategy PubMed, EMbase.com and Web of Science were searched on March 31, 2020 for relevant publications by two reviewers (RvdH and JAvT) with support of a medical information specialist (JCFK). The search terms included both words as keywords as well as free text terms for ‘endometrial carcinoma’ and ‘methylation’. Furthermore, the bibliography of identified articles was checked for other relevant publications. Google Scholar was also searched on March 31, 2020 for additional references. Duplicates were excluded. The full search strategy is outlined in the Supplementary Material. Eligibility criteria & study selection Two reviewers (RvdH and JAvT) independently selected studies based on title, abstract, and full text in particular cases, including only Dutch and English language articles. Any disagreement between reviewers was resolved by discussion with a molecular biologist specialized in epigenetics (RDMS). Articles were regarded as eligible to be included in this review when DNA methylation biomarkers were explored or evaluated for EC detection, using minimally invasive sample collection methods. In this review, minimally invasive sampling is defined as cytological sample (i.e. cell specimen) collection with minimal discomfort to the patient without local or general anesthesia. All studies on the detection of EC-specific DNA methylation markers in minimally invasive samples (i.e. cervical scrapings, endometrial brushes, vaginal swabs, and vaginal tampons) were included, regardless of the methodology used for DNA methylation detection. Moreover, studies that used liquid biopsies (i.e. blood or urine) for EC detection using DNA methylation markers were included. Both individual DNA methylation markers and DNA methylation marker panels were included. DNA methylation in this review covers CpG island methylation positioned in the promoter region of a gene as well as at other CpG-rich locations of the genome. To discover DNA methylation markers that allow detection of all histological subtypes of EC, the inclusion of articles was not restricted to specific subtypes of EC. Articles that merely used tissue samples, only focused on prognosis, therapeutic use or methylation markers related to Lynch syndrome (i.e. MLH1, MSH2, MSH6 or PMS2 promoter hypermethylation (21)), were excluded. Studies without healthy control subjects were also excluded. Methylation marker selection Diagnostic biomarker performance is usually evaluated by plotting sensitivity against 1 – specificity in a receiver operating characteristic (ROC) curve. The area under the ROC curve (AUC) summarizes the overall diagnostic accuracy of the biomarker or diagnostic test, with a value ranging from 0 to 1. An AUC of 1 represents an excellent 3
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