52 Chapter 3 A subset of ECs were previously found at cytological evaluation of cervical scrapes taken during cervical cancer screening programs. Malignant endometrial cells can be detected by cervical cytology of cervical scrapes with an overall efficacy of nearly 40% for EC detection (16). However, as most cervical cancer screening programs are moving toward a primary high-risk human papillomavirus (HPV) testing approach, the opportunity to detect EC during cervical cancer screening is often missed nowadays. The urgent need to improve EC diagnostics has led to the development of novel diagnostic approaches, combining the use of minimally invasive cytological specimen collection with the detection of epigenetic alterations (14). The analysis of methylated DNA in tampons for the purpose of EC detection was already pioneered in 2004 (17). DNA methylation is a common epigenetic change in cancer, which involves the addition of a methyl group to the cytosine base at regions of cytosine-guanine bonds (CpG). Promoter hypermethylation-induced silencing of tumor suppressor genes is known to occur during the early stages of carcinogenesis (18) and has therefore widely been appreciated as a biomarker for cancer detection (18-20). Notably, the abovementioned DNA methylation events in tumor suppressor genes differ from promoter hypermethylation associated with the inactivation of the MLH1, MSH2, MSH6 or PMS2 mismatch repair genes in Lynch syndrome (21). Despite the identification of EC-specific DNA methylation markers with high diagnostic potential (14), they are not yet being implemented in a clinical setting. Determining which marker deserves further development is challenging and a comprehensive overview of the available literature is lacking. Here, we conducted a systematic review to summarize current evidence on the clinical utility of DNA methylation markers for minimally invasive EC detection. Additionally, we critically comment on methodological aspects of the selected studies, aiming to identify the most promising DNA methylation markers for improved EC detection in high-risk women and during cancer screening programs. METHODS Review format This systematic review was executed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (22, 23), where applicable. The full PRISMA checklist can be found in the Supplementary Material. No review protocol on this topic was previously published.
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