General discussion and future perspectives 169 8 platforms and be used reliably and effectively in different settings; 4. The biomarker should be cost-effective, both in terms of the cost of the biomarker assay and its potential impact on patient outcomes. Persistent infection with carcinogenic human papillomavirus (HPV) genotypes has been established as the necessary cause of cervical cancer 3. Testing for HPV DNA provides a biologically salient biomarker approach for early detection of cervical cancer. HPV testing is currently the preferred primary method for cervical cancer screening due to its high sensitivity and negative predictive value (NPV) for identifying CIN3 and cervical cancer (CIN3+) 4, 5. However, since most HPV infections are harmless, additional tests, so-called triage tests, are required to identify women with clinically relevant infections, who would benefit from colposcopy and treatment, and to prevent unnecessary referral, excessive diagnostics and overtreatment. In today’s biomarker research for cervical cancer screening, a key focus is on identifying highly specific biomarkers. This emphasis is particularly important for triage tests, as their high specificity is crucial in reducing false positives and lessening the necessity for unnecessary follow-up procedures, thereby alleviating stress. Host genomic alterations following a persistent high-risk (hr) HPV infection are critical contributors in the pathogenesis of cervical cancer. DNA methylation changes in promoter regions of host genes are among these biological events associated with cervical cancer progression. Studies have shown that aberrant DNA methylation patterns are early events in cervical carcinogenesis 6. Genome-wide and targeted approaches have successfully identified various methylation markers associated with cervical cancer and CIN3, including ACAN 7, ANKRD18CP 8, ASCL1 7, ASTN1 9, ATP10A 10, C13orf18 11, CADM1 12, CDH6 13, EPB41L3 11, DLX1 9, DPP10 10, DPP6 14, FAM19A4 15, FMN2 10, GALR1 16, GATA4 13, GFRA1 13, GHSR 16, GSX1 14, HAS1 10, IRX1 13, ITG4 9, JAM3 11, KCNIP4 13, LHX8 7, MAL 17, miR1242 18, MYADM 7, NEUROG3 16, NRG3 7, PAX-1 19, PAX-2 13, PHACTR3 15, POU4F3 20, PRDM14 15, PROX1 16, RALYL 14, RGS7 7, RXFP3 9, SIM2 16, SLIT2 21, SOX1 8, 19, 22, SOX17 9, SST 16, ST6GALNAC3 7, ST6GALNAC5 7, TERT 8, WDR17 7, ZIC1 16, ZNF582 23, ZNF583 7, ZNF671 9, ZNF781 7 and ZSCAN1 24. DNA methylation levels of promoter regions of host genes increase with the severity of cervical disease and are significantly elevated in cervical cancer 25-27. Methylation positivity rates of methylation markers or marker panels in cervical cancer are reported to be high (between 93% and 100%), irrespective of histotype, FIGO stage and geographical region 26-37. The high methylation positivity rate in cervical carcinomas was also found to be independent of hrHPV status and genotype 28, indicating that hostcell methylation analysis can detect HPV-negative and -positive cervical cancers, as well
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