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The implementation of primary HPV-based screening has greatly improved the efficacy of cervical cancer screening. The majority of HPV infections is however self-limiting and does not lead to the development of cancer. The use of biomarkers involved in cervical carcinogenesis may result in a more accurate screening for and management of CIN lesions. In this thesis we aimed to assess the value of host cell DNA methylation markers in the detection and classification of cervical premalignant disease, and the management of women at risk for cervical cancer. Part I: Methylation markers in cervical cancer screening In Chapter 2, we described the FAM19A4/miR124-2 methylation positivity rate (98.3%) in a large worldwide series of 519 invasive cervical carcinomas. These results indicate that FAM19A4/miR124-2 methylation has a very high sensitivity for cervical cancer and that a negative test is likely to rule out the presence of cervical cancer. In Chapter 3, we evaluated cross-sectional and long-term triage performance of FAM19A4/miR124-2 methylation analysis in a Dutch population-based HPV-positive screening cohort. This study underlines that methylation analysis has a good triage performance on baseline Dutch screening samples and may be used to build robust triage algorithms with more objective stratification of women referred for colposcopy versus re-testing compared with cytology. In Chapter 4, we studied the discriminative power of FAM19A4/miR124-2 methylation and HPV genotyping in 294 HPV-positive women with BMD cytology. This study shows that the use of FAM19A4/miR124-2 methylation and/or HPV genotyping in HPV-positive women with BMD can lead to a substantial reduction in the number of direct colposcopy referrals. In Chapter 5, we aimed to validate methylation markers ASCL1 and LHX8 for primary methylation analysis in an South African cohort of 411 women living with HIV (WLHIV). Our results confirmed that primary methylation analysis of ASCL1 and LHX8 genes is an full- molecular alternative to cytology- or HPV-based screening in LMIC, without the need for additional triage testing. Part II: Methylation and immunohistochemical markers for improved classi- fication and clinical management of cervical precursor lesions In Chapter 6, we described FAM19A4/miR124-2 methylation and HPV16/18 genotyping patterns in 1061 HPV-positive women |
