Introduction/Background*Cervical cancer is one of the most prevalent and leading cause of cancer mortality for women worldwide. Persistent infection with HPV is associated with the development of cervical cancer. Although most infections are cleared by the immune response, the factors related to persistent infection and carcinogenesis are less well understood. Epigenetic alterations are essential in the development of many cancers; while aberrant hypermethylation in cervical carcinogenesis has been identified in several targeted studies, epigenome-wide exploration has been limited. In this epigenome-wide association study (EWAS) we explore differential DNA methylation signatures associated to CIN3 and Cervical Cancer, to better understand potential drivers and biomarkers of cervical carcinogenesis.
Methodology 247 women (119 normal, 74 CIN3/CGIN and 54 cervical cancer) attending gynaecological appointments, cervical screening and oncological treatment between 2014-2020 at English and Greek referral hospitals were recruited. Methylation signatures were obtained following bisulphite conversion of DNA extracted from exfoliated cervical cells and sequenced using the Illumina 850k array data. After normalisaton and data QC, mixed linear models and a penalised regression were used to test for independent associations between methylation CpG sites and case-control status. P-values were Bonferroni corrected and adjusted for batch, chip, age and HPV status.
Result(s)*177 CpG sites were strongly assosicated with CIN3 or cervical cancer, as measured by a P-value <5x10-8 and a gain/loss in methylation of >15% between cases and controls. Epigenetic signals were located in over 141 unique genes genome-wide, with a gain in methylation in CIN3 or cancer cases being more common (n=77/80).
Conclusion*This is potentially the first adequately powered study to highlight genome-wide epigenetic signatures associated to carcinoma in situ and cervical cancer. This builds on previous genetic signals associated with cervical cancer identified by our group (Bowden et al, Lancet Oncol, 2021). While around 59 genes were previously reported associations to CIN or cervical cancer, the remaining 82 signals appear to be novel. Functional annotation highlighted several genes related to tumour suppresor function, transcription factors and apoptosis – important for cervical cancer tumorigenesis. Methylation signatures of cervical cancer genes are promising for future diagnostic and prognostic tools.
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