Alteration of Human Papillomavirus Type 16 Genetic and Epigenetic Profiles in Cervical Cancer Patients Is Indicative of Poor Disease Prognosis A Cohort Analysis

Objective: Aim of this study was to assess the changes in genetic and epigenetic profiles of human papillomavirus type 16 (HPV16), if any, in primary cervical cancer (CaCx) and corresponding plasma before and after therapy for possible prognostic evaluation. Methods: The genetic (integration status) and epigenetic (methylation of enhancer, early promoter, and late promoter sequences) profiles of HPV16 were analyzed in pretherapy CaCx (n = 46), corresponding plasma, posttherapy cervical swabs (n = 39), and corresponding plasma from a single patient cohort. Quantitative viral load was also measured in these HPV16-positive primary CaCx and posttherapy cervical swabs. Results: Presence of HPV16 in the patients' plasma before/after therapy was significantly (P = 0.03) associated with higher viral load in the primary tumor site. Human papillomavirus type 16 integration and hypomethylation of the early (14 of 29, Z = 4.47, P < 0.01) and late promoters (20 of 29, Z = 3.74, P < 0.01) were more prevalent in the plasma than the corresponding pretherapy CaCx samples. However, the dissimilarity in integration status (5 of 24) was less evident between posttherapy cervical swabs and corresponding plasma, although hypomethylation of the early promoter and hypermethylation of the late promoter (8 of 24, Z= 2.6, P < 0.01) was seen in posttherapy plasma samples. Whereas in the posttherapy swabs, integrated (22 of 29) or mixed (7 of 29) form of HPV16 prevailed with hypomethylation of the enhancer (6 of 29, Z= 2.0, P< 0.05) and late promoter (18 of 29, Z= 4.4, P< 0.01) compared with the corresponding primary tumors. The patients having high HPV16 copy number in pretherapy and posttherapy cervical lesions and hypomethylation of early promoter/late promoter in the corresponding plasma showed increased disease recurrence with distant metastases. Conclusions: The genetic-epigenetic profile of HPV16 in pretherapy/posttherapy CaCx samples showed significant association with disease prognosis.