Disruption of the E2 Gene Is a Common and Early Event in the Natural History of Cervical Human Papillomavirus Infection: A Longitudinal Cohort Study

Abstract

Integration of high-risk human papillomavirus (HPV) types into the host-cell genome disrupts the HPV regulatory E2 protein, resulting in a loss of negative feedback control of viral oncogene expression; this disruption has been considered a critical event in the pathogenesis of cervical neoplasia, and a potential biomarker of progressive disease. However, using serial samples taken from a cohort of young women who were recruited soon after they first had sexual intercourse, we show that disruption of the E2 gene is a common and early event in the natural history of incident cervical HPV infections. The E2 gene was significantly more likely to be disrupted in women who tested positive for HPV18 in their baseline sample than in those who tested positive for HPV16 [26% versus 58%; relative risk, 2.26; 95% confidence interval (CI), 1.38-3.71; C 2 , 9.23; 1 degree of freedom (df); P = 0.002]. Among women with an intact E2 gene in their baseline sample, the median time to first detection of E2 disruption was also shorter for those who tested positive for HPV18 than HPV16 (5.7 versus 10.9 months; hazards ratio, 1.93; 95% CI, 0.84-4.44; C 2 , 2.49; 1 df; P = 0.11).This tendency for HPV18 to integrate early, coupled with the substantial reduction in viral load in HPV18-positive samples in which E2 is disrupted, may explain why HPV18-associated disease is often reported to be characterized by minor cytologic changes, which underestimate the severity of the underlying histologic abnormality. [Cancer Res 2009; 69(9):3828-32]

State of HPV16 integration in Lithuanian women with cervical neoplasia

“…The opinions and data concerning the relationship between the HPV integration and the level of cervical intraepithelial lesions differ according to various authors. Some researchers suggest that integration of HPV is an early event of carcinogenesis [25,26], while others believe that integration is more frequently detected in already existing significant intraepithelial changes [8,9]. However, there is no doubt about the importance of HPV integration and its influence on cervical changes.…”

Is Human Papillomavirus Viral Load a Clinically Useful Predictive Marker? A Longitudinal Study

“…Where appropriate, to avoid confusion, we subsequently refer to this testing strategy as the "GP5+/GP6+ system." A 2-μL aliquot was taken from the stored sample and DNA was extracted using guanidinium thiocyanate acid; 100 ng of sample DNA were then used in a 50-μL PCR reaction, as previously described (7). The study was approved by the appropriate ethical committee and informed oral consent was obtained from all women.…”

“…For this analysis, DNA was isolated from study samples using proteinase K digestion and phenol/chloroform extraction, according to methods previously described (7). HPV viral load was measured using a modified singleplex qPCR assay (ABI 7700 Applied Biosystems).…”

HPV mRNA test in women with minor cervical lesions: Experience of the University Hospital of North Norway

“…There may be several reasons why E6 and E7 are over-expressed, but one of the main reasons is integration of the virus into the human genome (loss of E2 gene results in loss of regulation of transcripts). The loss of the E2 gene only occurs in a small fraction of the high number of women with HPV infection (Collins et al, 2009). This implies that a test that detects the over-expression of E6 and E7 mRNA is more specific than a test that detects the general presence of viral DNA.…”