title: 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; chi(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; chi(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.
authors.affiliation: Cancer Research UK Clinical Trials Unit, Institute for Cancer Studies, and Cancer Research UK Institute for Cancer Studies, University of Birmingham, Edgbaston, Birmingham, United Kingdom. s.i.collins@bham.ac.uk
authors.forename: Stuart I
authors.initials: SI
authors.lastname: Collins
authors.forename: Christothea
authors.initials: C
authors.lastname: Constandinou-Williams
authors.forename: Kaisheng
authors.initials: K
authors.lastname: Wen
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Young
authors.forename: Sally
authors.initials: S
authors.lastname: Roberts
authors.forename: Paul G
authors.initials: PG
authors.lastname: Murray
authors.forename: Ciaran B J
authors.initials: CB
authors.lastname: Woodman
mesh_terms: D000293:Adolescent; D015331:Cohort Studies; D004279:DNA, Viral / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D052162:Human papillomavirus 16 / Q000235:genetics*; D052161:Human papillomavirus 18 / Q000235:genetics*; D006801:Humans; D008137:Longitudinal Studies; D009856:Oncogene Proteins, Viral / Q000235:genetics*; D030361:Papillomavirus Infections / Q000821:virology*; D002577:Uterine Cervical Diseases / Q000821:virology*; D019562:Viral Load
chemical_list: D004279:DNA, Viral; D004268:DNA-Binding Proteins; C054855:E2 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral