title: The carcinogenicity of human papillomavirus types reflects viral evolution.
abstract: Persistent infections with carcinogenic human papillomaviruses (HPV) cause virtually all cervical cancers. Cervical HPV types (n > 40) also represent the most common sexually transmitted agents, and most infections clear in 1-2 years. The risks of persistence and neoplastic progression to cancer and its histologic precursor, cervical intraepithelial neoplasia grade 3 (CIN3), differ markedly by HPV type. To study type-specific HPV natural history, we conducted a 10,000-woman, population-based prospective study of HPV infections and CIN3/cancer in Guanacaste, Costa Rica. By studying large numbers of women, we wished to separate viral persistence from neoplastic progression. We observed a strong concordance of newly-revised HPV evolutionary groupings with the separate risks of persistence and progression to CIN3/cancer. HPV16 was uniquely likely both to persist and to cause neoplastic progression when it persisted, making it a remarkably powerful human carcinogen that merits separate clinical consideration. Specifically, 19.9% of HPV16-infected women were diagnosed with CIN3/cancer at enrollment or during the five-year follow-up. Other carcinogenic types, many related to HPV16, were not particularly persistent but could cause neoplastic progression, at lower rates than HPV16, if they did persist. Some low-risk types were persistent but, nevertheless, virtually never caused CIN3. Therefore, carcinogenicity is not strictly a function of persistence. Separately, we noted that the carcinogenic HPV types code for an E5 protein, whereas most low-risk types either lack a definable homologous E5 ORF and/or a translation start codon for E5. These results present several clear clues and research directions in our ongoing efforts to understand HPV carcinogenesis.
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, US Department of Health and Human Services, Bethesda, MA, USA. schiffmm@mail.nih.gov
authors.forename: Mark
authors.initials: M
authors.lastname: Schiffman
authors.forename: Rolando
authors.initials: R
authors.lastname: Herrero
authors.forename: Rob
authors.initials: R
authors.lastname: Desalle
authors.forename: Allan
authors.initials: A
authors.lastname: Hildesheim
authors.forename: Sholom
authors.initials: S
authors.lastname: Wacholder
authors.forename: Ana Cecilia
authors.initials: AC
authors.lastname: Rodriguez
authors.forename: Maria C
authors.initials: MC
authors.lastname: Bratti
authors.forename: Mark E
authors.initials: ME
authors.lastname: Sherman
authors.forename: Jorge
authors.initials: J
authors.lastname: Morales
authors.forename: Diego
authors.initials: D
authors.lastname: Guillen
authors.forename: Mario
authors.initials: M
authors.lastname: Alfaro
authors.forename: Martha
authors.initials: M
authors.lastname: Hutchinson
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Wright
authors.forename: Diane
authors.initials: D
authors.lastname: Solomon
authors.forename: Zigui
authors.initials: Z
authors.lastname: Chen
authors.forename: John
authors.initials: J
authors.lastname: Schussler
authors.forename: Philip E
authors.initials: PE
authors.lastname: Castle
authors.forename: Robert D
authors.initials: RD
authors.lastname: Burk
mesh_terms: D003043:Cocarcinogenesis; D019143:Evolution, Molecular; D005260:Female; D006801:Humans; D027383:Papillomaviridae / Q000145:classification / Q000502:physiology*; D030361:Papillomavirus Infections / Q000150:complications / Q000453:epidemiology; D011446:Prospective Studies; D002583:Uterine Cervical Neoplasms / Q000453:epidemiology / Q000209:etiology* / Q000517:prevention & control*