The carcinogenicity of human papillomavirus types reflects viral evolution.
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.
Schiffman
Mark
M
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
Herrero
Rolando
R
Desalle
Rob
R
Hildesheim
Allan
A
Wacholder
Sholom
S
Rodriguez
Ana Cecilia
AC
Bratti
Maria C
MC
Sherman
Mark E
ME
Morales
Jorge
J
Guillen
Diego
D
Alfaro
Mario
M
Hutchinson
Martha
M
Wright
Thomas C
TC
Solomon
Diane
D
Chen
Zigui
Z
Schussler
John
J
Castle
Philip E
PE
Burk
Robert D
RD
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*