The carcinogenicity of human papillomavirus types reflects viral evolution

Mark Schiffman, Rolando Herrero, Rob Desalle, Allan Hildesheim, Sholom Wacholder, Ana Cecilia Rodriguez, Maria C. Bratti, Mark E. Sherman, Jorge Morales, Diego Guillen, Mario Alfaro, Martha Hutchinson, Thomas C. Wright, Diane Solomon, Zigui Chen, John Schussler, Philip E. Castle, Robert D. Burk

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417 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)76-84
Number of pages9
JournalVirology
Volume337
Issue number1
DOIs
StatePublished - Jun 20 2005

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ASJC Scopus subject areas

  • Virology

Cite this

Schiffman, M., Herrero, R., Desalle, R., Hildesheim, A., Wacholder, S., Rodriguez, A. C., Bratti, M. C., Sherman, M. E., Morales, J., Guillen, D., Alfaro, M., Hutchinson, M., Wright, T. C., Solomon, D., Chen, Z., Schussler, J., Castle, P. E., & Burk, R. D. (2005). The carcinogenicity of human papillomavirus types reflects viral evolution. Virology, 337(1), 76-84. https://doi.org/10.1016/j.virol.2005.04.002