TY - JOUR
T1 - The carcinogenicity of human papillomavirus types reflects viral evolution
AU - Schiffman, Mark
AU - Herrero, Rolando
AU - Desalle, Rob
AU - Hildesheim, Allan
AU - Wacholder, Sholom
AU - Rodriguez, Ana Cecilia
AU - Bratti, Maria C.
AU - Sherman, Mark E.
AU - Morales, Jorge
AU - Guillen, Diego
AU - Alfaro, Mario
AU - Hutchinson, Martha
AU - Wright, Thomas C.
AU - Solomon, Diane
AU - Chen, Zigui
AU - Schussler, John
AU - Castle, Philip E.
AU - Burk, Robert D.
N1 - Funding Information:
The Guanacaste Project was supported by the National Cancer Institute, National Institutes of Health, Department of Health and Human Services contracts NO1-CP-21081, NO1-CP-33061, NO1-CP-40542 and NO1-CP-506535. We are grateful for the support of Costa Rican health authorities and for the decade-long dedication of the superb project staff. Dr. Burk was supported by National Cancer Institute grant CA78527.
PY - 2005/6/20
Y1 - 2005/6/20
N2 - 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.
AB - 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.
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U2 - 10.1016/j.virol.2005.04.002
DO - 10.1016/j.virol.2005.04.002
M3 - Article
C2 - 15914222
AN - SCOPUS:21144433509
SN - 0042-6822
VL - 337
SP - 76
EP - 84
JO - Virology
JF - Virology
IS - 1
ER -