Age-Related Changes of the Cervix Influence Human Papillomavirus Type Distribution Philip E. Castle, 1 Jose Jeronimo, 1 Mark Schiffman, 1 Rolando Herrero, 3 Ana C. Rodrı ´guez, 1,3 M. Concepcio ´n Bratti, 3 Allan Hildesheim, 1 Sholom Wacholder, 1 L. Rodney Long, 2 Leif Neve, 2 Ruth Pfeiffer, 1 and Robert D. Burk 4 1 Division of Cancer Epidemiology and Genetics, National Cancer Institute, and 2 Communications Engineering Branch, National Library of Medicine, NIH, Bethesda, Maryland; 3 Proyecto Epidemiolo ´gico Guanacaste, Fundacio ´n INCIENSA, San Jose ´, Costa Rica; and 4 Albert Einstein College of Medicine, New York, New York Abstract Approximately 15 human papillomavirus (HPV) types cause virtually all cervical cancer whereas other HPV types are unrelated to cancer. We were interested in whether some noncarcinogenic types differ from carcinogenic in their affinity for the cervical transformation zone, where nearly all HPV- induced cancers occur. To examine this possibility, we tested cervical specimens from 8,374 women without cervical precancer and cancer participating in a population-based study in Guanacaste for >40 HPV types using PCR. We compared age-group specific prevalences of HPV types of the A9 species, which are mainly carcinogenic and include HPV16, to the genetically distinct types of the A3/A15 species (e.g., HPV71), which are noncarcinogenic and common in vaginal specimens from hysterectomized women. We related HPV detection of each group to the location of the junction between the squamous epithelium of the ectocervix and vagina and the columnar epithelium of the endocervical canal. Models evaluated the independent effects of amount of exposed columnar epithelium (ectopy) and age on the presence of A9 or A3/A15 types. Prevalence of A9 types (7.6%) peaked in the youngest women, declined in middle-aged women, and then increased slightly in older women. By contrast, prevalence of A3/A15 types (7.6%) tended to remain invariant or to increase with increasing age. Detection of A9 infections increased (P trend < 0.0005) but A3/A15 infections decreased (P trend < 0.0005) with increasing exposure of the columnar epithelia. Older age and decreasing cervical ectopy were independently positively associated with having an A3/A15 infection com- pared with having an A9 infection. These patterns need to be confirmed in other studies and populations. We suggest that these genetically distinct groups of HPV types may differ in tissue preferences, which may contribute to their differences in carcinogenic potential. (Cancer Res 2006; 66(2): 1218-24) Introduction Over 100 human papillomaviruses (HPV) types infect humans and these types are primarily classified in the a and h genera (1, 2). Approximately 40 HPV types sorting into 15 a species infect mucosal epithelia, and approximately 15 carcinogenic HPV types from 5 a species cause virtually all cervical cancers (3–5) and a subset of head and neck, vaginal, vulvar, penile, and anal cancers worldwide (6, 7). Differences in carcinogenicity have been primarily ascribed to sequence-related functional differences in E6 and E7 proteins and their interaction with a variety of cellular proteins but most notably with p53 and Rb, respectively (8, 9). In addition, carcinogenic HPV types code for an E5 protein, implicated in carcinogenic transformation (9) and immune evasion (10), whereas many noncarcinogenic types either lack an open reading frame (ORF) or the necessary start codon for E5 expression (11). Thus, several mechanisms may simultaneously contribute to the carci- nogenic potential of HPV. Another plausible mechanism to explain differences in carcino- genicity is viral tropism for the target cell type. Profound examples of papillomavirus tropism exist: animal papillomaviruses do not infect human tissues and HPV types primarily of the h species infect skin (some types of the a species also infect skin) rather than mucosal epithelia. However, it is unclear whether subtle differences in tropism between a species populated by carcinogenic HPV types (e.g., a9) versus noncarcinogenic HPV types (e.g., a3 and a15) occur. Most cervical cancers arise in the cervical transformation zone, a region of squamous metaplasia between the proximal squamous epithelia found in the vagina and ectocervix and the columnar epithelia in the endocervix. Thus, for the cervical cancer to possibly occur, infection by carcinogenic types must occur in the tissue of the cervical transformation zone. We recently reported a comparative analysis of vaginal HPV in hysterectomized women and cervical HPV in nonhysterectomized women from our population-based study in Guanacaste, Costa Rica (12). We found that ( a ) carcinogenic HPV types were similarly prevalent in both groups of women; (b) some noncarcinogenic HPV types, especially those types within a3 species (e.g., HPV61 and HPV72) and the closely related a15 species (HPV71), were more common in the vaginal specimens from hysterectomized women than cervical specimens in nonhysterectomized women; and (c) the difference in noncarcinogenic HPV type prevalences was primarily observed in women 55 years of age and younger. Data from cervicovaginal specimens collected by self-sampling have found an increase in prevalence of these same a3/a15 types compared with cervical specimens (13, 14). Together, we hypothesized that some HPV types might preferentially infect the squamous epithelium of the vagina rather than the metaplastic cells of the cervical transformation zone, where HPV-induced cancer primarily occurs. If our hypothesis is true, we could anticipate that the physio- logic age of the cervix (i.e., aging-related atrophy of the epithelial layer) and ‘‘migration’’ of the cervical transformation zone and the Note: Consent was obtained from all participants in accordance with the guidelines of U.S. Department of Health and Human Services. NIH and Costa Rica institutional review boards approved this study. Requests for reprints: Philip E. Castle, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Room 7074, 6120 Executive Boulevard, EPS MSC 7234, Bethesda, MD 20892-7234. Phone: 301-435-3976; Fax: 301-402-0916; E-mail: castlep@mail.nih.gov. I2006 American Association for Cancer Research. doi:10.1158/0008-5472.CAN-05-3066 Cancer Res 2006; 66: (2). January 15, 2006 1218 www.aacrjournals.org Research Article Research. on August 22, 2015. © 2006 American Association for Cancer cancerres.aacrjournals.org Downloaded from