Abstract 3297: A cell of origin for cervical cancer
Authors: Michael Herfs, Yusuke Yamamoto, Anna R. Laury, Xia Wang, Margaret Mclaughlin-Druben, Marisa R. Nucci, Frank D. McKeon, Wa Xian, Christopher P. Crum
Journal: Cancer Research (2012)

Abstract Background Squamous cell carcinoma of the cervix and its precursor [cervical intraepithelial neoplasia (CIN)] are thought to develop either within, or in close proximity to, the squamo-columnar (SC) junction of the ecto and endocervix. Despite this assumption, one issue unresolved in cervical cancer research is the identity of the normal cervical cell type in the SC junction in which tumorigenesis begins. Methods Using GeneChip Human Exon Arrays (Affymetrix), we compared the gene expression profiles of the ecto and endocervical epithelia with the SC junctional cells. Fetal and adult cervical specimens were studied in situ to identify, characterize and determine the dynamics of junctional cell development. CINs and cancers were stained with junction-specific antibodies to ascertain their relationship to the SC junctional cell population. Cervices in which the transformation zone had been excised were analyzed for evidence of the SC junctional immunophenotype. Results Human adult cervices displayed a unique monolayer of cuboidal cells at the SC junction that displayed a unique 77 gene expression signature. Analysis of fetal and postnatal mouse and human cervices using biomarkers from this unique gene signature revealed broad expression in the lining cells of the lower genital tract that, over time, become concentrated in the region of the SC junction. Junction-specific biomarkers consistently immunostained high-grade CINs and squamous and glandular cancers associated with both carcinogenic human papillomaviruses (HPV) and strong expression of p16ink4. Non-carcinogenic HPV-associated CINs and low-grade CINs predominated in the ectocervical location and were usually SC junctional-marker negative. Cervices previously subjected to surgical excision of the SC junction did not remanufacture junctional cells at the new SC junction. Conclusions This study shows, for the first time, that a discrete, residual embryonic cell population in the cervix is uniquely susceptible to carcinogenic HPV infection and is lost following surgical excision of the SC junction. The negative association between the junctional immunophenotype and noncarcinogenic HPV-related CIN may signify different affinities for the SC junction between carcinogenic and non-carcinogenic HPVs. Because junction-specific biomarkers highlight CINs and all cancers with carcinogenic HPVs, they may facilitate interpretation of cervical cancer precursors as well as propose a novel cell type for studies of experimental papillomaviral carcinogenesis. The possibility that unique populations of junctional cells are also involved in the pathogenesis of other HPV-related cancers (anogenital and oropharyngeal) merits investigation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3297. doi:1538-7445.AM2012-3297