title: Carcinogenic HPV infection in the cervical squamo-columnar junction.
abstract: Recent studies have suggested the involvement of a unique population of cells at the cervical squamo-columnar junction (SCJ) in the pathogenesis of early (squamous intraepithelial lesion or SIL) and advanced (squamous cell and adeno-carcinomas) cervical neoplasia. However, there is little evidence to date showing that SCJ cells harbour carcinogenic HPV or are instrumental in the initial phases of neoplasia. This study was designed to (1) determine if normal-appearing SCJ cells contained evidence of carcinogenic HPV infection and (2) trace their transition to early SIL. Sections of cervix from high-risk reproductive age women were selected and SCJ cells were analysed by using several techniques which increasingly implicated HPV infection: HPV DNA (genotyping and in situ hybridization)/RNA (PCR), immunostaining for HPV16 E2 (an early marker of HPV infection), p16(ink4), Ki67, and HPV L1 protein. In 22 cases with a history of SIL and no evidence of preneoplastic lesion in the excision specimen, HPV DNA was isolated from eight of ten with visible SCJ cells, six of which were HPV16/18 DNA-positive. In five of these latter cases, the SCJ cells were positive for p16(ink4) and/or HPV E2. Transcriptionally active HPV infection (E6/E7 mRNAs) was also detected in microdissected SCJ cells. Early squamous atypia associated with the SCJ cells demonstrated in addition diffuse p16(ink4) immunoreactivity, elevated proliferative index, and rare L1 antigen positivity. We present for the first time direct evidence that normal-appearing SCJ cells can be infected by carcinogenic HPV. They initially express HPV E2 and their progression to SIL is heralded by an expanding metaplastic progeny with increased proliferation and p16(ink4) expression. Whether certain SCJs are more vulnerable than others to carcinogenic HPV genotypes and what variables determine transition to high-grade SIL remain unresolved, but the common event appears to be a vulnerable cell at the SCJ.
authors.affiliation: Department of Pathology, Division of Women's and Perinatal Pathology, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Jelena
authors.initials: J
authors.lastname: Mirkovic
authors.affiliation: Department of Pathology, Division of Women's and Perinatal Pathology, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Brooke E
authors.initials: BE
authors.lastname: Howitt
authors.affiliation: Laboratory of Experimental Pathology, GIGA-Cancer, University of Liège, Liège, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Roncarati
authors.affiliation: Laboratory of Experimental Pathology, GIGA-Cancer, University of Liège, Liège, Belgium.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Demoulin
authors.affiliation: Laboratory of Experimental Pathology, GIGA-Cancer, University of Liège, Liège, Belgium.
authors.forename: Meggy
authors.initials: M
authors.lastname: Suarez-Carmona
authors.affiliation: Laboratory of Experimental Pathology, GIGA-Cancer, University of Liège, Liège, Belgium.
authors.forename: Pascale
authors.initials: P
authors.lastname: Hubert
authors.affiliation: Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
authors.forename: Frank D
authors.initials: FD
authors.lastname: McKeon
authors.affiliation: Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
authors.forename: Wa
authors.initials: W
authors.lastname: Xian
authors.affiliation: Department of Pathology, Division of Women's and Perinatal Pathology, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Anita
authors.initials: A
authors.lastname: Li
authors.affiliation: Laboratory of Experimental Pathology, GIGA-Cancer, University of Liège, Liège, Belgium.
authors.forename: Philippe
authors.initials: P
authors.lastname: Delvenne
authors.affiliation: Department of Pathology, Division of Women's and Perinatal Pathology, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Crum
authors.affiliation: Laboratory of Experimental Pathology, GIGA-Cancer, University of Liège, Liège, Belgium.
authors.forename: Michael
authors.initials: M
authors.lastname: Herfs
mesh_terms: D036022:Capsid Proteins / Q000378:metabolism; D002472:Cell Transformation, Viral; D002584:Cervix Uteri / Q000473:pathology; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004279:DNA, Viral / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D004847:Epithelial Cells / Q000473:pathology* / Q000821:virology; D005260:Female; D005838:Genotype; D006801:Humans; D017403:In Situ Hybridization; D019394:Ki-67 Antigen / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D009856:Oncogene Proteins, Viral / Q000378:metabolism; D027383:Papillomaviridae / Q000235:genetics / Q000502:physiology*; D030361:Papillomavirus Infections / Q000473:pathology* / Q000821:virology; D012367:RNA, Viral / Q000235:genetics; D002583:Uterine Cervical Neoplasms / Q000473:pathology* / Q000821:virology
chemical_list: C000614131:CDKN2A protein, human; D036022:Capsid Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004279:DNA, Viral; D004268:DNA-Binding Proteins; C114580:HPV L1 protein, Human papillomavirus; D019394:Ki-67 Antigen; D009363:Neoplasm Proteins; D009856:Oncogene Proteins, Viral; D012367:RNA, Viral; C076036:oncogene protein E2, Human papillomavirus type 1
keywords: HPV; cervical intraepithelial neoplasia; squamo-columnar junction