title: HPV integration begins in the tonsillar crypt and leads to the alteration of p16, EGFR and c-myc during tumor formation.
abstract: The prevalence of human papillomavirus (HPV) infection is high in the oropharyngeal mucosal regions, of which the tonsil is the most commonly affected. There may be a link between HPV and the pathogenesis of tonsillar cancer (TC), because of common anatomical characteristics between cervical and tonsillar cancer. We aimed to clarify whether HPV directly affects the oncogenesis and biologic behavior of TC by making a comparison between infection prevalence, physical status and viral loading numbers, and clinicopathologic prognostic factors. To compare HPV-related molecules between TC and tonsillitis (CFT), p16, survivin, HIF-1alpha, skp-1, cyclin A, cyclin B1, c-myc and EGFR were investigated. We observed a significant difference in HPV prevalence between 52 TCs and 69 CFTs (73.1% vs. 11.6%), and most of the HPVs were type 16 (87.2%) and nonepisomal (94.1%). Most TCs associated with HPV arose from the tonsillar crypts, and tended to be inverted and poorly differentiated. Compared with HPV-negative TC, HPV-positive TC showed a strong association with p16 overexpression (p<0.0001), and an inverse association with EGFR amplification (p=0.0478). HPV-16 integration status was strongly associated with c-myc amplification (p=0.034) and HIF-1alpha overexpression (p=0.022). HPV-16 integration could be directly related to tonsillar carcinogenesis initially in tonsillar crypts, followed by cell cycle aberration such as p16 overexpression related to the G1-S phase.
authors.affiliation: Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Se-Heon
authors.initials: SH
authors.lastname: Kim
authors.forename: Bon-Seok
authors.initials: BS
authors.lastname: Koo
authors.forename: Suki
authors.initials: S
authors.lastname: Kang
authors.forename: Kyeongmee
authors.initials: K
authors.lastname: Park
authors.forename: Haeryoung
authors.initials: H
authors.lastname: Kim
authors.forename: Kyung Ryul
authors.initials: KR
authors.lastname: Lee
authors.forename: Moo Joo
authors.initials: MJ
authors.lastname: Lee
authors.forename: Jong Man
authors.initials: JM
authors.lastname: Kim
authors.forename: Eun Chang
authors.initials: EC
authors.lastname: Choi
authors.forename: Nam Hoon
authors.initials: NH
authors.lastname: Cho
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D019925:Cyclin A / Q000235:genetics / Q000378:metabolism; D056750:Cyclin A1; D019926:Cyclin B / Q000235:genetics / Q000378:metabolism; D056744:Cyclin B1; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D004279:DNA, Viral / Q000235:genetics / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics*; D005784:Gene Amplification; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D017404:In Situ Hybridization, Fluorescence; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D027383:Papillomaviridae / Q000502:physiology*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism; D000077022:Survivin; D046888:Tissue Array Analysis; D014067:Tonsillar Neoplasms / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D014069:Tonsillitis / Q000235:genetics / Q000473:pathology / Q000821:virology*; D016662:Virus Integration / Q000502:physiology*
chemical_list: C107489:BIRC5 protein, human; C503745:CCNA1 protein, human; C534699:CCNB1 protein, human; D019925:Cyclin A; D056750:Cyclin A1; D019926:Cyclin B; D056744:Cyclin B1; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004279:DNA, Viral; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D044786:S-Phase Kinase-Associated Proteins; D000077022:Survivin; D066246:ErbB Receptors