title: Pathogenic role of the eight probably/possibly carcinogenic HPV types 26, 53, 66, 67, 68, 70, 73 and 82 in cervical cancer.
abstract: Eight HPV types (HPV26, 53, 66, 67, 68, 70, 73 and 82) that are phylogenetically closely related to 12 WHO-defined high-risk (HR) HPV have been rarely but consistently identified as single HPV infections in about 3% of cervical cancer (CxCa) tissues. Due to lack of biological data, these types are referred to as probable/possible (p) HR-HPV. To analyse their biological activity in direct comparison to HR-HPV types, we selected 55 formalin-fixed, paraffin-embedded (FFPE) CxCa tissues harbouring single pHR-HPV infections (2-13 cases per type) and 266 tissues harbouring single HR-HPV (7-40 cases per type) from a worldwide, retrospective, cross-sectional study. Single HPV infection was verified by two genotyping methods. Presence of type-specific spliced E6*I mRNA transcripts and expression of cellular proteins indicative of HPV transformation were assessed in all cases. In 55 CxCa tissues with pHR-HPV, E6*I mRNA expression was 100%; high p16(INK4a) , 98%; low pRb, 96%; low CyD1, 93%; and low p53, 84%. Compared to HPV16 tissues as a reference, individual frequencies of these five markers did not differ significantly, either for any of the eight pHR-HPV and the 11 other HR types individually or for the groups of pHR and HR types without HPV16. We conclude that the eight pHR-HPV types, when present as a single infection in CxCa, are biologically active and affect the same cellular pathways as any of the fully recognized carcinogenic HR-HPV types. Therefore we have provided molecular evidence of carcinogenicity for types currently classified as probably/possibly carcinogenic. Although this evidence is crucial for HPV-type carcinogenicity classification, per se it is not sufficient for inclusion of these HPV types into population-wide primary and secondary prevention programmes. Such decisions have to include careful estimation of effectiveness and cost-benefit analyses.
authors.affiliation: Division of Genome Modifications and Carcinogenesis, Infections and Cancer Program, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Gordana
authors.initials: G
authors.lastname: Halec
authors.forename: Laia
authors.initials: L
authors.lastname: Alemany
authors.forename: Belen
authors.initials: B
authors.lastname: Lloveras
authors.forename: Markus
authors.initials: M
authors.lastname: Schmitt
authors.forename: Maria
authors.initials: M
authors.lastname: Alejo
authors.forename: Franz X
authors.initials: FX
authors.lastname: Bosch
authors.forename: Sara
authors.initials: S
authors.lastname: Tous
authors.forename: Jo Ellen
authors.initials: JE
authors.lastname: Klaustermeier
authors.forename: Nuria
authors.initials: N
authors.lastname: Guimerà
authors.forename: Niels
authors.initials: N
authors.lastname: Grabe
authors.forename: Bernd
authors.initials: B
authors.lastname: Lahrmann
authors.forename: Lutz
authors.initials: L
authors.lastname: Gissmann
authors.forename: Wim
authors.initials: W
authors.lastname: Quint
authors.forename: Francesc X
authors.initials: FX
authors.lastname: Bosch
authors.forename: Silvia
authors.initials: S
authors.lastname: de Sanjose
authors.forename: Michael
authors.initials: M
authors.lastname: Pawlita
mesh_terms: D003430:Cross-Sectional Studies; D005260:Female; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D027383:Papillomaviridae / Q000235:genetics*; D030361:Papillomavirus Infections / Q000821:virology*; D016133:Polymerase Chain Reaction; D012367:RNA, Viral / Q000032:analysis; D012189:Retrospective Studies; D002583:Uterine Cervical Neoplasms / Q000821:virology*
chemical_list: D012367:RNA, Viral
keywords: HPV; WHO classification; cervical cancer; p16INK4a; viral carcinogenicity