Pathogenic role of the eight probably/possibly carcinogenic HPV types 26, 53, 66, 67, 68, 70, 73 and 82 in cervical cancer

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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 p16INK4a, 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. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd
Funding Information
  • Agència de Gestió dAjuts Universitaris i de Recerca (AGAUR 2005SGR 00695 and 2009SGR126)
  • GlaxoSmithKline Biologicals
  • Instituto de Salud Carlos III (FIS PI030240, FIS PI061246, RCESP C03/09, RTICESP C03/10, RTIC RD06/0020/0095 and CIBERESP)
  • Marató de TV3 Foundation (051530)

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