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p16INK4a-expression in relation to E6/E7-mRNA-expression of human papillomaviruses in tonsillar squamous cell carcinoma

Kopf- und Neurozentrum Klinik für Hals-, Nasen-, Ohrenheilkunde Direktor Prof. Dr. med. R. Knecht. p16INK4a-expression in relation to E6/E7-mRNA-expression of human papillomaviruses in tonsillar squamous cell carcinoma (TSCC). Anna Sophie Ihloff Journal Club. Basics.

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p16INK4a-expression in relation to E6/E7-mRNA-expression of human papillomaviruses in tonsillar squamous cell carcinoma

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  1. Kopf- und NeurozentrumKlinik für Hals-, Nasen-, OhrenheilkundeDirektor Prof. Dr. med. R. Knecht p16INK4a-expression in relation to E6/E7-mRNA-expression of human papillomaviruses in tonsillar squamous cell carcinoma (TSCC) Anna Sophie Ihloff Journal Club

  2. Basics HPV prevalence in head and neck (HN) SCC all anatomical sites 20 % - 30 %  tonsillar carcinoma 50 % - 60 % Hoffmann et al., Acta Otolarygol (Stckh) 1998 Gillison et al., J Natl Cancer Inst. 2000 Klussmann et al., Cancer 2001 Hoffmann et al., Cancer Lett 2005

  3. Basics Patients with HPV positive tumours present with more aggressive biological behaviour  better survival rates in comparison to HPV negative cases Andl et al., Cancer Research 1998 Gillison et al., Semin Oncol 2004 Klussmann et al., Am J Pathol 2003 Ritchie et al., Int J Cancer 2003 Hoffmann et al., Cancer Lett 2005

  4. Basics HPV infection leads to inactivation of p53 by E6 => no p53-mutations  inactivation of pRb by E7 => reduced pRb-level => overexpression of p16  HPV positive SCC are considered to be a specific tumor entity in head and neck cancer Klussmann et al., Cancer 2001 Hafkamp et al., Int J Cancer 2003 Braakhuis et al., J Natl Cancer Inst. 2004 Begum et al., Clin Cancer Res 2005

  5. Material and Methods • 39 patients with TSCC • 8 female & 31 male / 44-85 (62,1) years • 30 palatine tonsil / 9 lingual tonsil • HPV-DNA-detection PCR MY09/11 and GP5+/6+ with Luminex Southern Blot Hybridization (SBH) • HPV-E6/E7-mRNA-detection RT-PCR with SBH Northern Blot Hybridization • p16-Immunohistochemistry paraffinembedded antibody MTS-1, BIOLOGO Klaes et al., Int J Cancer 2001

  6. Results • HPV-DNA • 21/39 HPV-positive TSCC (53,8 %) • 20/21 infected with HPV16 • 01/21 infected with HPV35

  7. Results • Gelspur DNA Result • SmartLadder • SiHa (250 ng) HPV16 • 3 SiHa (2.5 ng) • 4 SiHa (25 pg) • 5 Nr. 110 HPV16 • 6 Nr. 194 HPV • 7 Nr. 201 HPV16 • 8 Nr. 274 HPV16 • 9 Nr. 275 negative • 10 Nr. 295 HPV? • 11 Nr. 339 HPV? • 12 Nr. 362 HPV16 • 13 Nr. 401 HPV16 • 14 Nr. 417 negative • 15 H2O • 16 SmartLadder MY09/11-PCR   

  8. Results • HPV-E6/E7-mRNA • 11/21 with strong expression of E6/E7-mRNA (52%)

  9. Results • p16-immunohistochemistry • 12/39 with p16-overexpression • 12/21 HPV-positive TSCC with p16-overexpression • 9/21 HPV-positive TSCC without p16-overexpression 6/9 without E6/E7-mRNA-expression 3/9 with E6/E7-mRNA-expression-signals only after hybridization

  10. Weak expression

  11. Strong expression

  12. Results p16 expression in correlation to HPV DNA and E6/E7 mRNA expression • elevated p16 expression could be assigned to HPV DNA positive tumours • correlation of p16 overexpression and HPV-positivity proofed to be statistically highly significant (p=0.0018) • 10 HPV DNA positive cases with p16 overexpression expressed E6/E7 mRNA in the tumour tissue

  13. Summary • The predominant majority of HPV DNA positive TSCC show an E6/E7-mRNA-expression. • The detection of p16-overexpression correlates with the pattern of E6/E7-mRNA-expression, yet not with the HPV DNA status.

  14. Conclusion • HPV DNA presence is correlated with viral mRNA expression and subsequent enhancement of p16 levels reflecting biological activity of the viruses in the infected tissue • p16-overexpression predicts translational active HPV-infection in head and neck cancers, thus giving rise to the opportunity to identify active HPV infections in HNSCC on a practicable and routine way applying p16 immuno-histochemistry

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