title: p16(INK4a) overexpression predicts translational active human papillomavirus infection in tonsillar cancer.
abstract: The causal role of human papillomaviruses (HPV) in squamous cell carcinogenesis of tonsillar cancers (TSCC) depends on the activity of the viral oncoproteins E6 and E7, leading to inactivation of the cellular tumor suppressor p53 and the retinoblastoma gene product pRb. Because of the negative feedback mechanisms, the pRb inactivation causes an increase of the inhibitor of the cyclin-dependent kinases p16(INK4a). In 39 TSCC specimens, genotyping based on the amplification of HPV DNA was carried out using PCR by applying HPV type-specific oligonucleotides. Subsequently, amplicons were hybridised with fluorescence-labeled complementary probes using the Southern blot technology. For HPV E6/E7 mRNA expression, Northern hybridization and RT-PCR were performed, and for p16(INK4a) detection, immunohistochemistry was performed. With 21/39 (53%) HPV-positives, the detection rate is within the range that can be expected in TSCC. The E6/E7 oncogene mRNA was detectable in 11 cases, 10 of which showed positive signals after p16(INK4a) staining. Albeit the small study group was investigated, the correlation of the HPV DNA status with the p16(INK4a) expression was of statistical significance (p = 0.02). Kaplan-Meier estimations revealed better survival outcome for patients with HPV-positive tumors with detectable E6/E7 mRNA and p16(INK4a) overexpression (p = 0.02, median observation time 29 months). As mRNA expression tests are not routinely available in many clinical diagnostic laboratories, and based on the high correlation of p16(INK4a) staining with HPV E6/E7 mRNA expression, in conclusion we suggest for a deeper exploration for the use of p16(INK4a) as a surrogate marker with the potential to impact the standard of care of HPV DNA-positive head and neck carcinomas.
authors.affiliation: Klinik für Hals-, Nasen-, und Ohrenheilkunde, Kopf- und Halschirurgie, Christian-Albrechts-Universität Kiel, Arnold-Heller-Str. 14, Kiel, Germany. mhoffmann@hno.uni-kiel.de
authors.forename: Markus
authors.initials: M
authors.lastname: Hoffmann
authors.forename: Anna Sophie
authors.initials: AS
authors.lastname: Ihloff
authors.forename: Tibor
authors.initials: T
authors.lastname: Görögh
authors.forename: Jan B
authors.initials: JB
authors.lastname: Weise
authors.forename: Asita
authors.initials: A
authors.lastname: Fazel
authors.forename: Matthias
authors.initials: M
authors.lastname: Krams
authors.forename: Werner
authors.initials: W
authors.lastname: Rittgen
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Schwarz
authors.forename: Tomas
authors.initials: T
authors.lastname: Kahn
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D004279:DNA, Viral / Q000302:isolation & purification; D005260:Female; D005786:Gene Expression Regulation; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000821:virology; D006801:Humans; D008297:Male; D008875:Middle Aged; D030361:Papillomavirus Infections / Q000150:complications / Q000235:genetics*; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics; D014067:Tonsillar Neoplasms / Q000150:complications / Q000235:genetics* / Q000821:virology; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D004279:DNA, Viral; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53