title: P21 Cip1/WAF1 expression is strongly associated with HPV-positive tonsillar carcinoma and a favorable prognosis.
abstract: Human papillomavirus is involved in the carcinogenesis of tonsillar squamous cell carcinomas. Here, we investigated the expression and the prognostic value of key cell cycle proteins in the pRb and p53 pathways in both human papillomavirus type 16-positive and -negative tonsillar squamous cell carcinomas. Using immunohistochemistry, 77 tonsillar squamous cell carcinomas with known human papillomavirus type 16 status and clinical outcome were analyzed for expression of Ki67, p16(INK4A,) cyclin D1, pRb, p14(ARF), MDM2, p53, p21(Cip1/WAF1), and p27(KIP1). Results were correlated with each other and with clinical and demographic patient data. A total of 35% of tonsillar carcinomas harbored integrated human papillomavirus type 16 DNA and p16(INK4A) overexpression, both being considered essential features for human papillomavirus association. These tumors also showed the overexpression of p14(ARF) (P<0.0001) and p21(Cip1/WAF1) (P=0.001), and downregulation of pRb (P<0.0001) and cyclin D1 (P=0.027) compared with the human papillomavirus-negative cases. Univariate Cox regression analyses revealed a favorable survival rate for non-smokers (P=0.006), as well as for patients with T1-2 tumors (P<0.0001) or tumors showing low expression of cyclin D1 (P=0.028), presence of human papillomavirus and overexpression of p16(INK4A) (P=0.01), p14(ARF) (P=0.02) or p21(Cip1/WAF1) (P=0.004). In multivariate regression analyses, smoking and tumor size, as well as expression of cyclin D1 and p21(Cip1/WAF1), were found to be independent prognostic markers. We conclude that human papillomavirus positivity in tonsillar squamous cell carcinomas strongly correlates with p21(Cip1/WAF1) and p14(ARF) overexpression and downregulation of pRb and cyclin D1. In particular p21(Cip1/WAF1) overexpression is an excellent favorable prognosticator in tonsillar squamous cell carcinomas.
authors.affiliation: Department of Otorhinolaryngology and Head and Neck Surgery, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Harriët C
authors.initials: HC
authors.lastname: Hafkamp
authors.forename: Jeroen J
authors.initials: JJ
authors.lastname: Mooren
authors.forename: Sandra M H
authors.initials: SM
authors.lastname: Claessen
authors.forename: Boris
authors.initials: B
authors.lastname: Klingenberg
authors.forename: Adri C
authors.initials: AC
authors.lastname: Voogd
authors.forename: Fredrik J
authors.initials: FJ
authors.lastname: Bot
authors.forename: J Peter
authors.initials: JP
authors.lastname: Klussmann
authors.forename: Anton H N
authors.initials: AH
authors.lastname: Hopman
authors.forename: Johannes J
authors.initials: JJ
authors.lastname: Manni
authors.forename: Bernd
authors.initials: B
authors.lastname: Kremer
authors.forename: Frans C S
authors.initials: FC
authors.lastname: Ramaekers
authors.forename: Ernst-Jan M
authors.initials: EJ
authors.lastname: Speel
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000401:mortality / Q000821:virology; D018797:Cell Cycle Proteins / Q000096:biosynthesis; D019938:Cyclin D1 / Q000096:biosynthesis; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis*; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D027383:Papillomaviridae; D030361:Papillomavirus Infections / Q000378:metabolism* / Q000401:mortality; D011379:Prognosis; D016160:Retinoblastoma Protein / Q000096:biosynthesis; D012907:Smoking / Q000009:adverse effects; D014067:Tonsillar Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000821:virology; D025803:Tumor Suppressor Protein p14ARF / Q000096:biosynthesis
chemical_list: D014408:Biomarkers, Tumor; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016160:Retinoblastoma Protein; D025803:Tumor Suppressor Protein p14ARF; D019938:Cyclin D1