title: Etiologic role of human papillomavirus infection in bladder carcinoma.
abstract: BACKGROUND
  The authors elucidated an etiologic role of human papillomavirus (HPV) infection in carcinoma of the bladder.
  
  
  METHODS
  One hundred seventeen of 224 patients with bladder carcinoma who were treated between 1997 and 2009 were enrolled in this study. The presence of HPV DNA was tested on frozen carcinoma tissues that were obtained by transurethral resection using a polymerases chain reaction-based method. Localization of HPV was observed on archival tissue specimens by in situ hybridization (ISH) for high-risk HPV DNA. Cyclin-dependent kinase (CDK) inhibitor 2A (inhibits CDK4) (p16-INK4a) and minichromosome maintenance protein-7 (mcm-7)-surrogate markers for high-risk HPV-E7 oncoprotein-and HPV-L1 (capsid) protein expression were evaluated by immunohistochemistry.
  
  
  RESULTS
  HPV types 16, 18, 31, 33, 52, and 58, and an unknown HPV type were detected in 18 of 117 samples (15%) from patients with bladder carcinoma. HPV16 was identified in 6 samples, HPV18 was identified in 4 samples, and HPV33 was identified in 3 samples. All were single HPV type infections. HPV was detected in 38% (12 of 28) of histologic grade 1 bladder carcinomas, 8.5% (6 of 71) of grade 2 bladder carcinomas, and in 0% (0 of 18) of grade 3 bladder carcinomas. Multivariate analysis indicated that younger age (<60 years; odds ratio [OR], 10.9; 95% confidence interval [CI], 2.6-45.3) and grade 1 tumors (OR, 4.5; 95% CI, 1.2-17.0) were associated with HPV infection. ISH analysis indicated that high-risk HPV DNA was localized in the nuclei of tumor cells of all HPV-positive samples. p16-INK4a and mcm-7 were expressed in 94% and 89% of HPV-positive carcinoma cells, respectively. HPV-L1 protein expression, which suggested reproductive HPV infection, was not observed in any carcinoma.
  
  
  CONCLUSIONS
  The current results indicated that high-risk HPV is likely to be a causative agent of some low-grade bladder carcinomas that develop in younger patients.
authors.affiliation: Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Shigehara
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sasagawa
authors.forename: Shohei
authors.initials: S
authors.lastname: Kawaguchi
authors.forename: Takao
authors.initials: T
authors.lastname: Nakashima
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Shimamura
authors.forename: Yuji
authors.initials: Y
authors.lastname: Maeda
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Konaka
authors.forename: Atsushi
authors.initials: A
authors.lastname: Mizokami
authors.forename: Eitetsu
authors.initials: E
authors.lastname: Koh
authors.forename: Mikio
authors.initials: M
authors.lastname: Namiki
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000032:analysis; D036022:Capsid Proteins / Q000032:analysis; D018797:Cell Cycle Proteins / Q000032:analysis; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004279:DNA, Viral / Q000032:analysis; D004268:DNA-Binding Proteins / Q000032:analysis; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D064168:Minichromosome Maintenance Complex Component 7; D009363:Neoplasm Proteins / Q000032:analysis; D009687:Nuclear Proteins / Q000032:analysis; D009856:Oncogene Proteins, Viral / Q000032:analysis; D027383:Papillomaviridae / Q000235:genetics; D030361:Papillomavirus Infections / Q000150:complications*; D001749:Urinary Bladder Neoplasms / Q000378:metabolism / Q000821:virology*
chemical_list: D015415:Biomarkers; C000614131:CDKN2A protein, human; D036022:Capsid Proteins; D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004279:DNA, Viral; D004268:DNA-Binding Proteins; C114580:HPV L1 protein, Human papillomavirus; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D009856:Oncogene Proteins, Viral; C101624:MCM7 protein, human; D064168:Minichromosome Maintenance Complex Component 7