title: p16(INK4a) overexpression is not linked to oncogenic human papillomaviruses in patients with high-grade urothelial cancer cells.
abstract: BACKGROUND
  p16(INK4a) Is overexpressed in almost all precancerous and carcinomatous lesions of the uterine cervix, secondary to interference between high-risk human papillomaviruses (hr-HPVs) and the retinoblastoma gene product. Overexpression of p16(INK4a) has also been identified in patients with high-grade urothelial lesions, both cytologically and histologically. However, the etiological role of HPV has not been documented except in inverted papillomas, low-grade bladder tumors, and younger patients. We therefore attempted to verify if HPV DNA was detectable in p16(INK4a) -positive urothelial tumors.
  
  
  METHODS
  A total of 90 urinary cytology samples (33 negative/low-grade cases and 57 high-grade proliferations) were analyzed for p16(INK4a) and HPV DNA. HPV genotyping was performed by polymerase chain reaction using a low-density DNA microarray enabling the detection of 35 HPVs. A reasoned approach combining tissue genotyping and in situ hybridization (ISH) for hr-HPVs was used in patients with urinary HPV.
  
  
  RESULTS
  Low-risk HPV (HPV-84) and hr-HPVs (HPV-16, -31, and -70) were detected. The prevalence of hr-HPVs in the urine was low: 5 of 82 patients (6.1%) and only 4 of 50 patients (8.0%) with high-grade urothelial malignancy. p16(INK4a) overexpression was noted in 49 high-grade samples (85.9%). In patients with p16(INK4a) -positive tumor cells and hr-HPV in the urine, HPV genotyping and ISH for hr-HPVs were negative in matched tissue sections.
  
  
  CONCLUSIONS
  Our study shows a low prevalence of hr-HPVs in the urine of patients with high-grade urothelial malignancy. In those, p16(INK4a) overexpression occurs in the absence of demonstrable HPV DNA in the tissue sections, contrary to what is noted in gynecopathology.
authors: Université Claude Bernard Lyon 1, Lyon, France; Centre de Pathologie Est, Hôpital Femme-Mère-Enfant, Hospices Civils de Lyon, Bron, France.
authors: Eric
authors: E
authors: Piaton
authors: Jean-Sébastien
authors: JS
authors: Casalegno
authors: Anne-Sophie
authors: AS
authors: Advenier
authors: Myriam
authors: M
authors: Decaussin-Petrucci
authors: Florence
authors: F
authors: Mege-Lechevallier
authors: Alain
authors: A
authors: Ruffion
authors: Yahia
authors: Y
authors: Mekki
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002295:Carcinoma, Transitional Cell / Q000235:genetics* / Q000473:pathology / Q000601:surgery / Q000821:virology; D015331:Cohort Studies; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D015653:Cystectomy / Q000379:methods; D003558:Cystoscopy / Q000379:methods; D004279:DNA, Viral / Q000032:analysis; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D006801:Humans; D017403:In Situ Hybridization; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology; D009367:Neoplasm Staging; D027383:Papillomaviridae / Q000235:genetics*; D030361:Papillomavirus Infections / Q000235:genetics / Q000473:pathology / Q000601:surgery; D012680:Sensitivity and Specificity; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery / Q000821:virology
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D004279:DNA, Viral
keywords: HPV genotyping; bladder cancer; cytology; p16INK4a; urine; urothelial