title: Human papillomavirus genotyping, human papillomavirus mRNA expression, and p16/Ki-67 cytology to detect anal cancer precursors in HIV-infected MSM.
abstract: OBJECTIVE
  Anal cancer incidence is high in HIV-infected MSM. Screening for anal intraepithelial lesions and cancers is performed at specialized clinics and relies on high-resolution anoscopy (HRA) and anal cytology. Both approaches have limited reproducibility and sensitivity for detecting anal cancer precursors. We evaluated biomarkers for human papillomavirus (HPV)-related disease in a population of HIV-infected MSM.
  
  
  METHODS
  A cross-sectional screening study with passive follow-up included 363 MSM followed at a HIV/AIDS clinic. All men had anal cytology samples taken and were evaluated using HRA and anal biopsies. Using a composite endpoint of biopsy results and cytology, we compared the performance of HPV16/18 genotyping, HPVE6/E7 mRNA expression, and p16/Ki-67 cytology to detect high-grade anal intraepithelial neoplasias (AINs).
  
  
  RESULTS
  For all biomarkers analyzed, there was a significant trend of increasing percentage of men testing positive with increasing severity of disease (P < 0.001). HPV DNA testing had the highest sensitivity for anal intraepithelial neoplasia grade 2 and anal intraepithelial neoplasia grade 3 (AIN3), followed by p16/Ki-67, HPVE6/E7 mRNA testing, and HPV16/18 genotyping. The highest Youden's index was observed for HPVE6/E7 mRNA testing, followed by HPV16/18 genotyping, p16/Ki-67 cytology, and HPV DNA testing. Increasing the threshold for positivity of p16/Ki-67 to five or more positive cells led to significantly higher specificity, but unchanged sensitivity for detecting AIN3.
  
  
  CONCLUSIONS
  Molecular features of anal disease categories are similar to those of corresponding cervical lesions. Biomarkers evaluated for cervical cancer screening may be used for primary anal cancer screening or to decide who should require immediate treatment vs. expectant management.
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD 20852, USA. wentzenn@mail.nih.gov
authors.forename: Nicolas
authors.initials: N
authors.lastname: Wentzensen
authors.forename: Stephen
authors.initials: S
authors.lastname: Follansbee
authors.forename: Sylvia
authors.initials: S
authors.lastname: Borgonovo
authors.forename: Diane
authors.initials: D
authors.lastname: Tokugawa
authors.forename: Lauren
authors.initials: L
authors.lastname: Schwartz
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Lorey
authors.forename: Vikrant V
authors.initials: VV
authors.lastname: Sahasrabuddhe
authors.forename: Brandon
authors.initials: B
authors.lastname: Lamere
authors.forename: Julia C
authors.initials: JC
authors.lastname: Gage
authors.forename: Barbara
authors.initials: B
authors.lastname: Fetterman
authors.forename: Teresa M
authors.initials: TM
authors.lastname: Darragh
authors.forename: Philip E
authors.initials: PE
authors.lastname: Castle
mesh_terms: D000328:Adult; D000368:Aged; D001003:Anal Canal / Q000473:pathology* / Q000821:virology; D001005:Anus Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D015415:Biomarkers / Q000032:analysis; D002140:California / Q000453:epidemiology; D003430:Cross-Sectional Studies; D019941:Cyclin-Dependent Kinase Inhibitor p16; D005500:Follow-Up Studies; D005838:Genotype; D018451:Homosexuality, Male; D052162:Human papillomavirus 16 / Q000235:genetics / Q000302:isolation & purification*; D052161:Human papillomavirus 18 / Q000235:genetics / Q000302:isolation & purification*; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis*; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000032:analysis*; D030361:Papillomavirus Infections / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology / Q000821:virology; D011230:Precancerous Conditions / Q000175:diagnosis* / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000821:virology*; D011237:Predictive Value of Tests; D012333:RNA, Messenger / Q000302:isolation & purification; D012367:RNA, Viral / Q000302:isolation & purification; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity
chemical_list: D015415:Biomarkers; C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D019394:Ki-67 Antigen; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012367:RNA, Viral