title: High-sensitivity human papilloma virus genotyping reveals near universal positivity in anal squamous cell carcinoma: different implications for vaccine prevention and prognosis.
abstract: BACKGROUND
  Characterisation of human papilloma virus (HPV) infection in anal squamous cell carcinoma (ASCC) may have dual importance: first, aetiological; second, prognostic, informing outcome after chemo-radiotherapy (CRT). We undertook HPV genotyping, and allelic characterisations, to evaluate the aetiological role of HPV while simultaneously evaluating the impact of HPV genotyping on relapse-free (RFS) and overall survival (OS).
  
  
  METHODS
  Dual-primer HPV genotyping (subtypes 6, 11, 16, 18, 31, 33, 45, 52, 58) and DNA sequencing of HPV 16 positive tumours were analysed in 151 consecutively referred ASCCs, previously characterised by immunohistochemistry for p16 expression. In 110 patients treated with CRT, factors influencing RFS and OS were evaluated using univariate and multivariate models.
  
  
  RESULTS
  HPV positivity was observed in 95%. HPV 16 accounted for 89%; of these, 64% harboured the T350G E6 variant. HPV 16 positivity was significantly correlated with improved 5-year RFS (62% versus 40%; p = 0.027) and OS (59% versus 38%; p = 0.019). p16 expression was also significantly correlated with improved 5-year RFS (positive versus negative: 65% versus 16%; p < 0.0001) and OS (63% versus 13%; p < 0.0001). In multivariable models that included HPV 16 status, p16 status, sex, and age, p16 expression remained an independent prognostic factor for RFS (p < 0.0001) and OS (p = 0.002).
  
  
  CONCLUSIONS
  In ASCC, near-universal HPV detection rates were demonstrated, higher than generally reported in the literature, and supporting the development of multivalent HPV vaccinations for prevention. By contrast, p16 negatively, but not HPV 16 genotype, is an independent adverse prognosticator after chemo-radiotherapy in patients with ASCC.
authors.affiliation: Viral Oncology Group, Institute of Cancer Sciences, University of Manchester, Manchester, UK.
authors.forename: Ivona
authors.initials: I
authors.lastname: Baricevic
authors.affiliation: Viral Oncology Group, St Mary's Hospital, University of Manchester, Manchester, UK.
authors.forename: Xiaotong
authors.initials: X
authors.lastname: He
authors.affiliation: Department of Histopathology, The Christie NHS Foundation Trust, Manchester, UK.
authors.forename: Bipasha
authors.initials: B
authors.lastname: Chakrabarty
authors.affiliation: Viral Oncology Group, St Mary's Hospital, University of Manchester, Manchester, UK.
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Oliver
authors.affiliation: Kent Oncology Centre, Maidstone and Tunbridge Wells Hospital, UK.
authors.forename: Charles
authors.initials: C
authors.lastname: Bailey
authors.affiliation: Kent Oncology Centre, Maidstone and Tunbridge Wells Hospital, UK.
authors.forename: Jeff
authors.initials: J
authors.lastname: Summers
authors.affiliation: Viral Oncology Group, St Mary's Hospital, University of Manchester, Manchester, UK.
authors.forename: Lynne
authors.initials: L
authors.lastname: Hampson
authors.affiliation: Viral Oncology Group, St Mary's Hospital, University of Manchester, Manchester, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Hampson
authors.affiliation: Sussex Cancer Centre, Royal Sussex County Hospital, Brighton, UK.
authors.forename: Duncan C
authors.initials: DC
authors.lastname: Gilbert
authors.affiliation: Department of Surgery, The Christie NHS Foundation Trust, Manchester, UK; Institute of Cancer Sciences, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK. Electronic address: andrew.renehan@ics.manchester.ac.uk.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Renehan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001005:Anus Neoplasms / Q000473:pathology / Q000517:prevention & control* / Q000821:virology*; D002294:Carcinoma, Squamous Cell / Q000473:pathology / Q000517:prevention & control* / Q000821:virology*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D027383:Papillomaviridae / Q000235:genetics / Q000276:immunology / Q000302:isolation & purification*; D030361:Papillomavirus Infections / Q000517:prevention & control* / Q000821:virology; D053918:Papillomavirus Vaccines / Q000008:administration & dosage*; D011379:Prognosis; D016032:Randomized Controlled Trials as Topic
chemical_list: D053918:Papillomavirus Vaccines
keywords: Anal cancer; Chemo-radiotherapy; HPV genotyping; HPV vaccination; Human papilloma virus