Active human papillomavirus involvement in Barrett's dysplasia and oesophageal adenocarcinoma is characterized by wild-type p53 and aberrations of the retinoblastoma protein pathway

Int J Cancer. 2017 Nov 15;141(10):2037-2049. doi: 10.1002/ijc.30896. Epub 2017 Aug 4.

Abstract

We have previously demonstrated that transcriptionally active high-risk HPV (hr-HPV) is strongly incriminated in Barrett's dysplasia (BD) and oesophageal adenocarcinoma (OAC) using mainly fresh frozen tissue. This study aimed to identify biomarkers of active HPV infection in Barrett's metaplasia, (BM)/BD/OAC by immunohistochemical staining (IHC) of formalin-fixed paraffin embedded (FFPE) tissue for aberrations of p53 and the retinoblastoma (pRb) pathway, which are targets for the viral oncoproteins, E6/E7, respectively. Prospectively, BM (n = 81)/BD (n = 72)/OAC (n = 65) FFPE specimens were subjected to IHC staining for pRb, p16INK4A , cyclin D1 , p53 and RNA in-situ hybridization for E6/E7 transcripts. HPV DNA was determined via PCR in fresh frozen specimens. Viral load measurement (real-time PCR) and Next Generation Sequencing of TP53 was performed. Of 218 patients, 56 were HPV DNA positive [HPV16 (n = 42), 18 (n = 13), 6 (n = 1)]. Viral load was low. Transcriptionally active HPV (DNA+ /RNA+ ) was only found in the dysplastic and adenocarcinoma group (n = 21). The majority of HPV DNA+ /RNA+ BD/OAC were characterized by p 16highINK4A (14/21, 66.7%), pRblow (15/21, 71.4%) and p53low (20/21, 95%) and was significantly different to controls [combination of HPV DNA- /RNA- (n = 94) and HPV DNA+ /RNA- cohorts (n = 22)]. p53low had the strongest association with DNA+ /RNA+ oesophageal lesions (OR = 23.5, 95% CI = 2.94-187.8, p = 0.0029). Seventeen HPV DNA+ /RNA+ BD/OAC identified as p53low, were sequenced and all but one exhibited wild-type status. pRblow /p53low provided the best balance of strength of association (OR = 8.0, 95% CI = 2.6-25.0, p = 0.0003) and sensitivity (71.4%)/specificity (71.6%) for DNA+ /RNA+ BD/OAC. Active HPV involvement in BD/OAC is characterized by wild-type p53 and aberrations of the retinoblastoma protein pathway.

Keywords: Barrett's oesophagus; human papillomavirus; oesophageal adenocarcinoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / genetics
  • Adenocarcinoma / pathology
  • Adenocarcinoma / virology*
  • Barrett Esophagus / genetics
  • Barrett Esophagus / pathology
  • Barrett Esophagus / virology*
  • Biomarkers, Tumor / genetics*
  • Cross-Sectional Studies
  • Esophageal Neoplasms / genetics
  • Esophageal Neoplasms / pathology
  • Esophageal Neoplasms / virology*
  • Female
  • Follow-Up Studies
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Male
  • Middle Aged
  • Neoplasm Staging
  • Papillomaviridae / isolation & purification*
  • Papillomavirus Infections / genetics
  • Papillomavirus Infections / pathology
  • Papillomavirus Infections / virology*
  • Prognosis
  • Prospective Studies
  • Retinoblastoma Protein / genetics*
  • Tumor Suppressor Protein p53 / genetics*

Substances

  • Biomarkers, Tumor
  • Retinoblastoma Protein
  • TP53 protein, human
  • Tumor Suppressor Protein p53