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

作者：Rajendra Shanmugarajah^*; Yang Tao; Xuan Wei; Sharma Prateek; Pavey Darren; Lee Cheong Soon; Le Son; Collins Josephine; Wang Bin

来源：International Journal of Cancer, 2017, 141(10): 2037-2049.

DOI：10.1002/ijc.30896

• Barrett's oesophagus
• oesophageal adenocarcinoma
• human papillomavirus

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, p16(INK4A), cyclin D-1, 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 1/RNA 1) was only found in the dysplastic and adenocarcinoma group (n=21). The majority of HPV DNA 1/RNA 1 BD/OAC were characterized by p16(high)(INK4A)(14/21, 66.7%), pRb(low) (15/21, 71.4%) and p53(low) (20/21, 95%) and was significantly different to controls [combination of HPV DNA(+)/RNA(+)(n=94) and HPV DNA 1/RNA-cohorts (n=22)]. p53(low) had the strongest association with DNA 1/RNA 1 oesophageal lesions (OR=23.5, 95% CI=2.94-187.8, p=0.0029). Seventeen HPV DNA 1/RNA 1 BD/OAC identified as p53(low), were sequenced and all but one exhibited wild-type status. pRb(low)/p53(low) 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.

• 出版日期2017-11-15