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Transcriptionally Active Human Papillomavirus Is Strongly Associated With Barrett's Dysplasia and Esophageal Adenocarcinoma

Citation

Rajendra, S and Wang, B and Snow, ET and Sharma, P and Pavey, D and Merrett, N and Ball, MJ and Brain, T and Fernando, R and Robertson, IK, Transcriptionally Active Human Papillomavirus Is Strongly Associated With Barrett's Dysplasia and Esophageal Adenocarcinoma, The American Journal of Gastroenterology, 108 pp. 1082-1093. ISSN 0002-9270 (2013) [Refereed Article]

Copyright Statement

Copyright 2013 American College of Gastroenterology

DOI: doi:10.1038/ajg.2013.94

Abstract

OBJECTIVES: The role of human papillomavirus (HPV) in Barrett ’ s esophagus (BE) remains unclear. The few studies that have previously investigated HPV and esophageal adenocarcinoma (EAC) or BE have produced either negative data or positive results of doubtful clinical / etiological significance or have detected only low-risk HPV types. We therefore prospectively determined the prevalence of biologically active HPV in esophageal epithelium of patients representing the Barrett ’ s metaplasia –dysplasia – adenocarcinoma sequence. METHODS: HPV DNA was estimated by nested PCR and viral transcriptional activity detected by E6 / 7 oncogene mRNA expression and p16INK4A immunohistochemistry in fresh frozen and paraffin-embedded esophageal biopsies of patients with BE, Barrett ’ s dysplasia (BD), and EAC, as well as controls. Biopsies were obtained from the transformation zone (squamocolumnar junction (SCJ)) and the lesion, or corresponding site in controls, i.e., 2 cm above the gastroesophageal junction (GEJ). RESULTS: Of the 261 patients, 81 were positive for HPV DNA. In controls and BE, the virus was mostly detected at the transformation zone. Compared with controls (18.0 % ), HPV positivity was significantly more common in BD (68.6 % , incidence rate ratio (IRR) 2.94, 95 % confidence interval (CI)1.78 – 4.85, P < 0.001) and EAC (66.7 % , IRR 2.87, 95 % CI 1.69 – 4.86, P < 0.001), but not in BE(22.1 % , IRR 1.06, 95 % CI 0.60 – 1.85, P = 0.85). Of the patients, 92.6 % were high-risk (HR) HPV, i.e., types 16 and 18. Again, p16INK4A positivity was greatest in BD and EAC and much less in BE patients (44.1 % , IRR 17.0 (95 % CI 4.86 – 59.6, P < 0.001), 44.4 % , 17.0 (95 % CI 4.87 – 59.4,P < 0.001), and 10.6 % , 3.93 (95 % CI 1.01 – 15.3, P = 0.048) respectively). In 66 HPV DNA – positive patients tested for E6 / E7 mRNA, none of the control ( n = 16) or BE ( n = 13) individuals were positive, whereas 9 / 22 BD and 9 / 15 EAC patients demonstrated oncogene expression ( P < 0.001). When HPV DNA, p16INK4A, and E6 / E7 mRNA were all positive, there was a very strong association with disease severity (SCJ: odds ratio (OR) 104, 95 % CI 20.3 – 529, P < 0.001; lesion: OR 62.2, 95 % CI 12.4 – 311, P < 0.001) than when all were negative. CONCLUSIONS: Transcriptionally active HR-HPV was strongly associated with BD and EAC, but was largely biologically irrelevant in BE and controls, suggesting a potential role in esophageal carcinogenesis. These data provide robust justification for further detailed longitudinal, interventional, and molecular studies.

Item Details

Item Type:Refereed Article
Research Division:Medical and Health Sciences
Research Group:Oncology and Carcinogenesis
Research Field:Cancer Genetics
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Digestive System Disorders
Author:Snow, ET (Associate Professor Elizabeth Snow)
Author:Ball, MJ (Professor Madeleine Ball)
Author:Robertson, IK (Dr Iain Robertson)
ID Code:84120
Year Published:2013
Web of Science® Times Cited:19
Deposited By:Health Sciences A
Deposited On:2013-04-18
Last Modified:2017-11-02
Downloads:0

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