Transcriptionally Active Human Papillomavirus Is Strongly Associated With Barrett's Dysplasia and Esophageal Adenocarcinoma
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 2013 American College of Gastroenterology
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.