title: Possible contributing role of Epstein-Barr virus (EBV) as a cofactor in human papillomavirus (HPV)-associated cervical carcinogenesis.
abstract: BACKGROUND
  Persistent infection with EBV has been linked to the development of malignancies including HPV-associated cervical carcinoma. However, the role of EBV in HPV-associated cervical cancer is still poorly understood.
  
  
  OBJECTIVE
  To determine the possible contributing role of EBV in HPV-associated cervical carcinogenesis according to HPV genotypes, HPV genome status and EBV localization.
  
  
  METHODS
  Cervical tissues, including 82 with no squamous intraepithelial lesions (noSILs), 85 low-grade SILs (LSILs), 85 high grade SILs (HSILs) and 40 squamous cell carcinoma samples (SCC) were investigated using PCR and dot blot hybridization for EBV detection and PCR and reverse line blot hybridization for HPV genotyping. The amplification of papillomavirus oncogene transcripts assay and in situ hybridization were used to determine HPV physical status and EBV EBER localization, respectively.
  
  
  RESULTS
  EBV was detected increasingly from noSIL (13.4%), LSIL (29.4%) to HSIL (49.4%) samples. The prevalence of HPV-EBV co-infection was significantly higher in any grade of lesion than in noSIL samples (p<0.05) including noSIL (1.2%; 95% confidence intervals [CI]=0.0-3.6%, relative risk [RR]=1), LSIL (18.8%, 95% CI=10.5-27.1%, RR=15.4), HSIL (41.2%, 95% CI=30.7-51.6%, RR=33.8) and SCC (30.0%, 95% CI=15.8-44.2%, RR=24.6). Interestingly, HPV-EBV co-infection was more common in cases with episomal forms of high-risk (HR) HPV whereas HPV alone was more common in cases with integrated HR-HPV. In addition, EBER staining demonstrated that EBV was mainly present in infiltrating lymphocytes.
  
  
  CONCLUSIONS
  Infiltrating EBV-infected lymphocytes may play a role in cancer progression of cervical lesion containing episomal HR-HPV.
authors.affiliation: Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; HPV & EBV and carcinogenesis Research Group, Khon Kaen University, Khon Kaen, Thailand. Electronic address: sirinart_a@kkumail.com.
authors.forename: Sirinart
authors.initials: S
authors.lastname: Aromseree
authors.affiliation: Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; HPV & EBV and carcinogenesis Research Group, Khon Kaen University, Khon Kaen, Thailand. Electronic address: chapie@kku.ac.th.
authors.forename: Chamsai
authors.initials: C
authors.lastname: Pientong
authors.affiliation: Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; HPV & EBV and carcinogenesis Research Group, Khon Kaen University, Khon Kaen, Thailand. Electronic address: s.piyawut@gmail.com.
authors.forename: Piyawut
authors.initials: P
authors.lastname: Swangphon
authors.affiliation: Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand. Electronic address: aeyoo20@yahoo.com.
authors.forename: Arkom
authors.initials: A
authors.lastname: Chaiwongkot
authors.affiliation: Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; HPV & EBV and carcinogenesis Research Group, Khon Kaen University, Khon Kaen, Thailand. Electronic address: nuapat@kku.ac.th.
authors.forename: Natcha
authors.initials: N
authors.lastname: Patarapadungkit
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; HPV & EBV and carcinogenesis Research Group, Khon Kaen University, Khon Kaen, Thailand. Electronic address: kpilai@kku.ac.th.
authors.forename: Pilaiwan
authors.initials: P
authors.lastname: Kleebkaow
authors.affiliation: Department of Obstetrics and Gynecology, Khon Kaen Hospital, Khon Kaen 40000, Thailand; HPV & EBV and carcinogenesis Research Group, Khon Kaen University, Khon Kaen, Thailand. Electronic address: thumwadee@hotmail.com.
authors.forename: Thumwadee
authors.initials: T
authors.lastname: Tungsiriwattana
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand. Electronic address: bunkon@kku.ac.th.
authors.forename: Bunkerd
authors.initials: B
authors.lastname: Kongyingyoes
authors.affiliation: Department of Pathology, Cancer Center Amsterdam, VU University Medical Center, 1081HV Amsterdam, The Netherlands. Electronic address: tineke.vendrig@gmail.com.
authors.forename: Tineke
authors.initials: T
authors.lastname: Vendrig
authors.affiliation: Department of Pathology, Cancer Center Amsterdam, VU University Medical Center, 1081HV Amsterdam, The Netherlands. Electronic address: j.middeldorp@vumc.nl.
authors.forename: Jaap M
authors.initials: JM
authors.lastname: Middeldorp
authors.affiliation: Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; HPV & EBV and carcinogenesis Research Group, Khon Kaen University, Khon Kaen, Thailand. Electronic address: tipeka@kku.ac.th.
authors.forename: Tipaya
authors.initials: T
authors.lastname: Ekalaksananan
mesh_terms: D052685:Alphapapillomavirus / Q000145:classification* / Q000235:genetics; D060085:Coinfection / Q000453:epidemiology / Q000821:virology; D020031:Epstein-Barr Virus Infections / Q000175:diagnosis*; D005260:Female; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000302:isolation & purification*; D006801:Humans; D008214:Lymphocytes / Q000821:virology; D030361:Papillomavirus Infections / Q000821:virology*; D010957:Plasmids / Q000235:genetics; D002583:Uterine Cervical Neoplasms / Q000473:pathology / Q000821:virology*
keywords: Cervical cancer; Episomal; Epstein-Barr virus; Human papillomavirus; Integration