PMID- 23437342
OWN - NLM
STAT- MEDLINE
DCOM- 20130806
LR  - 20220331
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 8
IP  - 2
DP  - 2013
TI  - Integration of HPV6 and downregulation of AKR1C3 expression mark malignant 
      transformation in a patient with juvenile-onset laryngeal papillomatosis.
PG  - e57207
LID - 10.1371/journal.pone.0057207 [doi]
LID - e57207
AB  - Juvenile-onset recurrent respiratory papillomatosis (RRP) is associated with low 
      risk human papillomavirus (HPV) types 6 and 11. Malignant transformation has been 
      reported solely for HPV11-associated RRP in 2-4% of all RRP-cases, but not for 
      HPV6. The molecular mechanisms in the carcinogenesis of low risk HPV-associated 
      cancers are to date unknown. We report of a female patient, who presented with a 
      laryngeal carcinoma at the age of 24 years. She had a history of juvenile-onset 
      RRP with an onset at the age of three and subsequently several hundred surgical 
      interventions due to multiple recurrences of RRP. Polymerase chain reaction (PCR) 
      or bead-based hybridization followed by direct sequencing identified HPV6 in 
      tissue sections of previous papilloma and the carcinoma. P16(INK4A), p53 and pRb 
      immunostainings were negative in all lesions. HPV6 specific fluorescence in situ 
      hybridization (FISH) revealed nuclear staining suggesting episomal virus in the 
      papilloma and a single integration site in the carcinoma. Integration-specific 
      amplification of papillomavirus oncogene transcripts PCR (APOT-PCR) showed 
      integration in the aldo-keto reductase 1C3 gene (AKR1C3) on chromosome 10p15.1. 
      ArrayCGH detected loss of the other gene copy as part of a deletion at 
      10p14-p15.2. Western blot analysis and immunohistochemistry of the protein AKR1C3 
      showed a marked reduction of its expression in the carcinoma. In conclusion, we 
      identified a novel molecular mechanism underlying a first case of HPV6-associated 
      laryngeal carcinoma in juvenile-onset RRP, i.e. that HPV6 integration in the 
      AKR1C3 gene resulted in loss of its expression. Alterations of AKR1C gene 
      expression have previously been implicated in the tumorigenesis of other 
      (HPV-related) malignancies.
FAU - Huebbers, Christian Ulrich
AU  - Huebbers CU
AD  - Jean-Uhrmacher-Institute for Otorhinolaryngological Research, University of 
      Cologne, Cologne, Germany. christian.huebbers@uni-koeln.de
FAU - Preuss, Simon Florian
AU  - Preuss SF
FAU - Kolligs, Jutta
AU  - Kolligs J
FAU - Vent, Julia
AU  - Vent J
FAU - Stenner, Markus
AU  - Stenner M
FAU - Wieland, Ulrike
AU  - Wieland U
FAU - Silling, Steffi
AU  - Silling S
FAU - Drebber, Uta
AU  - Drebber U
FAU - Speel, Ernst-Jan M
AU  - Speel EJ
FAU - Klussmann, Jens Peter
AU  - Klussmann JP
LA  - eng
PT  - Case Reports
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130220
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Cyclin-Dependent Kinase Inhibitor p16)
RN  - 0 (Retinoblastoma Protein)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - EC 1.1.- (3-Hydroxysteroid Dehydrogenases)
RN  - EC 1.1.1.- (Hydroxyprostaglandin Dehydrogenases)
RN  - EC 1.1.1.357 (AKR1C3 protein, human)
RN  - EC 1.1.1.357 (Aldo-Keto Reductase Family 1 Member C3)
RN  - Laryngeal papillomatosis
SB  - IM
MH  - 3-Hydroxysteroid Dehydrogenases/*genetics
MH  - Adult
MH  - Age of Onset
MH  - Aldo-Keto Reductase Family 1 Member C3
MH  - Carcinoma/*genetics/pathology
MH  - Cell Transformation, Neoplastic/*genetics/pathology
MH  - Cyclin-Dependent Kinase Inhibitor p16/genetics
MH  - Down-Regulation
MH  - Fatal Outcome
MH  - Female
MH  - Human papillomavirus 6/*genetics/pathogenicity
MH  - Humans
MH  - Hydroxyprostaglandin Dehydrogenases/*genetics
MH  - Laryngeal Neoplasms/*genetics/pathology
MH  - Papilloma/*genetics/pathology
MH  - Retinoblastoma Protein/genetics
MH  - Tumor Suppressor Protein p53/genetics
PMC - PMC3577740
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2013/02/26 06:00
MHDA- 2013/08/07 06:00
PMCR- 2013/02/20
CRDT- 2013/02/26 06:00
PHST- 2012/06/28 00:00 [received]
PHST- 2013/01/21 00:00 [accepted]
PHST- 2013/02/26 06:00 [entrez]
PHST- 2013/02/26 06:00 [pubmed]
PHST- 2013/08/07 06:00 [medline]
PHST- 2013/02/20 00:00 [pmc-release]
AID - PONE-D-12-19430 [pii]
AID - 10.1371/journal.pone.0057207 [doi]
PST - ppublish
SO  - PLoS One. 2013;8(2):e57207. doi: 10.1371/journal.pone.0057207. Epub 2013 Feb 20.