title: Integration of HPV6 and downregulation of AKR1C3 expression mark malignant transformation in a patient with juvenile-onset laryngeal papillomatosis.
abstract: 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.
authors: Jean-Uhrmacher-Institute for Otorhinolaryngological Research, University of Cologne, Cologne, Germany. christian.huebbers@uni-koeln.de
authors: Christian Ulrich
authors: CU
authors: Huebbers
authors: Simon Florian
authors: SF
authors: Preuss
authors: Jutta
authors: J
authors: Kolligs
authors: Julia
authors: J
authors: Vent
authors: Markus
authors: M
authors: Stenner
authors: Ulrike
authors: U
authors: Wieland
authors: Steffi
authors: S
authors: Silling
authors: Uta
authors: U
authors: Drebber
authors: Ernst-Jan M
authors: EJ
authors: Speel
authors: Jens Peter
authors: JP
authors: Klussmann
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000235:genetics*; D000328:Adult; D017668:Age of Onset; D000074425:Aldo-Keto Reductase Family 1 Member C3; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D015536:Down-Regulation; D017809:Fatal Outcome; D005260:Female; D052163:Human papillomavirus 6 / Q000235:genetics* / Q000472:pathogenicity; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000235:genetics*; D007822:Laryngeal Neoplasms / Q000235:genetics* / Q000473:pathology; D010212:Papilloma / Q000235:genetics* / Q000473:pathology; D016160:Retinoblastoma Protein / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D015096:3-Hydroxysteroid Dehydrogenases; D006911:Hydroxyprostaglandin Dehydrogenases; C487341:AKR1C3 protein, human; D000074425:Aldo-Keto Reductase Family 1 Member C3