Clonal expansion and HPV-induced immortalization are early molecular alterations in cervical carcinogenesis.
BACKGROUND
Monoclonality, a hallmark of most neoplasias, is found in high-grade squamous intraepithelial lesions (Hi-SIL) and some low-grade SILs (Lo-SIL). The transforming genes E6/E7 of HPV 16 have been shown to induce telomerase activity and immortalization. We investigated the role of immortalization in monoclonal and polyclonal SILs.


METHODS
Telomerase RNA (hTR) and HPV 16 E6/E7 were investigated in 45 Lo-, 33 Hi-SILs and 11 cervical carcinomas (SCC) by RNA/RNA in situ hybridization. Clonality in this series has been described previously.


RESULTS
Expression of hTR and viral oncogenes correlated significantly with the histological severity of the lesion (p < 0.001). Intense focal up-regulation of hTR was found in 14 out of 22 monoclonal Hi-SILs, 4 out of 20 monoclonal Lo-SILs but only 1 out of 15 polyclonal Lo-SIL. HPV 16 E6/E7 expression was detected in 20 out of 22 monoclonal Hi-SILs but only in 5 out of 21 monoclonal Lo-SILs.


CONCLUSIONS
Monoclonal expansion and immortalization are early alterations predominantly found in SCC and Hi-SILs, but also in a subset of Lo-SILs.
Park
Tjoung-Won
TW
Department of Obstetrics and Gynaecology, University of Bonn, Bonn 53105. park@uke.uni-hamburg.de
Riethdorf
Sabine
S
Schulz
Gudrun
G
Riethdorf
Lutz
L
Wright
Thomas
T
Löning
Thomas
T
D002472:Cell Transformation, Viral / Q000502:physiology*; D002999:Clone Cells; D004279:DNA, Viral / Q000235:genetics; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015967:Gene Expression Regulation, Viral; D005814:Genes, Viral; D006801:Humans; D017403:In Situ Hybridization; D009856:Oncogene Proteins, Viral / Q000235:genetics; D027383:Papillomaviridae / Q000235:genetics*; D050725:Papillomavirus E7 Proteins; D016133:Polymerase Chain Reaction; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D012097:Repressor Proteins; D019098:Telomerase / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation; D002583:Uterine Cervical Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology* / Q000821:virology*; D002578:Uterine Cervical Dysplasia / Q000201:enzymology / Q000235:genetics / Q000473:pathology* / Q000821:virology*
D004279:DNA, Viral; C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012334:RNA, Neoplasm; D012097:Repressor Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; D019098:Telomerase