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The Majority of Viral-Cellular Fusion Transcripts in Cervical Carcinomas Cotranscribe Cellular Sequences of Known or Predicted Genes

¹ Institute of Pathology, Rikshospitalet University Hospital; ² Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo, Norway; ³ NorChip AS, Klokkarstua, Norway; ⁴ Gynäkologische Molekularbiologie, Frauenklinik der Friedrich-Schiller-Universität, Jena, Germany; ⁵ Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany; and ⁶ Frauenklinik mit Hochschulambulanz der Charité, Campus Benjamin Franklin und Campus Mitte, Berlin, Germany

Requests for reprints: Matthias Dürst, Gynäkologische Molekularbiologie, Frauenklinik der Friedrich-Schiller-Universität, Bachstrasse 18, 07743 Jena, Germany. Phone: 49-3641-933720; Fax: 49-3641-934272; E-mail: matthias.duerst{at}med.uni-jena.de.

Key Words: cervical cancer • human papillomavirus • integration • fusion transcripts • fragile sites

Integration of human papillomavirus (HPV) DNA into the host genome is a frequent event in cervical carcinogenesis and is reported to occur at randomly selected chromosomal sites. However, as the databases are being up-dated continuously, the knowledge based on sequenced viral integration sites also expands. In this study, viral-cellular fusion transcripts of a preselected group of 74 cervical carcinoma or cervical intraepithelial neoplasia grade 3 (CIN3) biopsies harboring integrated HPV16, HPV18, HPV31, HPV33, or HPV45 DNA were amplified by 3'-rapid amplification of cDNA ends PCR and sequenced. Consistent with previous reports, integration sites were found to be distributed throughout the genome. However, 23% (17 of 74) of the integration sites were located within the cytogenetic bands 4q13.3, 8q24.21, 13q22.1, and 17q21, in clusters ranging from 86 to 900 kb. Of note is that clusters 8q24.21 and 13q22.1 are within 1.5 Mbp of an adjacent fragile site whereas clusters 4q13.3 and 17q21 are >15 Mbp distant to any known fragile sites. It is tempting to speculate that as yet unknown fragile sites may be identified on the basis of HPV integration hotspots. No correlation between HPV type and specific integration loci was found. Of 74 fusion transcripts, 28 contained cellular sequences, which were homologous to known genes, and 40 samples contained sequences of predicted genes. In 33 fusion transcripts, both viral and cellular sequences were in sense orientation, indicating that the gene itself or upstream sequences were affected by integration. These data suggest that the influence of HPV integration on host gene expression may not be a rare effect and should encourage more detailed analyses. [Cancer Res 2008;68(7):2514–22]