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Project description:

Cancer of the uterine cervix (cervical cancer) is the second most common cancer in women worldwide. This cancer type is induced by persistent infection with human papillomavirus (HPV), in particular with high-risk types like HPV16 and HPV18. An important step in the multistep development of cervical cancer is the integration of HPV DNA into the host cell genome. In this process the circular structure of the HPV genome is destroyed thereby abrogating the production of infectious viral particles. HPV integration provokes inactivation of the viral regulatory gene E2 and thereby induces constitutive expression of the HPV oncogenes E6 and E7. Transcription from the integrated HPV genome results in viral-cellular hybrid transcripts which contain the viral oncogenes E6 and E7 in the 5’-terminal viral part and cellular sequences in the 3’-part. Since HPV integration affects different chromosomal regions, the junction sequences of integrated HPV DNA and cellular target sites are highly specific genomic markers for each tumor. HPV integration can also result in insertional mutagenesis of cellular cancer-associated genes which will additionally promote carcinogenesis.

In our projects we investigate HPV integration as risk and progression marker and as important step in HPV-induced carcinogenesis. Our work is performed as part of a cooperation project with French research groups of Cancéropôle du Grand-Est. We have developed an innovative strategy for HPV16 integration analysis employing novel methods for genome amplification and DNA sequencing. This strategy permits the determination of HPV16 integration sites of many clinical samples in a single sequencing run. The determination of viral and cellular integration sites will contribute to comprehend the role of HPV integration and insertional mutagenesis of cellular cancer genes in cervical carcinogenesis and to identify lesions of highly advanced or progressive disease.