Integrated Papillomavirus DNA in HPV-induced Carcinomas and Precancerous Lesions as Biomarker

The large family of human papillomaviruses (HPV) includes high-risk types which cause cancer of the uterine cervix (cervical cancer; the third most common cancer in women worldwide) and other malignant tumors. HPV16 is the most common and most carcinogenic high-risk HPV, followed by HPV18. HPV-induced oropharyngeal carcinomas harbor almost exclusively HPV16.

HPV-induced carcinogenesis is a multistep process of accumulating genetic changes, initiated by persistent infection of the epithelial cells with high-risk HPV, followed by the development of precancerous lesions and eventual progression to invasive carcinoma. A frequent mutation is the integration of HPV DNA into the host cell genome. The circular structure of the HPV genome is disrupted thereby abrogating the production of infectious viral particles. HPV integration leads to inactivation of the viral regulatory gene E2 and to constitutive expression of the HPV oncogenes E6 and E7. Transcription of the integrated HPV oncogenes results in viral-cellular hybrid transcripts. Insertional mutagenesis of cellular cancer-associated genes by HPV integration might additionally promote carcinogenesis.

Since HPV integration occurs into different chromosomal regions, and the integrated HPV genomes have different breakpoints at their 5’ and 3’ junctions, the junction sequences of integrated HPV DNA and cellular target sites are highly specific genomic markers for each tumor. Recently, we have developed an innovative approach for the multiplex identification of HPV16 integration sites in multiple tumors employing high-throughput DNA sequencing and data processing (TEN16: Tagging, Enrichment and Next-Generation Sequencing of HPV16). The candidate viral-cellular junction sequences are validated by PCR analysis of the tumor samples. In various cooperation projects, we apply the TEN16 approach for HPV16 integration analysis of cervical carcinomas, cervical precancerous lesions and oropharyngeal carcinomas. This will open new possibilities to exploit the viral-cellular junction sequences as individualized biomarkers for early detection and prediction of progression of precancerous lesions as well as for early detection of residual and recurrent disease after cancer treatment.

Selected Publication:

Xu B, Chotewutmontri S, Wolf S, Schmitz M, Dürst M, Schwarz E (2013). Multiplex identification of human papillomavirus 16 DNA integration sites in cervical carcinomas. PLoS ONE, 8(6):e66693.

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