<p>HPV16 is the most oncogenic type of human papillomaviruses (HPV). Integration of HPV into the human genome is an important mechanism of carcinogenesis but is absent in at least 30% of HPV16+ tumors. We applied long-read whole-genome sequencing (WGS) to cervical cancer cell lines and tumors to characterize HPV16 carcinogenesis in the absence of integration. WGS of HPV16+ cervical tumor samples from Latin America revealed that 11/20 tumors with only episomal HPV (EP) had intact monomer episomes. The remaining 9 EP tumors had multimer and rearranged HPV genomes. The majority (80%) of the HPV rearrangements and deletions disrupted the <a href="https://www.ncbi.nlm.nih.gov/gene/1489075">E1 </a>and <a href="https://www.ncbi.nlm.nih.gov/gene/1489080">E2</a> genes, and EP tumors overexpressed the <a href="https://www.ncbi.nlm.nih.gov/gene/1489078">E6</a> and <a href="https://www.ncbi.nlm.nih.gov/gene/1489079">E7</a> viral oncogenes, a similar profile to tumors with HPV integration. Tumors with putative multimer HPV integrations display HPV multimers and concatemers of human and viral sequences. Our data uncovered a novel mechanism for HPV16 to cause cancer without integration through aberrant episomal replication, and forming rearranged, mutated, and multimer episomes.</p>

Genetic Analysis of Latin American Cervical Cancer

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