RT Journal
A1 Porter, Vanessa L.
A1 Ng, Michelle
A1 O'Neill, Kieran
A1 MacLennan, Signe
A1 Corbett, Richard D.
A1 Culibrk, Luka
A1 Hamadeh, Zeid
A1 Iden, Marissa
A1 Schmidt, Rachel
A1 Tsaih, Shirng-Wern
A1 Nakisige, Carolyn
A1 Origa, Martin
A1 Orem, Jackson
A1 Chang, Glenn
A1 Fan, Jeremy
A1 Nip, Ka Ming
A1 Akbari, Vahid
A1 Chan, Simon K.
A1 Hopkins, James
A1 Moore, Richard A.
A1 Chuah, Eric
A1 Mungall, Karen L.
A1 Mungall, Andrew J.
A1 Birol, Inanc
A1 Jones, Steven J.M.
A1 Rader, Janet S.
A1 Marra, Marco A.
T1 Rearrangements of viral and human genomes at human papillomavirus integration events and their allele-specific impacts on cancer genome regulation
JF Genome Research 
JO Genome Research 
YR 2025 
FD April 01 
VO 35 
IS 4 
SP 653 
OP 670 
DO 10.1101/gr.279041.124 
UL http://genome.cshlp.org/content/35/4/653.abstract 
AB Human papillomavirus (HPV) integration has been implicated in transforming HPV infection into cancer. To resolve genome dysregulation associated with HPV integration, we performed Oxford Nanopore Technologies long-read sequencing on 72 cervical cancer genomes from a Ugandan data set that was previously characterized using short-read sequencing. We find recurrent structural rearrangement patterns at HPV integration events, which we categorize as del(etion)-like, dup(lication)-like, translocation, multi-breakpoint, or repeat region integrations. Integrations involving amplified HPV–human concatemers, particularly multi-breakpoint events, frequently harbor heterogeneous forms and copy numbers of the viral genome. Transcriptionally active integrants are characterized by unmethylated regions in both the viral and human genomes downstream from the viral transcription start site, resulting in HPV–human fusion transcripts. In contrast, integrants without evidence of expression lack consistent methylation patterns. Furthermore, whereas transcriptional dysregulation is limited to genes within 200 kb of an HPV integrant, dysregulation of the human epigenome in the form of allelic differentially methylated regions affects megabase expanses of the genome, irrespective of the integrant's transcriptional status. By elucidating the structural, epigenetic, and allele-specific impacts of HPV integration, we provide insight into the role of integrated HPV in cervical cancer.