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Cancer Cell Study Suggests Instability Around HPV Insertion Sites in Host Genome

NEW YORK (GenomeWeb News) – A study published online today in Genome Research is highlighting the havoc that human papillomavirus integration can wreak on nearby portions of the genome in infected cells.

An Ohio State University-led team used genome sequencing to characterize mutation patterns in a dozen cell lines and primary tumors representing not only HPV-positive cervical cancers, but also HPV-negative and -positive head and neck cancers. Results of the analysis revealed rampant structural changes, rearrangements, and/or mutations in parts of the genome neighboring HPV insertions — a pattern that the study's authors suspect may be partly due to "looping" interactions between viral and host DNA.

"HPV can act like a tornado hitting the genome, disrupting and rearranging nearby host-cell genes," co-corresponding author David Symer, a researcher with the Ohio State University Comprehensive Cancer Center, said in a statement.

"This can lead to over-expression of cancer-causing genes in some cases, or it can disrupt protective tumor-suppressor genes in others," Symer said. "Both kinds of damage likely promote the development of cancer."

An estimated 5 percent of human cancers can be traced back to HPV infections, Symer and his colleagues noted. But while the virus is particularly common in cervical cancers, a growing number of head, neck, and other tumors have been turning up HPV-positive in recent years as well, underscoring the importance of untangling HPV interactions with the human genome.

Past studies indicate that the HPV proteins E6 and E7 contribute to cancer development by interfering with the function of tumor suppressor genes such as TP53. Even so, the nature and extent of the genomic alterations associated with HPV infection, including those leading to cancer, have not been fully defined.

In an effort to more clearly unravel cancer-related interactions between HPV and host DNA, Symer and his colleagues used Illumina's HiSeq 2000 to sequence genomic DNA from 10 cell lines: two HPV16-positive cervical cancer cell lines, five head and neck squamous cell carcinoma lines that were positive for HPV16, and three HPV-free HNSCC lines.

To that, the team added genome sequence data for two primary HNSCC tumors infected with HPV16 or HPV18, along with RNA sequencing profiles, spectral karyotyping patterns, and fluorescence in situ hybridization information.

From this data, the group focused in on genetic alterations that appeared to stem from viral integration — the process that occurs as viruses go from replicating on their own in human cells to tucking themselves into the host genome.

In addition to finding insertional breakpoints in the HPV-positive cell lines and tumors, for instance, investigators looked at the impact that such insertions had on both viral and host sequences and their expression.

In samples with many copies of the HPV genome, researchers detected a range of nearby variations in the host genome — from translocations and inversions to amplifications and deletions.

"We observed fragments of the host-cell genome to be removed, rearranged, or increased in number at sites of HPV insertion into the genome," co-corresponding author Maura Gillison, a viral oncology researcher and chair of cancer research with the OSUCCC, said in a statement.

Though additional research is needed to continue teasing apart such processes, the team speculated that the structural changes associated with HPV integration may be due to viral interactions between bits of sequence spanning different parts of the host genome.

This so-called looping model "provides a framework to understand how HPV integrants could become flanked by neighboring CNVs in human cancers," study authors noted.

"Studies are ongoing to extend this looping model to additional HPV-associated primary tumors … and to evaluate the significance of these genomic alterations for cervical cancer progression, targeted therapeutics, and patient outcomes," they concluded.

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