November 8, 2013
Cancer-Causing HPV Virus Directly Damages DNA
redOrbit Staff & Wire Reports - Your Universe Online
Human papillomavirus (HPV) can damage chromosomes and genes directly, researchers from the Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) report in a new study.
Writing in the journal Genome Research, OSUCCC assistant professor of molecular virology, immunology and medical genetics Dr. David Symer and his colleagues explain how they used whole-genome sequencing to investigate the relationship between the virus and host genomes in human cancer.
“Our sequencing data showed in vivid detail that HPV can damage host-cell genes and chromosomes at sites of viral insertion,” Symer explained. “HPV can act like a tornado hitting the genome, disrupting and rearranging nearby host-cell genes. This can lead to overexpression of cancer-causing genes in some cases, or it can disrupt protective tumor-suppressor genes in others. Both kinds of damage likely promote the development of cancer.”
“We observed fragments of the host-cell genome to be removed, rearranged or increased in number at sites of HPV insertion into the genome,” added co-senior author Dr. Maura Gillison, an epidemiology and otolaryngology professor and the Jeg Coughlin Chair of Cancer Research at OSUCCC. “These remarkable changes in host genes were accompanied by increases in the number of HPV copies in the host cell, thereby also increasing the expression of viral E6 and E7, the cancer-promoting genes.”
HPV is said to be responsible for over 600,000 cases of cancer worldwide each year, including nearly all instances of cervical cancer. However, the method by which it does so remains unclear. While the cancer-causing E6 and E7 proteins play the “critically important” role of silencing a pair of tumor-suppressing genes in host cells, Gillison explained that her team’s research provides new insight into how the virus can actually alter the structure of host genes and chromosomes in order to contribute to cancer development.
As part of their research, the OSUCCC investigators studied 10 cancer-cell lines and two head and neck tumor samples obtained from patients. In addition to whole-genome sequencing, they used RNA sequencing, spectral karyotyping (SKY), fluorescence in situ hybridization (FISH) and other molecular assays.
The genome-wide study at single nucleotide resolution identified “a striking and recurrent association between HPV integrants and adjacent genomic amplifications, deletions and translocations,” OSU officials explained. Furthermore, the study authors found that “the HPV integrants mapped broadly across the human genome, with no evidence of recurrent integration into particular chromosomal hotspots.”
Following their analysis, the researchers proposed what they refer to as a “looping” model, through which abnormal viral replication causes damage to occur in host chromosomes at the point of viral DNA insertion. Experts from the National Cancer Institute (NCI), Massachusetts General Hospital and Harvard Medical School were also involved in the research.
“Our study reveals new and interesting information about what happens to HPV in the 'end game' in cancers,” Symer said. “Overall, our results shed new light on the potentially critical, catastrophic steps in the progression from initial viral infection to development of an HPV-associated cancer.”