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Researchers piece together how virus causes human cancers

Human papillomavirus (HPV) is the culprit in about 5% of all cancers, including almost all cervical cancers and an increasing number of head and neck cancers. Having the virus, however, doesn't always mean you'll get cancer. In fact, how it causes cancer is still a bit of a mystery - one that doctors and scientists have long been working to unravel.

Human papillomavirus, seen in a colored transmission electron micrograph. Image courtesy Pasieka/SPL/Getty/Nature Publishing Group.

Most adults, over the course of their lifetimes, are infected by HPV. Fortunately, most never go on to develop cancer. HPV-associated cancers include almost all cervical cancers, as well as a very large number of head and neck, anal, vulvar, and other cancers. From the point of initial HPV infection to a resulting tumor, researchers believe that the process of forming a cancer can take approximately 15 to 30 years.

"The virus is pretty nefarious," says David Symer, an assistant professor in the Human Cancer Genetics Program at the Ohio State University Comprehensive Cancer Center in Columbus, US. "It makes proteins that knock out important human genes that normally would protect against cancers."

What we know is that HPV includes two viral genes that contribute to cancer formation. These well-known genes are called E6 and E7. While they are necessary for cancer formation, we also know that they can't cause cancer on their own. Symer and his colleagues are studying HPV-associated tumor DNA sequences to investigate what other genetic events are happening that also contribute to cancer formation.

The sequencing of the human genome just over a decade ago has provided Symer and his fellow researchers with a valuable asset. Using this sequence as their reference point, scientists can now study the mutations that occur in various cancers to figure out how a virus causes a cancer. The more they learn about HPV, the better chance they'll have of finding new and different genetic mutations that, in the future, could be promising targets for new treatments.

Symer. Image courtesy Ohio State University Comprehensive Cancer Center.

Symer and his colleagues, including Keiko Akagi, an expert in bioinformatics analysis at The Ohio State University in Columbus, US, have been using whole-genome sequencing to probe HPV's deepest secrets. Whole-genome sequencing determines the complete DNA sequence of an organism's genome. The researchers started with 10 cell lines, seven HPV-positive and three HPV-negative. They also studied two primary tumors that were HPV-positive. But genomes are vast, and the datasets generated by sequencing are massive. Their desktop computers were not up to the challenge. They needed something much, much bigger, so they called upon the Ohio Supercomputer Center (OSC) for help.

"We simply wouldn't have been able to do this analysis without a large cluster of high-performance computer units," Symer says. "Each genome is between half a terabyte and a terabyte in size, so just to store them would take a pretty big disk. To analyze them and run all the sophisticated applications and software needed to understand what's going on in the whole genome takes more space and more CPUs. We needed a cluster like what's at the Ohio Supercomputer Center."

Working with OSC's Oakley cluster, a powerful new system with a total peak performance of just over 154 teraFLOPS, Symer and his colleagues were able to observe what happens to the virus upon causing a cancer. Frequently, HPV can disrupt the human DNA sequence locally with repeating loops where the virus is inserted into host-cell DNA. In turn, this may result in the disruption of neighboring genes, which may also contribute to cancer formation.

"Our study reveals new and interesting information about what happens to HPV in the 'end game' in cancers," explains Symer. "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."

Huge strides have been made recently in preventing HPV-associated cancers. Vaccines for preteens have proven very effective. However, a substantial number of preteens are not being vaccinated. Also, the vaccines do not fully protect those who have already been exposed to the virus, which is still a very large portion of the world's population.

Further research is needed to determine what the virus does after infection and its role in causing cancers. The more we know about what HPV is doing in human cancers, the more chance we have of being able to help those who develop cancers caused by the virus.

Read more published research on this topic from Symer and his colleagues in Genome Research.

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