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Mayo Team Turns to NGS Method to Understand Role of HPV in Cancer

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NEW YORK (GenomeWeb) – The human papillomavirus is known to play a role in the development of cervical cancer, but increasingly the virus is being found in individuals that develop other types of cancer, including head and neck as well as the whole spectrum of anogenital cancers.

Although HPV has been found to be associated with such cancers, its role in progression, aggressiveness, and prognosis remains largely unknown. In addition, whether the virus manifests itself in the same way for the various cancer types is also unknown.

Researchers from the Mayo Clinic have now begun using a next-generation sequencing method, called mate-pair sequencing, or MP-seq, that could cost-effectively shed light on the role of HPV in these cancer types and lead to better prognostics and decision making for patient management, David Smith, professor of laboratory medicine and pathology and co-author of a recent review published in the journal Viruses, told GenomeWeb.

"If you can look at a cancer and determine where the virus is integrated, you may begin to be able to tell if that cancer is going to be aggressive or not" and make a decision on how to treat that patient, he said.

Understanding HPV's role in cancer etiology could have implications for a range of cancers, but Smith said his group is especially focused on oropharyngeal cancers. The rate of cervical cancer has been declining because of vaccines, and the rate of most head and neck cancers has been declining because fewer people smoke, but the incidence of one subset — oropharyngeal cancer — has been increasing, he said. In addition, the frequency of oropharyngeal cancer patients at Mayo that are HPV positive has increased to 80 percent from less than 20 percent over the past several decades.

Viral integration is "probably really important," Smith said, adding that with the advancement of NGS technology, it is now possible to look at these events in closer detail.

Smith's group is employing MP-seq, a low-pass sequencing strategy being developed by another group at Mayo, led by George Vasmatzis, co-director of the Mayo's biomarker discovery program. Vasmatzis' group is developing MP-seq to eventually offer as a clinical test.

In essence, MP-seq involves circularizing fragments of DNA around 5 kb long and adding a biotin at the junction. The circularized DNA is fragmented and sequenced at low coverage, and the biotin-labeled ends can be used to provide information about the entire 5-kb fragment.

The strategy does not yield nucleotide-resolution information, but instead provides genome-wide information. Vasmatzis' group is focused on using MP-seq to identify rearrangements, with the idea being that the DNA fragment will be long enough to span the breakpoint, but Smith said it can also be applied to identify viral integration sites.

One genome can be sequenced via MP-seq for around $500.

Last year, Smith's team applied MP-seq to 20 oropharyngeal cancer patients, 13 of which were positive for HPV16. That initial study demonstrated that HPV likely plays a different role in oropharyngeal cancers than it does in cervical cancers. For instance, in cervical cancer, HPV is typically integrated into the patient's genome. However, in the 13 HPV16-positive oropharyngeal patients, Smith's team found that the virus was only integrated into the genomes of two patients, although one patient who was negative for HPV16 was found to have HPV26 integration.

Aside from identifying HPV integration sites, MP-seq also identified inter- and intra-chromosome translocations as well as copy number changes. Smith said the team is now studying whether there are any relationships between viral integration and translocations, and how those impact patient outcome.

Currently, said Smith, most of what is known about HPV and cancer is based on studies of cervical cancer. But better technology is changing researchers' understanding of HPV's role in both cervical cancer and also finding out that it may have a very different role in other cancers, he said. For instance, researchers previously assumed that HPV integration occurred at random spots in the genome; however, genomic hotspots have been found in cervical cancer. In addition, the HPV integration site likely matters in terms of the cancer's progression.

For instance, when the whole genome of HeLa cells was sequenced, HPV integration was found in the vicinity of known oncogene c-myc, and caused increased expression of that gene, which may in part help to explain why Henrietta Lacks suffered from such an aggressive form of cancer, Smith said.

Knowing whether, where, and how often the virus has integrated could determine how aggressive a cancer will be, Smith said. "Preliminary studies suggest that the more insertions and the more rearrangements [there are] …  those tend to be the patients that recur," he said.

In the future, Smith said MP-seq could be a replacement for array CGH. "It is super high resolution," and identifies "important information about changes in the genome." If it is done on enough patients, "we'll begin to get a true signature" in terms of how specific genomic changes correlate with cancer etiology and patient outcomes.

Although the same information and much more could be identified through whole-genome sequencing, MP-seq has the advantage of being less expensive, less complicated to interpret, and producing less data. At Mayo, patient test data must be stored for 20 years, Smith said. MP-seq produces much less data so is much less expensive to store.

"It's a simpler way to characterize the genome," Smith said. "You don't get base-pair resolution, but you do get a lot of information about what's happening to the genome, including actionable things that you can potentially make clinical decisions on at a really decent price point."

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