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UPitt Researchers Use Novel Transcriptome Screening Method to Uncover Potential Cancer-Causing Virus

NEW YORK (GenomeWeb News) – A newly found virus — identified using a novel sequence analysis approach — may play a role in the development of a rare but aggressive type of cancer, according to research published today.
Molecular virologists Patrick Moore and Yuan Chang, a husband and wife team from the University of Pittsburgh, led a group of researchers who used digital transcriptome subtraction to identify a new virus that is associated with — and may influence the development of — Merkel cell carcinoma, a rare skin cancer more often found in immunocompromised individuals. Their findings appear in the online edition of Science today.
“It’s an exciting and very interesting report,” Eric Engels, an epidemiologist with the National Cancer Institute who was not involved in the study, told GenomeWeb Daily News today. “If these results are validated, it could be a very important result.”
Merkel cell carcinoma is very rare. For example, a 2002 study from Engels’ group showing that the risk of MCC is roughly 13 times higher in AIDS patients only identified six cases of MCC in a cohort of more than 300,000 people. When present, though, it can become extremely aggressive.
Because MCC risk increases in immunocompromised individuals, researchers have long suspected that a virus or other infectious agent might be at the heart of MCC etiology. To investigate this, Moore and Chang’s team used DTS on sequence information derived from MCC tumors.
The group extracted RNA from four MCC tumors and used it to create a cDNA library. After honing the sequence data through successive subtractions to remove vector sequence, highly repetitive sequences, sequencing error, poly-A sequences, and so on, the group had a high-fidelity dataset, which they compared to human genome databases. Finally, known human sequences were eliminated, leaving a much smaller group of potentially viral sequences that were aligned against the NCBI sequence databases.
Using DTS, the researchers found two viral sequences in the MCC tumors that were similar to the African green monkey polyomavirus and the human BK polyomavirus, respectively. Overall though, the polyomavirus was distinct from known human viruses and the group dubbed it the Merkel cell carcinoma virus.
Interestingly, when the group did subsequent PCR analysis of ten MCC tumors they found MCV in approximately 80 percent of these tumors. In contrast, they detected MCV in only eight to 16 percent of control tissues.
The UPitt group has been developing DTS technology for nearly 10 years. With the improvements in sequencing technology in that time, the method has become much more efficient. And Moore said that while the approach is still expensive, the cost has gone down at least an order of magnitude.
“It’s a very boutique technique,” Moore told GenomeWeb, “because you can’t, obviously, do this on many, many, many different samples.” Moore’s group usually sequences at least 200,000 transcripts. But while identifying MCV virus, for instance, the group sequenced almost twice that many transcripts.
DTS is not just useful for identifying viral interlopers, though. Moore says the method also holds promise for ruling out viral infections, something that is difficult to do using traditional approaches such as PCR amplification. The group previously demonstrated the usefulness of DTS for not only finding viruses in some tumor cells, but also for quantifying — or at least putting an upper limit — on the number of viruses found in a cell.
“The technique, if done properly and if done exhaustively … you have a good possibility of excluding a viral infection,” Moore said.
Although Moore said there is “strong evidence that the virus was present prior to the development of the tumor,” more research is necessary to determine whether MCV causes MCC and, if so, how. Even so, the finding will likely stimulate a great deal of interest in everything from the virus’ mechanism of action to its transmission and frequency in the population.
“If this pans out, it opens up a whole new area for both lab research and epidemiology,” Engels said.

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