Virus May Cause Aggressive Merkel Cell Skin Cancer

By Crystal Phend
PITTSBURGH, Jan. 17 - The rare and often-deadly Merkel cell carcinoma may be induced by a polyomavirus, researchers here reported. DNA sequences of the newly discovered Merkel cell polyomavirus were detected in 80% of tumors but only 8% to 16% of controls, reported Patrick S. Moore, M.D., M.P.H., of the University of Pittsburgh, and colleagues online in Science."It's integrated in such a way that it looks like it was present before the tumor actually started growing," Dr. Moore said. "That at least gives us some evidence that the virus may play a role in this tumor."Merkel cell carcinoma is a neuroectodermal tumor arising from mechanoreceptor Merkel cells. Merkel cell carcinoma is the most aggressive form of skin cancer, and about half of advanced cases survive no more than nine months. There are about 1,500 cases in the United States a year, with frequency weighted toward immunosuppressed transplant and AIDS patients, similar to Kaposi's sarcoma.
The polyomavirus is very strongly associated with Merkel cell carcinoma, said Dr. Moore, but the causal role is not established.
This would be the second oncovirus discovered by the research group, which also uncovered Kaposi's sarcoma-associated herpesvirus in 1993, and if confirmed, would be the eighth human tumor virus found over the past 40 years.
"Because it's an immune-related tumor, we thought there's a good possibility that there might be a directly transforming tumor virus in this tumor that we could search for," Dr. Moore said.
Over the course of nearly a decade, he and colleagues sequenced the cancer's transcriptome, sequencing the RNA from the tumor, and then using their digital transcriptome subtraction technique to subtract all the sequences common to the human genome. This left a relatively small pool of candidate viral sequences.
Two sequences identified a virus similar to African green monkey lymphotropic polyomavirus and to human BK polyomavirus T antigen sequences.
Tissue samples from Merkel cell carcinoma tumors of 10 patients were compared with control samples from skin and other tissues from 59 patients without skin cancer and from skin and other skin tumor types from 25 immunocompetent and immunosuppressed patients.
Eight of the 10 Merkel cell cancer samples tested positive for the virus sequences.
Five gastrointestinal tract tissues among the 59 control tissues (8%, P<0.0001) were weakly positive for the virus as were four of the 25 (16%, P=0.0007) additional skin and non-Merkel skin tumor samples from immunocompetent and immunosuppressed patients.
The researchers confirmed that this virus was integrated into the tumor DNA. The pattern of integration indicated the virus had integrated at several chromosomal sites prior to clonal tumor growth, suggesting it was possible the virus caused the cancer, the researchers said.
"Merkel cell polyomavirus in Merkel cell carcinoma may have some parallels to high-risk human papillomavirus," they wrote, "which causes cervical cancer mainly after viral episome disruption and integration into the cervical epithelial cell genome."
Like HPV, it's likely that few people infected with the virus develop cancer, Dr. Moore said.
"We think that it is a common infection, meaning that perhaps something between 5% and 20% of people may harbor this infection," he said, "Only some cells are going to be infected and harboring this virus."
Mutation of the virus leading to integration into the Merkel cell genome would then further be required before the cell would be predisposed to cancer, he said.
The researchers said they also hope to apply their subtraction technique to other tumors that physicians have long suspected might have a viral etiology.
The researchers provided no information on conflicts of interest.
Primary source: ScienceSource reference:Feng H, et al "Clonal integration of a polyomavirus in human Merkel cell carcinoma" Science 2008; DOI: 10.1126/science.1152586.