Merkel cell polyomavirus

Merkel cell polyomavirus
Virus classification
Group: Group I (dsDNA) Family: Polyomaviridae Genus: Polyomavirus Species: Merkel cell polyomavirus

Merkel cell polyomavirus (MCV or MCPyV) was first described in January 2008.^[1] It is the most recently discovered human polyomavirus, and may infect 15 to 25 percent of adults, or over 1 billion people.^[2] It is suspected to cause the majority of cases of Merkel cell carcinoma, a rare but aggressive form of skin cancer. Approximately 80% of Merkel cell carcinoma tumors have been found to be infected with MCV. MCV is one of seven known human tumor viruses.

1 Classification 2 Viral etiology for Merkel cell carcinoma 3 Discovery and characterization of MCV 4 Prevention, diagnosis, and treatment 5 References 6 External links

Polyomaviruses are small (~5400 base pair), non-enveloped, double-stranded DNA viruses. MCV is the fifth polyomavirus that infects humans to be discovered. It belongs to the murine polyomavirus group, one of the three main clades of polyomaviruses.^[1] (The group is named for murine polyomavirus, the earliest virus of the group to be discovered, and does not imply that MCV is transmitted to humans from rodents.) MCV is the only human polyomavirus discovered to date that does not fall within the SV40-like clade.^[1]

MCV is genetically most closely related to the African green monkey lymphotropic polyomavirus^[1] (formerly known as African green monkey lymphotropic papovavirus),^[3] which is consistent with MCV coevolving with human primates.

The prototype sequence of MCV has a 5387 base pair genome, and encodes characteristic polyomavirus genes including a large T antigen, small T antigen, VP1 and VP2/3 genes. MCV T antigen has similar features to the T antigens of other polyomaviruses, which are known oncoproteins, and is expressed in human tumors.^[1] The T antigen is a spliced gene that forms multiple different proteins depending on the splicing pattern. Both large T and small T antigen proteins can transform healthy cells into cancer cells by targeting tumor suppressor proteins, such as retinoblastoma protein. The large T antigen also possesses a helicase and a viral DNA replication origin binding motif that are needed for the virus to reproduce its own DNA.

Merkel cell carcinoma is a highly aggressive type of skin cancer that was first described by Cyril Toker in 1972 as "trabecular tumor of the skin".^[4] The cancer may derive from the microscopic Merkel cell nervous organ in the skin and viscera which is responsible for touch and pressure sensation. Based on its origin, the cancer cell type is called a neuroectodermal tumor. Although rare compared with other skin cancers, the incidence of Merkel cell carcinoma in the USA tripled between 1986 and 2001, to around 1400 cases per year.^[5]

Merkel cell carcinoma is mainly seen in older individuals.^[5] It is known to occur at increased frequency in people with immunodeficiency, including transplant recipients and people with AIDS,^[6][7] and this association suggests the possibility that a virus or other infectious agent might be involved in causing the cancer. Kaposi's sarcoma and Burkitt's lymphoma are examples of tumors known to have a viral etiology that occur at increased frequency in immunosuppressed people. Other factors associated with the development of this cancer include exposure to ultraviolet light.^[5]

Eight of 10 Merkel cell carcinoma tumors initially tested were found to be infected with MCV.^[1] In these tumors, the virus has integrated into the cancer cell genome and can no longer freely replicate. Recent studies from other laboratories have reproduced these findings: in one study 30 of 39 (77%) of Merkel cell tumors were MCV positive [1]; in another study, 45 of 53 (85%) Merkel cell tumors were positive.

The tumor is a "dead-end host" for MCV [2] . Normally, the virus exists as circular episome (or plasmid) within the cell and its DNA is packaged into viral capsids and transmitted to other cells. In tumors, the viral DNA has broken and become integrated into human DNA within the tumor, so that the virus is no longer transmissible. The integrated virus cannot be excised from the host cell and it must replicate as the host cell is replicated. Examination of infected tumors reveals that the majority have a clear monoclonal pattern, indicating that the virus integrated into a single cell before it began its cancerous expansion.^[1] For this reason, there is very strong evidence that MCV causes some, but not all, Merkel cell carcinomas. MCV can also be found in healthy tissues from people without Merkel cell carcinoma. While the precise prevalence of infection is unknown in humans, it is likely that most infections do not cause cancers.^[8]

Yuan Chang and Patrick S. Moore, who discovered Kaposi's sarcoma-associated herpesvirus in 1994,^[9] with colleagues at the University of Pittsburgh, USA, used the novel high-throughput sequencing technique of digital transcriptome subtraction (DTS)^[10] to search for the presence of a virus in Merkel cell tumors.^[1] In this method, all mRNAs from a tumor are converted into cDNAs and sequenced to a depth likely to sequence a viral cDNA if it is present. The sequences are then compared with the human genome and all human sequences are "subtracted" to leave a group of sequences that are most likely nonhuman. When this was performed on four cases of Merkel cell carcinoma, one cDNA was found that was similar to sequences of known polyomaviruses but clearly distinct enough that it could be shown to be a new virus.^[1] Genetic sequences from nearly 400,000 mRNAs were analyzed for the study.^[2] Once the virus was found, Feng and coworkers quickly determined that infected Merkel cell carcinomas have the virus in an integrated monoclonal pattern and only found 8-16% of tissues taken from patients without MCC were positive for the virus.

While the authors noted that it is "too early to tell" whether MCV is the cause of Merkel cell carcinoma, a growing body of evidence rapidly suggests that it does play a causal role in most Merkel cell carcinoma. The reasons why 20% of Merkel cell carcinoma are negative for the virus remain completely unknown but speculations include the possibility that "Merkel cell carcinoma" is actually two or more closely related cancers, only one of which is infected with MCV. Misdiagnosis of this difficult cancer may also account for some of the negative results. Only a very small proportion of people infected with the virus probably develop the cancer. At this time no test for the presence of the virus is generally available, nor would patients be advised to change their treatment based on knowledge of its presence. The authors will be enrolling MCC patients in research studies, but these are not likely to directly benefit participants.^[11] Merkel cell carcinoma is associated with exposure to ultraviolet (UV) light and to ionizing radiation. Reducing risk of UV exposure through sun screens is likely to reduce the risk of Merkel cell carcinoma as well as other skin cancers.

Moore has suggested that if his findings are confirmed, information about the virus could lead to a blood test or a vaccine that could improve the management of the disease or aid in prevention, much as the human papillomavirus vaccine can be used to prevent cervical cancer. Chang explained that study of the virus may assist in understanding other human cancers. "Once the virus integrates, it could express an oncoprotein, or it could knock out a gene that suppresses tumor growth. Either way, the results are bound to be interesting."^{[2] [12]}

• KSHV Laboratory: New pathogen discovery