Merkel cell polyomavirus
Encyclopedia
Merkel cell polyomavirus (MCV or MCPyV) was first described in January 2008. MCV is one of seven known human tumor viruses. It is suspected to cause the majority of cases of Merkel cell carcinoma
Merkel cell carcinoma
Merkel cell carcinoma Merkel cell carcinoma Merkel cell carcinoma (also known as a "Cutaneous apudoma," "Primary neuroendocrine carcinoma of the skin," "Primary small cell carcinoma of the skin," and "Trabecular carcinoma of the skin"...

, a rare but aggressive form of skin cancer
Skin cancer
Skin neoplasms are skin growths with differing causes and varying degrees of malignancy. The three most common malignant skin cancers are basal cell cancer, squamous cell cancer, and melanoma, each of which is named after the type of skin cell from which it arises...

. Approximately 80% of Merkel cell carcinoma (MCC) tumors have been found to be infected with MCV. MCV appears to be a common—if not universal—infection of older children and adults. It is found in respiratory secretions suggesting that it may be transmitted by a respiratory route. Most MCV viruses found in MCC tumors, however, have at least two mutations that render the virus nontransmissible: 1) The virus is integrated into the host genome in a monoclonal fashion and 2) The viral T antigen has truncation mutations that leave the T antigen unable to initiate DNA replication needed to propagate the virus.

Evidence that MCV is the cause of MCC tumors that are infected with the virus comes from studies in which oncoproteins from the virus are inhibited. Knock down of these viral proteins causes cells from MCV-positive MCC tumors to die whereas there is no effect on cells from tumors that are uninfected with the virus. This indicates that MCV is necessary to maintain the virus-positive tumor cells.

Classification

Polyomavirus
Polyomavirus
Polyomavirus is the sole genus of viruses within the family Polyomaviridæ. Murine polyomavirus was the first polyomavirus discovered by Ludwik Gross in 1953. Subsequently, many polyomaviruses have been found to infect birds and mammals...

es are small (~5400 base pair), non-enveloped
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...

, double-stranded DNA virus
DNA virus
A DNA virus is a virus that has DNA as its genetic material and replicates using a DNA-dependent DNA polymerase. The nucleic acid is usually double-stranded DNA but may also be single-stranded DNA . DNA viruses belong to either Group I or Group II of the Baltimore classification system for viruses...

es. MCV is the fifth polyomavirus that infects humans to be discovered. It belongs to the murine polyomavirus group, one of the three main clade
Clade
A clade is a group consisting of a species and all its descendants. In the terms of biological systematics, a clade is a single "branch" on the "tree of life". The idea that such a "natural group" of organisms should be grouped together and given a taxonomic name is central to biological...

s of polyomaviruses. (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
SV40
SV40 is an abbreviation for Simian vacuolating virus 40 or Simian virus 40, a polyomavirus that is found in both monkeys and humans...

-like clade.

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

The prototype sequence of MCV has a 5387 base pair genome, and encodes characteristic polyomavirus
Polyomavirus
Polyomavirus is the sole genus of viruses within the family Polyomaviridæ. Murine polyomavirus was the first polyomavirus discovered by Ludwik Gross in 1953. Subsequently, many polyomaviruses have been found to infect birds and mammals...

 genes including a large T antigen, small T antigen, VP1 and VP2/3 genes http://www.tumorvirology.pitt.edu/mcvrsch.html. MCV T antigen has similar features to the T antigens of other polyomaviruses, which are known oncoproteins
Oncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, they are often mutated or expressed at high levels.An oncogene is a gene found in the chromosomes of tumor cells whose activation is associated with the initial and continuing conversion of normal cells into cancer...

, and is expressed in human tumors. 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
Retinoblastoma protein
The retinoblastoma protein is a tumor suppressor protein that is dysfunctional in the majority types of cancer. One highly studied function of pRb is to prevent excessive cell growth by inhibiting cell cycle progression until a cell is ready to divide...

. The large T antigen also possesses a helicase
Helicase
Helicases are a class of enzymes vital to all living organisms. They are motor proteins that move directionally along a nucleic acid phosphodiester backbone, separating two annealed nucleic acid strands using energy derived from ATP hydrolysis.-Function:Many cellular processes Helicases are a...

 and a viral DNA replication origin binding motif that are needed for the virus to reproduce its own DNA.

Viral etiology for Merkel cell carcinoma

Merkel cell carcinoma
Merkel cell cancer
Merkel cell carcinoma Merkel cell carcinoma Merkel cell carcinoma (also known as a "Cutaneous apudoma," "Primary neuroendocrine carcinoma of the skin," "Primary small cell carcinoma of the skin," and "Trabecular carcinoma of the skin"...

 is a highly aggressive type of skin cancer
Skin cancer
Skin neoplasms are skin growths with differing causes and varying degrees of malignancy. The three most common malignant skin cancers are basal cell cancer, squamous cell cancer, and melanoma, each of which is named after the type of skin cell from which it arises...

 that was first described by Cyril Toker in 1972 as "trabecular tumor of the skin". The cancer may derive from the microscopic Merkel cell
Merkel cell
Merkel cells or Merkel-Ranvier cells are oval receptor cells found in the skin of vertebrates that have synaptic contacts with somatosensory afferents. They are associated with the sense of light touch discrimination of shapes and textures. They can turn malignant and form the skin tumor known as...

 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
Neuroectodermal tumor
A neuroectodermal tumor is a tumor of the central or peripheral nervous system.-See also:* Neuroendocrine tumors* Neuroectoderm* PNET* Medulloblastoma- External links :* entry in the public domain NCI Dictionary of Cancer Terms...

. 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.

Merkel cell carcinoma is mainly seen in older individuals. It is known to occur at increased frequency in people with immunodeficiency
Immunodeficiency
Immunodeficiency is a state in which the immune system's ability to fight infectious disease is compromised or entirely absent. Immunodeficiency may also decrease cancer immunosurveillance. Most cases of immunodeficiency are acquired but some people are born with defects in their immune system,...

, including transplant recipients
Organ transplant
Organ transplantation is the moving of an organ from one body to another or from a donor site on the patient's own body, for the purpose of replacing the recipient's damaged or absent organ. The emerging field of regenerative medicine is allowing scientists and engineers to create organs to be...

 and people with AIDS
AIDS
Acquired immune deficiency syndrome or acquired immunodeficiency syndrome is a disease of the human immune system caused by the human immunodeficiency virus...

, and this association suggests the possibility that a virus or other infectious agent might be involved in causing the cancer. Kaposi's sarcoma
Kaposi's sarcoma
Kaposi's sarcoma is a tumor caused by Human herpesvirus 8 , also known as Kaposi's sarcoma-associated herpesvirus . It was originally described by Moritz Kaposi , a Hungarian dermatologist practicing at the University of Vienna in 1872. It became more widely known as one of the AIDS defining...

 and Burkitt's lymphoma
Burkitt's lymphoma
Burkitt's lymphoma is a cancer of the lymphatic system...

 are examples of tumors known to have a viral etiology
Etiology
Etiology is the study of causation, or origination. The word is derived from the Greek , aitiologia, "giving a reason for" ....

 that occur at increased frequency in immunosuppressed people. Other factors associated with the development of this cancer include exposure to ultraviolet light.

Eight of 10 Merkel cell carcinoma tumors initially tested were found to be infected with MCV. 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; in another study, 45 of 53 (85%) Merkel cell tumors were positive.

Sequencing of the virus from Merkel cell cancers reveals that it has generally has tumor-specific mutations that truncate the MCV T antigen. These mutations (which are not found in native virus obtained from nontumor sites) eliminate the T antigen helicase, preventing the integrated virus from replicating independently from the host cancer cell. The tumor is a "dead-end host" for MCV. 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
Monoclonal
Monoclonal cells are defined as a group of cells produced from a single ancestral cell by repeated cellular replication. Thus they can be said to form a single "clone". The process of replication can occur in vivo, or may be stimulated in vitro for laboratory manipulations...

 pattern, indicating that the virus integrated into a single cell before it began its cancerous expansion. 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.

Prevention, diagnosis, and treatment

Persons who have Merkel cell carcinoma with this virus are not infectious to others and no infectious restrictions are warranted. The reasons for this are: 1) the virus in tumors is already mutated and no longer can be transmitted from tumors, and 2) most persons are already naturally exposed to this virus as children and young adults by other asymptomatic carriers.

Based on current data, prevention advice for MCC is similar to other skin cancers, such as avoiding sun burns and unnecessary sun exposure together with use of sun lotion. This may prevent mutations in the virus that increase risk for MCC among those already infected with MCV. Persons with immunosuppression (e.g., AIDS or transplant patients) are at higher risk for this cancer and may benefit from periodic skin examinations. Emergence of a painless lump that expands rapidly, especially among persons over age 50 or persons with immunosuppression, warrants examination by a physician. Biopsy of a Merkel cell tumor should readily provide a diagnosis and when caught early, has a good prognosis through standard treatment. At this time there are no vaccines or medications that can prevent MCV infection or prevent emergence of Merkel cell carcinoma.

Detection of the virus is still at a research phase and is generally not available as a clinical test. Detection of viral DNA is performed by PCR or by Southern blot
Southern blot
A Southern blot is a method routinely used in molecular biology for detection of a specific DNA sequence in DNA samples. Southern blotting combines transfer of electrophoresis-separated DNA fragments to a filter membrane and subsequent fragment detection by probe hybridization. The method is named...

. Caution is needed in interpreting results from PCR since it is prone to false-positive contamination and a substantial fraction of healthy skin samples may harbor low-level infection. Sequencing of the viral genome may determine whether or not tumor-specific mutations are present.

Antibodies have been developed to stain for T antigen in tumor tissues and appear to be specific for MCV-infected tumor cells. Blood tests have also been developed that show the majority of adults have been previously exposed to MCV and may continue to carry it as an asymptomatic infection.

Treatment guidelines do not differ for Merkel cell carcinoma infected with MCV or without MCV. A recent country-wide study from Finland suggests that MCV-positive tumors have a better prognosis than uninfected tumors (although this has not been found in other studies). If this is confirmed, routine detection of the virus may provide a future benefit for medical guidance. The virus itself is not known to be susceptible to current antiviral medications.

Discovery and characterization of MCV

Yuan Chang
Yuan Chang
Yuan Chang is an American virologist and pathologist who co-discovered Kaposi's sarcoma-associated herpesvirus and Merkel cell polyomavirus, two of the seven known human cancer viruses....

 and Patrick S. Moore
Patrick S. Moore
Patrick S. Moore is an American virologist and epidemiologist who co-discovered together with his wife, Yuan Chang, two different human viruses causing the AIDS-related cancer Kaposi's sarcoma and the skin cancer Merkel cell carcinoma...

, who discovered Kaposi's sarcoma-associated herpesvirus
Kaposi's sarcoma-associated herpesvirus
Kaposi's sarcoma-associated herpesvirus is one of seven currently known human cancer viruses, or oncoviruses. It is also the eighth human herpesvirus; its formal name according to the International Committee on Taxonomy of Viruses is HHV-8. Like other herpesviruses, its informal name is used...

 in 1994, with colleagues Huichen Feng and Masa Shuda at the University of Pittsburgh
University of Pittsburgh
The University of Pittsburgh, commonly referred to as Pitt, is a state-related research university located in Pittsburgh, Pennsylvania, United States. Founded as Pittsburgh Academy in 1787 on what was then the American frontier, Pitt is one of the oldest continuously chartered institutions of...

, USA, used the novel high-throughput sequencing technique of digital transcriptome subtraction (DTS)http://www.tumorvirology.pitt.edu/dts.html to search for the presence of a virus in Merkel cell tumors
Merkel cell cancer
Merkel cell carcinoma Merkel cell carcinoma Merkel cell carcinoma (also known as a "Cutaneous apudoma," "Primary neuroendocrine carcinoma of the skin," "Primary small cell carcinoma of the skin," and "Trabecular carcinoma of the skin"...

. 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. Genetic sequences from nearly 400,000 mRNAs were analyzed for the study. 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. This was quickly confirmed by studies of MCC patients from around the world, including evidence for monoclonal integration of the virus in these tumors.

MCV as a cause for Merkel cell carcinoma

While the original authors conservatively noted that it is "too early to tell" whether MCV is a cause of Merkel cell carcinoma, general scientific opinion now suggests that the virus causes most, but not all Merkel cell tumors. The virus is monoclonally integrated into the tumor when present, indicating that the proto-tumor cell was infected with the virus prior to its cancerous expansion. Mutations in the T antigen render the virus noninfectious, and therefore it is not a passenger virus that infected the tumor after the tumor had already started. Finally, the T antigen oncogene is expressed in all of the tumor cells and when it is inhibited ("knocked down" by RNAi
RNAI
RNAI is a non-coding RNA that is an antisense repressor of the replication of some E. coli plasmids, including ColE1. Plasmid replication is usually initiated by RNAII, which acts as a primer by binding to its template DNA. The complementary RNAI binds RNAII prohibiting it from its initiation role...

), MCV-positive cells die. Thus, the virus is required for MCV-positive tumors to grow. It is likely that additional host cell mutations act in concert with the integrated virus to actually cause the tumor. Merkel cell carcinoma is associated with exposure to ultraviolet (UV) light and to ionizing radiation, and it is likely that these mutagens increase the rate of mutation in either the virus or the Merkel cell genome, contributing to the risk for cancer after infection.

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 MCV 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 MCV infection status. MCC patients can be enrolled in research studies, but these are not likely to directly benefit participants. 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
Cervical cancer
Cervical cancer is malignant neoplasm of the cervix uteri or cervical area. One of the most common symptoms is abnormal vaginal bleeding, but in some cases there may be no obvious symptoms until the cancer is in its advanced stages...

. 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."

External links

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