Merkel Cell Polyomavirus
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Merkel cell polyomavirus (MCV or MCPyV) was first described in January 2008 in
Pittsburgh, Pennsylvania Pittsburgh ( ) is a city in the Commonwealth (U.S. state), Commonwealth of Pennsylvania, United States, and the county seat of Allegheny County, Pennsylvania, Allegheny County. It is the most populous city in both Allegheny County and Wester ...
. It was the first example of a human viral pathogen discovered using unbiased
metagenomic Metagenomics is the study of genetic material recovered directly from environmental or clinical samples by a method called sequencing. The broad field may also be referred to as environmental genomics, ecogenomics, community genomics or microb ...
next-generation sequencing Massive parallel sequencing or massively parallel sequencing is any of several high-throughput approaches to DNA sequencing using the concept of massively parallel processing; it is also called next-generation sequencing (NGS) or second-generation s ...
with a technique called digital transcriptome subtraction. MCV is one of seven currently known human
oncovirus An oncovirus or oncogenic virus is a virus that can cause cancer. This term originated from studies of acutely transforming retroviruses in the 1950–60s, when the term "oncornaviruses" was used to denote their RNA virus origin. With the lette ...
es. It is suspected to cause the majority of cases of
Merkel cell carcinoma Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer occurring in about 3 people per 1,000,000 members of the population. It is also known as cutaneous APUDoma, Primary tumor, primary neuroendocrine tumor, neuroendocrine carcinoma of ...
, a rare but aggressive form of
skin cancer Skin cancers are cancers that arise from the skin. They are due to the development of abnormal cells that have the ability to invade or spread to other parts of the body. There are three main types of skin cancers: basal-cell skin cancer (BCC) ...
. 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. But it also can be found shedding from healthy skin, and in gastrointestinal tract tissues and elsewhere, and so its precise mode of transmission remains unknown. In addition, recent studies suggest that this virus may latently infect the human sera and
peripheral blood mononuclear cell A peripheral blood mononuclear cell (PBMC) is any peripheral blood cell having a round nucleus. These cells consist of lymphocytes (T cells, B cells, NK cells) and monocytes, whereas erythrocytes and platelets have no nuclei, and granulocytes ( ...
s. 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 and 2) The viral T
antigen In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...
has truncation mutations that leave the T antigen unable to initiate DNA replication needed to propagate the virus. Evidence that MCV is the cause for most MCC tumors comes from studies in which T antigen
oncoprotein An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.
s from the virus are inhibited. Knockdown 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. Further, clonal pattern of MCV insertions into MCC cell genomes indicates that the virus was present in the Merkel cell before it underwent cancerous transformation. The
IARC IARC may refer to: * International Aerial Robotics Competition * International Age Rating Coalition * International Agency for Research on Cancer * International Arctic Research Center * Israel Amateur Radio Club The Israel Amateur Radio Club (IA ...
has recently classified MCV as a class 2A carcinogen.


Classification

Polyomavirus ''Polyomaviridae'' is a family of viruses whose natural hosts are primarily mammals and birds. As of 2020, there are six recognized genera and 117 species, five of which are unassigned to a genus. 14 species are known to infect humans, while othe ...
es are small (~5400 base pair), non-enveloped, double-stranded
DNA virus A DNA virus is a virus that has a genome made of deoxyribonucleic acid (DNA) that is replicated by a DNA polymerase. They can be divided between those that have two strands of DNA in their genome, called double-stranded DNA (dsDNA) viruses, and ...
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 A clade (), also known as a monophyletic group or natural group, is a group of organisms that are monophyletic – that is, composed of a common ancestor and all its lineal descendants – on a phylogenetic tree. Rather than the English term, ...
s of polyomaviruses. (The group is named for
murine polyomavirus Murine polyomavirus (also known as mouse polyomavirus, ''Polyomavirus muris'', or ''Mus musculus'' polyomavirus 1, and in older literature as SE polyoma or parotid tumor virus; abbreviated MPyV) is an unenveloped double-stranded DNA virus of the ...
, the earliest virus of the group to be discovered, and does not imply that MCV is transmitted to humans from rodents.) Although it has been confused with the controversial
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 other polyomaviruses, SV40 is a DNA virus that has the potential to cause tumors in animals, but most often ...
virus in some blog postings, it is a completely distinct virus. 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 double-stranded DNA (dsDNA) genome and encodes characteristic
polyomavirus ''Polyomaviridae'' is a family of viruses whose natural hosts are primarily mammals and birds. As of 2020, there are six recognized genera and 117 species, five of which are unassigned to a genus. 14 species are known to infect humans, while othe ...
genes from opposite strands including a large T antigen, a small T antigen (LT and sT, respectively, from early strand) and viral capsid proteins VP1 and VP2/3 genes (from late strand)
Our Viruses - MCV
MCV T antigen has similar features to the T antigens of other polyomaviruses, which are known
oncoproteins An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.
, 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 oncoproteins are probably needed to transform healthy cells into cancer cells, and they act by targeting
tumor suppressor A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or red ...
proteins, such as
retinoblastoma protein The retinoblastoma protein (protein name abbreviated pRb; gene name abbreviated ''Rb'', ''RB'' or ''RB1'') is a proto-oncogenic tumor suppressor protein that is dysfunctional in several major cancers. One function of pRb is to prevent excessive ...
. The LT antigen possesses a
helicase Helicases are a class of enzymes thought to be vital to all organisms. Their main function is to unpack an organism's genetic material. Helicases are motor proteins that move directionally along a nucleic acid phosphodiester backbone, separatin ...
motif needed for virus replication that is deleted in MCC tumors. Unlike for other polyomaviruses, MCV sT antigen transforms cells in vitro by activating
cap-dependent translation Eukaryotic translation is the biological process by which messenger RNA is translated into proteins in eukaryotes. It consists of four phases: gene translation, elongation, termination, and recapping. Initiation Translation initiation is the p ...
. MCV also expresses a microRNA (miRNA) known as MCV-miR-M1 from its late strand which bears perfect complementarity to LT and has been shown to negatively regulate LT expression . In addition to its role in regulating MCV LT expression and DNA replication, MCV-miR-M1 has been shown to directly target and downregulate the expression of host cell immune related transcript SP100 and its role in the establishment of long-term persistent infection has been demonstrated in vitro.


Viral cause for Merkel cell carcinoma

Merkel cell carcinoma Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer occurring in about 3 people per 1,000,000 members of the population. It is also known as cutaneous APUDoma, Primary tumor, primary neuroendocrine tumor, neuroendocrine carcinoma of ...
is a highly aggressive type of
skin cancer Skin cancers are cancers that arise from the skin. They are due to the development of abnormal cells that have the ability to invade or spread to other parts of the body. There are three main types of skin cancers: basal-cell skin cancer (BCC) ...
that was first described by Cyril Toker in 1972 as "trabecular tumor of the skin". 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 United States 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, also known as immunocompromisation, is a state in which the immune system's ability to fight infectious diseases and cancer is compromised or entirely absent. Most cases are acquired ("secondary") due to extrinsic factors that a ...
, including transplant recipients and people with
AIDS Human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS) is a spectrum of conditions caused by infection with the human immunodeficiency virus (HIV), a retrovirus. Following initial infection an individual m ...
, 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 (KS) is a type of cancer that can form masses in the skin, in lymph nodes, in the mouth, or in other organs. The skin lesions are usually painless, purple and may be flat or raised. Lesions can occur singly, multiply in a limite ...
and
Burkitt's lymphoma Burkitt lymphoma is a cancer of the lymphatic system, particularly B lymphocytes found in the germinal center. It is named after Denis Parsons Burkitt, the Irish surgeon who first described the disease in 1958 while working in equatorial Africa. ...
are examples of tumors known to have a viral
etiology Etiology (pronounced ; alternatively: aetiology or ætiology) is the study of causation or origination. The word is derived from the Greek (''aitiología'') "giving a reason for" (, ''aitía'', "cause"); and ('' -logía''). More completely, e ...
that occur at increased frequency in immunosuppressed people. Other factors associated with the development of this cancer include exposure to
ultraviolet light Ultraviolet (UV) is a form of electromagnetic radiation with wavelength from 10 nm (with a corresponding frequency around 30  PHz) to 400 nm (750  THz), shorter than that of visible light, but longer than X-rays. UV radiation i ...
. 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 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 therefore 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 Monoclonality refers to the state of a line of cells that have been derived from a single clonal origin. Thus "monoclonal cells" can be said to form a single clone. The term ''monoclonal'' comes from the Ancient Greek ''monos'', meaning "alone" o ...
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. A complete MCV genome (MCV-HF) was designed from multiple tumor-type MCV genomes and examined with successful replication capability in vitro. The identical sequences were found in human normal skins. 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 sunburns 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 organ 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. 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. Recent studies reveal that the
survivin Survivin, also called baculoviral inhibitor of apoptosis repeat-containing 5 or BIRC5, is a protein that, in humans, is encoded by the ''BIRC5'' gene. Survivin is a member of the inhibitor of apoptosis (IAP) family. The survivin protein functions ...
oncoprotein is activated by MCV large T protein targeting the cellular retinoblastoma protein and that survivin inhibitors can delay tumor progression in animal models. Clinical trials are now being organized to determine whether this has any benefit in humans. The importance of this finding is that a promising rational drug target was uncovered within four years of the initial discovery of the virus and that other new treatments might be rapidly developed now that the cause of the cancer is known. MCV is a target for cell-mediated immune responses, and so important research efforts are being focused on immunologic therapies that may benefit MCC patients.


Discovery and characterization

Yuan Chang Yuan Chang (; born 17 November 1959) is a Taiwanese-American virologist and pathologist who co-discovered together with her husband, Patrick S. Moore, the Kaposi's sarcoma-associated herpesvirus (KSHV) and Merkel cell polyomavirus, two of the s ...
and Patrick S. Moore discovered
Kaposi's sarcoma-associated herpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV) is the ninth known human herpesvirus; its formal name according to the International Committee on Taxonomy of Viruses (ICTV) is ''Human gammaherpesvirus 8'', or HHV-8 in short. Like other herpesvirus ...
by a physical subtraction method in 1994. A virtual subtraction method was developed by Huichen Feng in the lab as a novel
high-throughput sequencing DNA sequencing is the process of determining the nucleic acid sequence – the order of nucleotides in DNA. It includes any method or technology that is used to determine the order of the four bases: adenine, guanine, cytosine, and thymine. The ...
technique of digital transcriptome subtraction (DT
New Pathogen Discovery
ref name="ReferenceA"/> to search for the presence of a virus in Merkel cell tumors. In this method, all
mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein. mRNA is ...
s 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 80% of tissues taken from patients with 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.


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 RNA interference (RNAi) is a biological process in which RNA molecules are involved in sequence-specific suppression of gene expression by double-stranded RNA, through translational or transcriptional repression. Historically, RNAi was known by o ...
), 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 In genetics, a mutagen is a physical or chemical agent that permanently changes genetic material, usually DNA, in an organism and thus increases the frequency of mutations above the natural background level. As many mutations can cause cancer i ...
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 Human papillomavirus (HPV) vaccines are vaccines that prevent infection by certain types of human papillomavirus (HPV). Available HPV vaccines protect against either two, four, or nine types of HPV. All HPV vaccines protect against at least HP ...
can be used to prevent
cervical cancer Cervical cancer is a cancer arising from the cervix. It is due to the abnormal growth of cells that have the ability to invade or spread to other parts of the body. Early on, typically no symptoms are seen. Later symptoms may include abnormal ...
. Chang explained that study of the virus may assist in understanding other human cancers. "Once the virus integrates, it could express an
oncoprotein An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.
, or it could knock out a gene that suppresses tumor growth. Either way, the results are bound to be interesting."


Other associations

Possible associations with cervical carcinoma, cutaneous squamous cell carcinoma, Bowen's disease, basal cell skin carcinoma, extrapulmonary small cell carcinoma, and EGFR mutation-driven non-small cell lung cancer have been reported.


References


External links


KSHV Laboratory: New pathogen discovery
{{DEFAULTSORT:Merkel Cell Polyomavirus Polyomaviridae Infectious causes of cancer