Neurite+ Mcv T Antigen Knockdown Mcc Cells Fire Na+
Neurite+ MCC cells display neuronal, but not Merkel cell electrophysiological properties. Representative trace of an MS-1 cell transduced with shCtrl-puro. Current injection did not cause action potentials . TTX application had no effect . Sample trace of an MS-1 cell transduced with shpanT-puro that displays grade 3 differentiation. Current injection caused an action potential that was blocked by TTX . The effect of TTX on the action potential of a shpanT-purotransduced MCC cell. Step pulses from 0 to 340 pA were applied. Action potentials observed in the control sample were completely blocked by TTX . A TTX washout restores action potentials . The currentvoltage relationship is shown in a graph. The effect of Ca-free ACSF on the action potentials of a Pan-T treated MCC cell. Step pulses from 0 to 400 pA were applied. Action potential is not blocked by Ca-free ACSF , but additional TTX does block the action potential in the absence of calcium . Voltage-dependent sodium channel genes are up-regulated by T antigen knockdown in MCV+ MS-1 and MKL-2 cells. qRT-PCR was performed for SCN1A, SCN2A, SCN3A, SCN8A, and SCN9A, and relative expression to shCtrl transduced cells was determined by the 2CT method with the18S ribosomal RNA control. Data are shown as average ± SD, *P< 0.05 .
Dna Methylation Alterations Influence Global Loss Of Histone H3 Lysine 27 Trimethylation In Mcc
Global loss of H3K27me3 occupancy has been reported in MCC . In brain tumors, global loss of H3K27me3 may be explained by KDM6B over-expression, leading to H3K27me3 demethylation, and/or EZHIP over-expression that leads to inhibition of EZH2, resulting in global loss of H3K27me3 . However, these data have not been shown in MCC. We found that KDM6B promoter DNA hypomethylation was enriched in MCPyV-positive MCCs and correlates with KDM6B overexpression in MCC . In addition, EZHIP promoter DNA hypomethylation and subsequent gene expression was also identified in MCCs regardless of MCPyV status . These results suggested that the up regulation of KDM6B and EZHIP by DNA hypomethylation in their promoters may contribute to global loss of H3K27me3 in MCC.
DNA methylation in genes involved in H3K27me3demethylation. A, C Plots displaying all probes for KDM6B and EZHIP, arranged by genomic context showing promoter DNA hypomethylation after comparisons of normal, MCPyV-positive, and MCPyV-negative samples. B, D Changes in KDM6B and EZHIP promoter DNA methylation-based on box plot analyses. Adjusted p value significance thresholds are listed: 0.01 < p< 0.05 0.001 < p< 0.01 p< 0.001
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Treatment Of Stage Iv Merkel Cell Carcinoma
For information about the treatments listed below, see the Treatment Option Overview section.
- A clinical trial of immunotherapy .
Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.
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Having A Weakened Immune System
The immune system defends the body against germs such as viruses. It also seems to help the body fight cancer. People with weakened immune systems are more likely to develop some types of cancer, including MCC.
For example, people who get organ transplants usually are given drugs that weaken the immune system to help keep them from rejecting the new organ. This increases their risk of developing MCC. People with autoimmune diseases sometimes take medicines that suppress the immune system, which might increase their risk for other diseases.
People with HIV, the virus that causes AIDS, often have weakened immune systems and are also at increased risk for MCC.
People with some types of blood cancers, such as chronic lymphocytic leukemia or certain lymphomas, also tend to have weakened immune systems. This can be from the cancer itself, or from its treatment. People with these cancers are more likely to get MCC.
MCCs in people with weakened immune systems tend to grow faster and are more likely to be life-threatening.
Mcpyv Tropism And A Model Of Infection
Epidemiological evidence suggests that MCPyV establishes asymptomatic, persistent infections in most people. As many as 88% of healthy adults are positive for MCPyV-specific antibodies . Serological activity against the MCPyV major capsid protein increases as populations age, from about 10% in early childhood to about 80% in adults . MCPyV-specific antibody titers positively correlate with viral load as measured by MCPyV DNA encapsidated in viral particles shed from healthy skin, suggesting that MCPyV positivity rates could also increase as populations age .
Within a given healthy individual, MCPyV antibody titers remain relatively stable over a period of at least 15 months . By comparison, neutralizing antibody titers to MCPyV, but not other human polyomaviruses, are significantly higher in patients with MCPyV-positive MCC despite the fact that MCC tumors do not express capsid protein . Together, these findings suggest that MCPyV has the capacity to persist, and that MCPyV expansion within a host correlates with disease propensity. Inadequate restriction of MCPyV may be a critical factor in enabling MCC development. This hypothesis is supported by the fact that chronic UV-exposure, advanced age, and HIV-related or iatrogenic immunosuppression pose significant risk for MCC .
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What Does Mcc Look Like
MCC tumors often, but not always, appear on sun-exposed areas of the body. The tumors are not nearly as distinctive as other skin cancers and can appear as a pearly pimple-like lump, sometimes skin-colored, red, purple or bluish-red, though they are rarely tender to the touch. The rapid speed at which they grow is what often causes patients and doctors to take notice.
A recurrence of Merkel cell carcinoma on the forehead.
Merkel cell carcinoma on the lower leg.
Please note: Since not all Merkel cell carcinomas have the same appearance, these photos serve as a general reference for what MCC can look like. If you see something new, changing or unusual on your skin, schedule an appointment with your doctor. Photos courtesy of Paul Nghiem, MD, PhD
Is Skin Cancer Genetic
40-50% of Americans who live to the age of 65 will have skin cancer at least once. The most common types of skin cancer in the United States are basal cell carcinoma and squamous cell carcinomas. These are referred to as non-melanoma skin cancers and are generally the result of sun exposure. Learn more about the effects of UV exposure.
Approximately one in 60 people will develop invasive, cutaneous melanoma during their lifetime. Malignant melanoma is a cancer that begins in the melanocytes, the pigment-producing cells in the skin. In fair-complexioned individuals worldwide, the majority of melanoma cases are related to environmental factors such as excessive ultraviolet radiation . However, about 5-10% of melanoma cases are inherited in an autosomal dominant fashion. In other words, parents with a defined genetic mutation have a 50/50 chance to pass on the susceptibility to each of their children regardless of gender. Learn more about melanoma.
Learn more about genetic testing or make an appointment with our experts at the Skin Cancer Program.
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Clustering And Gene Enrichment Analyses
Clustering and gene enrichment analyses were performed on 18 selected tumor types sequenced by the FoundationOne assay. Clustering was achieved by comparing the prevalence of the top 10 most frequently altered genes within each tumor type and clustered based on Euclidean distance. To investigate which genes were driving the clustering seen between the TMB-high MCC samples and other neuroendocrine tumors , a gene enrichment analysis was performed by comparing the genomic alterations detected in these samples against the genomic alterations detected in the other tumor types. The odds ratios and P values were determined using Barnard’s test.
Probe Annotations And Pathway Analyses
We identified EPIC DNA methylation probes located in promoter and gene body regions and classified the remaining probes as intergenic. Probe annotations were obtained from the Infinium MethylationEPIC manifest . Hypergeometric test for determining the enrichment of probes in promoters, gene body, and intergenic regions was performed using the phyper function in R. GO annotation was performed using the R package RDAVIDWebService or enrichGO , and data were presented using the R package clusterProfiler .
Merkel Cell Polyomavirus Infection
The Merkel cell polyomavirus is found in the cancer cells of about 8 out of 10 people with MCC. MCV is a common virus. Most people are infected with it at some point . But the infection doesnt cause symptoms, and it rarely leads to MCC. Because of this, there are no recommended screening tests or treatments for MCV infection.
MCV was first discovered in 2008, and scientists are still learning about this virus. For example, its not clear how exactly how it might cause MCC, or why there are so few cases of MCC when infection with MCV is very common.
Immune Function & Merkel Cell Carcinoma
Patients with weakened immune systems are at significantly higher risk of developing MCC. Conditions associated with weakened immunity include HIV/AIDS, kidney or heart transplantation, and autoimmune diseases requiring medications that suppress the immune system, chronic lymphocytic leukemiachronic lymphocytic leukemiaA slow-growing type of leukemia associated with immune suppression. Patients with CLL have a markedly increased risk and severity of Merkel cell carcinoma. and certain types of lymphoma. The risk of developing MCC is 8 times greater in HIV patients, 10 times greater in organ transplant patients, and about 40 times greater in CLL.234 Long-term suppression of the immune system appears to be a risk factor for MCC in some patients. While patients with profound immune suppression are at a higher risk of developing MCC, over 90% of all people who develop MCC have no known immune deficiency.3
The immune system is also very important after diagnosis of MCC. Patients whose tumors show a robust immune response with certain immune cells present in their tumor tend to do better.5 MCC patients without a primary tumor also do better, likely because their immune system was able to eliminate the primary tumor and thus are more likely to be able to fight small amounts of MCC elsewhere in the body as well.6 In contrast, patients on medications that reduce immune function are at higher risk of having their MCC recur.
Identification Of Dna Methylation Regulated Genes Involved In Mcc Tumorigenesis Neuroendocrine Status And Mcpyv Infection
Aberrant DNA methylation aberrations have been described in most types of human cancers . However, most of the defined alterations appear to be passenger events that do not lead to gene expression changes . Understanding the relationship between DNA methylation alterations and gene expression changes will provide not only a functional DNA methylation marker for gene expression status, but also a potential therapeutic biomarker, especially for DNA methylation inhibitors . We recently demonstrated that epigenetic alterations are more frequent than genetic alterations in regulating gene expression, and this may be identified by correlating gene expression with DNA methylation and/or nucleosome accessibility of gene promoters or gene bodies .
The selected genes regulated by DNA methylation and those related to MCC tumorigenesis, MCPyV, and neuroendocrine status. A The genes related to A) MCC tumorigenesis, B MCPyV status, and C neuroendocrine signatures were identified by comparing DNA methylation of normal, primary, and metastatic MCC samples. The data recorded and depicted in bar-graphs. Adjusted p value significance thresholds are listed: 0.01 < p< 0.05 0.001 < p< 0.01 p< 0.001
What Is A Merkel Cell
Merkel cells are located deep in the top layer of skin. Merkel cells are connected to nerves, signaling touch sensation as touch receptors. MCC was named after Merkel cells due to the similar microscopic features however, recent research suggests that it is unlikely that MCC originates directly from normal Merkel cells.
Normal Merkel cells in the skin: In this illustration of a cross-section of the skin, normal Merkel cells are shown in red and connect to nerves shown in yellow. The structures drawn include the epidermis , dermis , and deeper adipose layer containing the fatty tissue. Arteries are depicted in red and veins are blue. Figure copyright by Paul Nghiem & Quade Medical Group.
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Dna Methylation Profiles In Mcc Specimens And Differentially Methylated Loci Involve Multiple Pathways
DNA methylation changes of only a limited set of genes have been identified in MCC thus, we investigated genome-scale DNA methylation profiling of primary MCC specimens, including primary tumors, adjacent-normal tissues, metastatic skin tissues, and metastatic lymph nodes across 11 patients, using the Illumina MethylationEPIC DNA methylation BeadArray system . The DNA methylation data were filtered to remove data from probes that are linked to known polymorphisms, located on the X- and Y-chromosomes, and related to aging . In addition, the data from two metastatic lymph nodes were omitted as these were shown to have < 50% purity after testing for infiltration of normal cells or leukocytes caused by inflammation using LUMP assay .
We performed ANOVA-based multiple comparison testing of the remaining 700,268 probes to find differentially methylated probes across the sample collection . A total of 181,429 probes were significantly differentially methylated between the four sample groups. Probes showing the highest variation of DNA methylation between the four groups were retained. Using a standard deviation of the four means greater than 0.25, 24,497 probes were selected .
Genetic Features Of Virus
The aggressive skin cancer Merkel cell carcinoma is caused by either Merkel cell polyomavirus or ultraviolet-induced damage from excessive sunlight exposure. Gabriel J. Starrett, PhD, of the National Institutes of Health, Bethesda, Maryland, and colleagues have developed a sequencing platform to more accurately distinguish between virus-positive and virus-negative Merkel cell carcinoma by genetic features.
As part of the platform described in Genome Medicine, the researchers developed a method that improves the accuracy and sensitivity for virus detection by identifying Merkel cell polyomavirus integration sites and structure. Integrating these data with clinical data revealed features that could impact patient outcome and improve our understanding of Merkel cell carcinoma risk factors, stated the authors.
Deep sequencing was performed on 71 patients with Merkel cell carcinoma using the OncoPanel next-generation sequencing assay, which targets more than 400 cancer-associated genes. To delineate between virus-positive and virus-negative diseases, the researchers also employed genetic software programs to detect viral integration in the entire Merkel cell polyomavirus genome.
These results demonstrate the value of high-confidence virus detection for identifying molecular mechanisms of and viral oncogenesis in Merkel cell carcinoma, concluded Dr. Starrett and colleagues.
Disclosure: The authors reported no conflicts of interest.
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After Merkel Cell Carcinoma Has Been Diagnosed Tests Are Done To Find Out If Cancer Cells Have Spread To Other Parts Of The Body
The process used to find out if cancer has spread to other parts of the body is called staging. The information gathered from the staging process determines the stage of the disease. It is important to know the stage in order to plan treatment.
The following tests and procedures may be used in the staging process:
Four Types Of Standard Treatment Are Used:
One or more of the following surgical procedures may be used to treat Merkel cell carcinoma:
- Wide local excision: The cancer is cut from the skin along with some of the tissue around it. A sentinel lymph node biopsy may be done during the wide local excision procedure. If there is cancer in the lymph nodes, a lymph node dissection also may be done.
- Lymph node dissection: A surgical procedure in which the lymph nodes are removed and a sample of tissue is checked under a microscope for signs of cancer. For a regional lymph node dissection, some of the lymph nodes in the tumor area are removed for a radical lymph node dissection, most or all of the lymph nodes in the tumor area are removed. This procedure is also called lymphadenectomy.
After the doctor removes all the cancer that can be seen at the time of the surgery, some patients may be given chemotherapy or radiation therapy after surgery to kill any cancer cells that are left. Treatment given after the surgery, to lower the risk that the cancer will come back, is called adjuvant therapy.
Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. External radiation therapy uses a machine outside the body to send radiation toward the area of the body with cancer. It is used to treat Merkel cell carcinoma, and may also be used as palliative therapy to relieve symptoms and improve quality of life.
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Epigenetic Dysregulations In Merkel
3.1. Aberrant Epigenetic Modifications in Merkel-Cell-Polyomavirus-Driven Merkel Cell Carcinoma
3.2. Role of Merkel Cell Polyomavirus Oncoproteins in the Epigenetic Dysregulation of MCPyV-Driven Merkel Cell Carcinoma
3.3. Epigenetic Dysregulations as Diagnostic, Prognostic, and Therapy Target Tools in Merkel Cell Polyomavirus-Driven Merkel Cell Carcinoma
Sun Exposure And Having A Weak Immune System Can Affect The Risk Of Merkel Cell Carcinoma
Anything that increases your risk of getting a disease is called a risk factor. Having a risk factor does not mean that you will get cancer not having risk factors doesn’t mean that you will not get cancer. Talk with your doctor if you think you may be at risk. Risk factors for Merkel cell carcinoma include the following:
- Being exposed to a lot of natural sunlight.
- Having an immune system weakened by disease, such as chronic lymphocytic leukemia or HIVinfection.
- Taking drugs that make the immune system less active, such as after an organ transplant.
- Having a history of other types of cancer.
- Being older than 50 years, male, or White.
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