Correlation of Merkel cell polyomavirus positivity with PDGFRα mutations and survivin expression in Merkel cell carcinoma.
BACKGROUND
Merkel cell carcinoma (MCC) is a neuroendocrine cancer of the skin postulated to originate through Merkel cell polyomavirus (MCPyV) oncogenesis and/or by mutations in molecules implicated in the regulation of cell growth and survival. Despite the fact that MCPvV is detected more broadly within the population, only a part of the infected people also develop MCC. It is thus conceivable that together, virus and for example mutations, are necessary for disease development. However, apart from a correlation between MCPyV positivity or mutations and MCC development, less is known about the association of these factors with progressive disease.


OBJECTIVE
To analyze MCPyV positivity, load and integration in MCC as well as presence of mutations in PDGFRα and TP53 genes and correlate these with clinical features and disease progression to identify features with prognostic value for clinical progression.


METHODS
This is a study on a MCC population group of 64 patients. MCPyV positivity, load and integration in parallel to mutations in the PDGFRα and TP53 were analyzed on genomic DNA from MCC specimens. In addition, expression of PDGFRα, survivin and p53 proteins was analyzed by immunodetection in tissues specimens. All these parameters were analyzed as function of patient's disease progression status.


RESULTS
83% of MCCs were positive for the MCPyV and among these 36% also displayed virus-T integration. Viral load ranged from 0.006 to 943 viral DNA copies/β-globin gene and was highest in patients with progressive disease. We detected more than one mutation within the PDGFRα gene and identified two new SNPs in 36% of MCC patients, whereas no mutations were found in TP53 gene. Survivin was expressed in 78% of specimens. We could not correlate either mutations in PDGFR or expression of PDGFR, p53 and surviving either to the disease progression or to the MCPyV positivity.


CONCLUSIONS
In conclusion, our data indicate that the viral positivity when associated with high viral load, correlates with poor disease outcome. Frequent mutations in the PDGFRα gene and high survivin expression were found in MCC independent of the viral positivity. These data suggest that these three factors independently contribute to Merkel cell carcinoma development and that only the viral load can be used as indicator of disease progression in virus positive patients.
Department of Dermatology and Venereology, University of Cologne, Germany.
M
M
Batinica
Institute of Virology, University of Cologne, Germany.
B
B
Akgül
Institute of Virology, University of Cologne, Germany; National Reference Center for Papillomaviruses and Polyomaviruses, Germany.
S
S
Silling
Department of Dermatology and Venereology, University of Cologne, Germany; CIO, Center for Integrated Oncology Cologne - Bonn, Cologne, Germany.
C
C
Mauch
Department of Dermatology and Venereology, University of Cologne, Germany. Electronic address: Paola.Zigrino@uni-koeln.de.
P
P
Zigrino
D000368:Aged; D015266:Carcinoma, Merkel Cell / Q000737:chemistry / Q000235:genetics* / Q000821:virology*; D018450:Disease Progression; D005260:Female; D016158:Genes, p53; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000032:analysis / Q000378:metabolism*; D008297:Male; D059965:Merkel cell polyomavirus / Q000302:isolation & purification*; D020641:Polymorphism, Single Nucleotide; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000032:analysis / Q000235:genetics*; D012878:Skin Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000821:virology*; D000077022:Survivin; D019562:Viral Load; D016662:Virus Integration
C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D000077022:Survivin; D020796:Receptor, Platelet-Derived Growth Factor alpha
Merkel cell carcinoma; Merkel cell polyomavirus; Mutations; PDGFR