Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Comparative Study
. 2013 Apr;133(4):936-45.
doi: 10.1038/jid.2012.445. Epub 2012 Dec 6.

Distinct gene expression profiles of viral- and nonviral-associated merkel cell carcinoma revealed by transcriptome analysis

Paul W Harms  1 , Rajiv M Patel, Monique E Verhaegen, Thomas J Giordano, Kevin T Nash, Craig N Johnson, Stephanie Daignault, Dafydd G Thomas, Johann E Gudjonsson, James T Elder, Andrzej A Dlugosz, Timothy M Johnson, Douglas R Fullen, Christopher K Bichakjian
Affiliations
Comparative Study

Distinct gene expression profiles of viral- and nonviral-associated merkel cell carcinoma revealed by transcriptome analysis

Paul W Harms et al. J Invest Dermatol. 2013 Apr.

Abstract

Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine tumor with high mortality rates. Merkel cell polyomavirus (MCPyV), identified in the majority of MCCs, may drive tumorigenesis via viral T antigens. However, the mechanisms underlying pathogenesis in MCPyV-negative MCCs remain poorly understood. To nominate genes contributing to the pathogenesis of MCPyV-negative MCCs, we performed DNA microarray analysis on 30 MCCs. The MCPyV status of MCCs was determined by PCR for viral DNA and RNA. A total of 1,593 probe sets were differentially expressed between MCPyV-negative and MCPyV-positive MCCs, with significant differential expression defined as at least a 2-fold change in either direction and a P-value 0.05. MCPyV-negative tumors showed decreased RB1 expression, whereas MCPyV-positive tumors were enriched for immune response genes. Validation studies included immunohistochemistry demonstration of decreased RB protein expression in MCPyV-negative tumors and increased peritumoral CD8+ T lymphocytes surrounding MCPyV-positive tumors. In conclusion, our data suggest that loss of RB1 expression may have an important role in the tumorigenesis of MCPyV-negative MCCs. Functional and clinical validation studies are needed to determine whether this tumor-suppressor pathway represents an avenue for targeted therapy.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest, The authors state no conflict of interest

Figures

Figure 1
Figure 1. Principal component analysis of Merkel cell carcinoma transcriptional profiles relative to Merkel cell carcinoma cell lines and nonmelanoma skin cancers
Merkel cell carcinomas have a distinct expression profile compared to squamous cell and basal cell carcinomas. Solid squares indicate primary cutaneous squamous cell carcinomas (SCC). Solid circles indicate basal cell carcinomas (BCC). Solid triangles indicate Merkel cell carcinoma primary tumors (MCC). Open triangles indicate metastatic MCC tumors (Met). Asterisks indicate MCC cell lines. PC1: principal component 1. PC2: principal component 2.
Figure 2
Figure 2. Principal component analysis of Merkel cell carcinoma tumors by Merkel cell polyomavirus status
The majority of Merkel cell polyomavirus (MCPyV)-positive tumors (open circles) display a distinct cluster which partially overlaps with MCPyV-negative tumors (solid squares). MCPyV-negative tumors are more heterogeneous. Negative: MCPyV T antigen (TAg) DNA and RNA negative. Positive: TAg DNA and RNA positive. PC1: principal component 1. PC2: principal component 2.
Figure 3
Figure 3. Genes with greatest differential expression in Merkel cell polyomavirus-positive tumors relative to -negative tumors
All genes shown have adjusted p-value ≤ 0.05. Fold values are in log2.
Figure 4
Figure 4. Merkel cell polyomavirus negativity is associated with relatively decreased immune response and loss of Retinoblastoma expression
Relative to Merkel cell polyomavirus-negative tumors (a-c), Merkel cell polyomavirus-positive tumors (d-f) display a trend toward increased CD3+ peritumoral lymphocytes (a, d, g), low CD4+ T lymphocytes (b, e, g) and significantly increased CD8+ T lymphocytes (c, f, g) by immunohistochemistry. Merkel cell polyomavirus-positive tumors uniformly express RB (h, j), whereas the majority of Merkel cell polyomavirus-negative tumors display loss of RB expression by immunohistochemistry (i, j). Scale bar = 50 microns.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Ames HM, Bichakjian CK, Liu GY, Oravecz-Wilson KI, Fullen DR, Verhaegen ME, et al. Huntingtin-interacting protein 1: a Merkel cell carcinoma marker that interacts with c-Kit. J Invest Dermatol. 2011;131:2113–20. - PMC - PubMed
    1. Becker JC. Merkel cell carcinoma. Ann Oncol. 2010;21(7):vii81–5. - PubMed
    1. Becker JC, Houben R, Ugurel S, Trefzer U, Pfohler C, Schrama D. MC polyomavirus is frequently present in Merkel cell carcinoma of European patients. J Invest Dermatol. 2009;129:248–50. - PubMed
    1. Ben-Arie N, Hassan BA, Bermingham NA, Malicki DM, Armstrong D, Matzuk M, et al. Functional conservation of atonal and Math1 in the CNS and PNS. Development. 2000;127:1039–48. - PubMed
    1. Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B Stat Methodol. 1995;57:289–300.

Publication types

MeSH terms

Substances