title: Distinct gene expression profiles of viral- and nonviral-associated merkel cell carcinoma revealed by transcriptome analysis.
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.
authors.affiliation: Department of Pathology, University of Michigan Medical Center, Ann Arbor, MI, USA. paulharm@med.umich.edu
authors.forename: Paul W
authors.initials: PW
authors.lastname: Harms
authors.forename: Rajiv M
authors.initials: RM
authors.lastname: Patel
authors.forename: Monique E
authors.initials: ME
authors.lastname: Verhaegen
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Giordano
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Nash
authors.forename: Craig N
authors.initials: CN
authors.lastname: Johnson
authors.forename: Stephanie
authors.initials: S
authors.lastname: Daignault
authors.forename: Dafydd G
authors.initials: DG
authors.lastname: Thomas
authors.forename: Johann E
authors.initials: JE
authors.lastname: Gudjonsson
authors.forename: James T
authors.initials: JT
authors.lastname: Elder
authors.forename: Andrzej A
authors.initials: AA
authors.lastname: Dlugosz
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Johnson
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Fullen
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Bichakjian
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015266:Carcinoma, Merkel Cell / Q000235:genetics* / Q000401:mortality / Q000821:virology; D002294:Carcinoma, Squamous Cell / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D015994:Incidence; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics; D008214:Lymphocytes / Q000502:physiology; D008297:Male; D059965:Merkel cell polyomavirus / Q000235:genetics*; D008875:Middle Aged; D018295:Neoplasms, Basal Cell / Q000235:genetics; D027601:Polyomavirus Infections / Q000235:genetics* / Q000401:mortality; D015995:Prevalence; D016160:Retinoblastoma Protein / Q000235:genetics; D012878:Skin Neoplasms / Q000235:genetics* / Q000401:mortality / Q000821:virology; D059467:Transcriptome; D014412:Tumor Virus Infections / Q000235:genetics* / Q000401:mortality
chemical_list: D016160:Retinoblastoma Protein