Gene Expression Profiling Reveals Two Distinct Subtypes of Merkel Cell Carcinoma

Summary

Merkel cell carcinoma (MCC) is a rare aggressive neuroendocrine tumor of the skin. The genetic mechanisms underlying the development and tumor progression of MCC are poorly understood. We showed by comparative genomic hybridization analysis that the pattern of chromosomal abnormalities in MCC resembles that of small cell lung carcinoma (SCLC). Both tumors also share clinical and immunophenotypical characteristics. In addition, MCC cell lines can also be grouped, analogous to SCLC, into two different biological subgroups, namely Variant versus Classic MCC cell lines. In order to obtain more insight into the molecular pathogenesis of MCC and to find typical gene expression signatures associated with the phenotypically different subgroups of MCC cell lines, we determined the gene expression profiles of five Variant and five Classic MCC cell lines by the use of Atlas cDNA expression arrays. Supervised analysis allowed us to identify a set of 89 highly significant differentially expressed genes, which allowed classification of the MCC cell lines into the Variant and Classic subgroups. Genes mainly involved in cell cycle progression and cell proliferation showed higher expression levels in Variant MCC cell lines, mainly reflecting their more clinical aggressive behavior. Genes involved in signal transduction, neurotransmission and neuronal development showed a higher expression level in Classic MCC types associated with their more neuroendocrine and differentiated character. We assume that the differential expression levels of some of these genes refleet, analogous to SCLC, the different biological and clinical properties of Variant and Classic MCC phenotypes. Some of these genes could serve as useful prognostic markers and potential targets for the development of new therapeutic interventions specific for each subgroup.