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Introduction Merkel cell carcinoma (MCC hereon) is a highly malignant neuroendocrine skin tumour. MCC has a relatively low incidence, but its mortality exceeds that of melanoma. MCC shares important features with other deadly cancers like SCLC or melanoma. Recent data have shown important mechanisms driving MCC. Nevertheless, the main molecular/biological mechanisms involved in its pathogenesis and clinical course remain essentially unveiled. In this work, we aimed at studying a number of MCC clinically characterised cases to identify potential new biomarkers for diagnosis and therapy. Material and methods NGS-Sequencing (WES) from a cohort of 15 clinically characterised patients. Bioinformatic analysis to detect altered genes and signalling pathways. Immunohistochemistry assays in a cohort of 50 clinically characterised patients Multivariable survival study. Functional analyses in MCC cell lines. Results and discussions We detected two groups with differential genetic characteristics: 1) MCC-MCPyV+: Expressing MCPyV and with a low mutational load (0.2–1 muts/Mb) and 2) MCC-MCPyV-: Without the virus but with a high mutational load (10–25 muts/Mb, similar to that of melanoma or lung cancer). Moreover MCC-MCPyV- tumours harboured typical U.V. mutational signatures with up to 60% C>T transitions in a dypirimidine context as recently published by others. Studying a number of transcription factors as end-points for the activity of the signalling pathways associated to the mutated genes found in our study, we found, that despite the differences between MCPyV +and MCPyV– tumours, both developed similar mechanisms of disease like P-CREB and P-STAT. Also MCPyV-cases (recently associated with more aggressiveMCCs) also developed alternative almost exclusive mechanisms like YAP, MYC and LEF1. We propose that these signalling proteins can serve as biomarkers for diagnosis (prognosis) and therapy. As part of our results a multivariable analysis identified P-CREB as independent survival biomarker. Also we have detected multiple mechanisms that can trigger P-CREB in MCC cells. Intriguingly, an algorithm that combined MCPyV-negative mechanism also showed poor survival outcome within our cohort of patients. Conclusion In the era of targeted and immune therapies, we need specific biomarkers. Despite important genetic differences between MCPyV +and MCPyV- tumours we show that both saher important mechanisms of disease. Amongst these, P-CREB was an independent survival factor and can serve for diagnosys and therapy of MCC and related tumours.

BACKGROUND Interferon (IFN)-alpha is widely used in the treatment of mycosis fungoides (MF) and when used in combination with photochemotherapy (psoralen plus ultraviolet A, PUVA) both improved response and duration of complete remission have been reported. However, in spite of encouraging results of the initial studies, currently there is no information available on specific prognostic factors enabling prediction of patients' resistance to PUVA +/- IFN-alpha treatment. OBJECTIVES To identify factors responsible for resistance to PUVA +/- IFN-alpha treatment in MF patients. PATIENTS/METHODS The gene expression profiling of pretreatment samples from 29 patients diagnosed as IA, IB or IIA stage of MF enrolled in a randomized PUVA vs. PUVA + IFN-alpha clinical trial was analysed using cDNA microarrays. A Cox model (SAM) and gene set enrichment analysis (GSEA) were used for identification of genes and biologically significant pathways related to resistance to treatment. RESULTS Genes involved in NF-kappaB signalling, T-cell receptor (TCR) signalling, cytokine signalling and proliferation were differentially expressed between responders and nonresponders. Interestingly, expression of markers representative of those pathways was found not only in the tumoral cells, but also in specific subpopulations of macrophages, dendritic cells and other non-neoplastic cell types constituting the tumour microenvironment, likely involved in the promotion of survival and proliferation of cutaneous T-cell lymphoma. CONCLUSIONS Gene expression changes in both the tumour and the tumour microenvironment are an important determinant of treatment outcome in early-stage MF patients. Some proinflammatory factors such as NF-kappaB, inflammatory cytokines and their receptors in addition to TCR-associated molecules could be promising targets for MF treatment.