Journal
JOURNAL OF INVESTIGATIVE DERMATOLOGY
Volume 137, Issue 1, Pages 197-206Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jid.2016.08.015
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Funding
- Instituto de Salud-Carlos III (ISCIII) - European Union
- (FEDER) [PI12/00357]
- MINECO [RYC-2013-14097]
- Asociacion Espanola Contra el Cancer
- ISCIII [RD06/0020/0107, RD012/0036/0060]
- Coordinated Project of Excellence inter-Institutos de investigacion acreditados institutes (ISCIII) [PIE15/00081]
- Ramon and Cajal research program
- MICINN [PTQ-12-05391]
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Merkel cell carcinoma (MCC) is a highly malignant neuroendocrine tumor of the skin whose molecular pathogenesis is not completely understood, despite the role that Merkel cell polyomavirus can play in 55-90% of cases. To study potential mechanisms driving this disease in clinically characterized cases, we searched for somatic mutations using whole-exome sequencing, and extrapolated our findings to study functional biomarkers reporting on the activity of the mutated pathways. Confirming previous results, Merkel cell polyomavirus-negative tumors had higher mutational loads with UV signatures and more frequent mutations in TP53 and RB compared with their Merkel cell polyomavirus-positive counterparts. Despite important genetic differences, the two Merkel cell carcinoma etiologies both exhibited nuclear accumulation of oncogenic transcription factors such as NFAT or nuclear factor of activated T cells (NFAT), P-CREB, and P-STAT3, indicating commonly deregulated pathogenic mechanisms with the potential to serve as targets for therapy. A multi-variable analysis identified phosphorylated CRE-binding protein as an independent survival factor with respect to clinical variables and Merkel cell polyomavirus status in our cohort of Merkel cell carcinoma patients.
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