Suchergebnisse

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 55e90% 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 multivariable 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. ; This work was supported by grants from Instituto de Salud-Carlos III (ISCIII); cofinanced by the European Union; (FEDER) (PI12/00357), and a Ramón and Cajal research program (MINECO; RYC-2013-14097) to JPV, Asociación Española Contra el Cáncer and ISCIII grants (RD06/0020/0107, RD012/0036/0060) to MAP, and Coordinated Project of Excellence inter-Institutos de investigación acreditados institutes (ISCIII; PIE15/00081) to MAP. The Ramón and Cajal research program also supports IV. SD was supported by the Torres Quevedo subprogram (MICINN; PTQ-12-05391).