Suchergebnisse

MdC González-Vela et al. ; 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 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). ; Peer Reviewed

This is an open-access article distributed under the terms of the Creative Commons Attribution License.-- et al. ; Targeted treatment of advanced melanoma could benefit from the precise molecular characterization of melanoma samples. Using a melanoma-specific selection of 217 genes, we performed targeted deep sequencing of a series of biopsies, from advanced melanoma cases, with a Breslow index of =4 mm, and/or with a loco-regional infiltration in lymph nodes or presenting distant metastasis, as well of a collection of human cell lines. This approach detected 3-4 mutations per case, constituting unique mutational signatures associated with specific inhibitor sensitivity. Functionally, case-specific combinations of inhibitors that simultaneously targeted MAPK-dependent and MAPK-independent mechanisms were most effective at inhibiting melanoma growth, against each specific mutational background. These observations were challenged by characterizing a freshly resected biopsy from a metastatic lesion located in the skin and soft tissue and by testing its associated therapy ex vivo and in vivo using melanocytes and patient-derived xenografted mice, respectively. The results show that upon mutational characterization of advanced melanoma patients, specific mutational profiles can be used for selecting drugs that simultaneously target several deregulated genes/pathways involved in tumor generation or progression. ; This work was supported by grants from the ISCIII, co-financed by the European Union (FEDER) (PI12/00357) and a Ramón and Cajal research program from MINECO (RYC-2013-14097) to JPV, and from the ISCIII (RTIC; RD06/0020/0107, RD012/0036/0060) and the Asociación Española Contra el Cáncer (AECC) to MAP. The work was also supported by a research award from LUCHAMOS POR LA VIDA to JPV and AGC. I.V. is supported by the Ramón and Cajal research program. ; Peer Reviewed