Shared Oncogenic Pathways Implicated in Both Virus-Positive and UV-Induced Merkel Cell Carcinomas
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González Vela, María del Carmen; Curiel Olmo, Soraya; Derdak, Sophia; Beltran, Sergi; Santibáñez Margüello, Miguel; Martínez, Nerea; Castillo Trujillo, Alfredo; Gut, Martha; Sánchez Pacheco, Roxana; Almaraz, Carmen; Cereceda, Laura; Llombart, Beatriz; Agraz Doblas, Antonio Manuel; Revert Arce, José; López Guerrero, José Antonio; Mollejo, Manuela; Marrón, Pablo Isidro; Ortiz Romero, Pablo; Fernández Cuesta, Lynnette; [et al.]Fecha
2017Derechos
© 2016 The Authors. Published by Elsevier, Inc. on behalf of the Society for Investigative Dermatology. This is an open access article under the CC BY-NC-ND license
Publicado en
Journal of Investigative Dermatology Volume 137, Issue 1, January 2017, Pages 197-206
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Elsevier
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Resumen/Abstract
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.
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