1. Shared Oncogenic Pathways Implicated in Both Virus-Positive and UV-Induced Merkel Cell Carcinomas.
- Author
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González-Vela MDC, Curiel-Olmo S, Derdak S, Beltran S, Santibañez M, Martínez N, Castillo-Trujillo A, Gut M, Sánchez-Pacheco R, Almaraz C, Cereceda L, Llombart B, Agraz-Doblas A, Revert-Arce J, López Guerrero JA, Mollejo M, Marrón PI, Ortiz-Romero P, Fernandez-Cuesta L, Varela I, Gut I, Cerroni L, Piris MÁ, and Vaqué JP
- Subjects
- Aged, Aged, 80 and over, Biopsy, Needle, Carcinogenesis genetics, Carcinoma, Merkel Cell mortality, Carcinoma, Merkel Cell pathology, Cohort Studies, Female, Gene Expression Regulation, Neoplastic, Humans, Immunohistochemistry, Male, Merkel cell polyomavirus isolation & purification, Multivariate Analysis, Mutation, Oncogenes genetics, Prognosis, Risk Assessment, Signal Transduction genetics, Skin Neoplasms mortality, Skin Neoplasms pathology, Survival Analysis, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Tumor Virus Infections mortality, Tumor Virus Infections pathology, Ultraviolet Rays adverse effects, Biomarkers, Tumor genetics, Carcinoma, Merkel Cell genetics, Carcinoma, Merkel Cell virology, Merkel cell polyomavirus genetics, Skin Neoplasms genetics, Skin Neoplasms virology
- 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 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., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2017
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