Shared Oncogenic Pathways Implicated in Both Virus-Positive and UV-Induced Merkel Cell Carcinomas

• Published in: Journal of investigative dermatology Vol. 137; no. 1; pp. 197 - 206
• Main Authors: González-Vela, María del Carmen, Curiel-Olmo, Soraya, Derdak, Sophia, Beltran, Sergi, Santibañez, Miguel, Martínez, Nerea, Castillo-Trujillo, Alfredo, Gut, Martha, Sánchez-Pacheco, Roxana, Almaraz, Carmen, Cereceda, Laura, Llombart, Beatriz, Agraz-Doblas, Antonio, Revert-Arce, José, López Guerrero, José Antonio, Mollejo, Manuela, Marrón, Pablo Isidro, Ortiz-Romero, Pablo, Fernandez-Cuesta, Lynnette, Varela, Ignacio, Gut, Ivo, Cerroni, Lorenzo, Piris, Miguel Ángel, Vaqué, José Pedro
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-01-2017; Elsevier
• Subjects: Aged; Aged, 80 and over; Biomarkers, Tumor - genetics; Biopsy, Needle; Carcinogenesis; Carcinogenesis - genetics; Carcinoma, Merkel Cell - genetics; Carcinoma, Merkel Cell - mortality; Carcinoma, Merkel Cell - pathology; Carcinoma, Merkel Cell - virology; Cohort Studies; Female; Gene expression regulation; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Male; Merkel cell carcinoma; Merkel cell polyomavirus - genetics; Merkel cell polyomavirus - isolation & purification; Multivariate Analysis; Mutation; Oncogenes - genetics; Prognosis; Risk Assessment; Signal Transduction - genetics; Skin neoplasms; Skin Neoplasms - genetics; Skin Neoplasms - mortality; Skin Neoplasms - pathology; Skin Neoplasms - virology; Survival Analysis; Tumor suppressor protein p53; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumor virus infections; Tumor Virus Infections - mortality; Tumor Virus Infections - pathology; Ultraviolet Rays - adverse effects; RB; P-CREB; IHC; P-STAT; RTK; KEGG; MCPyV; MCC; SSM; NFAT
• ISSN: 0022-202X; 1523-1747
• DOI: 10.1016/j.jid.2016.08.015

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.