Shared oncogenic pathways implicated in both virus-positive and UV-induced merkel cell carcinomas

González Vela, María del Carmen; Derdak, Sophia; Beltran, Sergi; Gut, Marta; Gut, Ivo Glynne; Vaqué, José Pedro

doi:http://dx.doi.org/10.1016/j.jid.2016.08.015

Shared oncogenic pathways implicated in both virus-positive and UV-induced merkel cell carcinomas

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González-Vela MD, Curiel-Olmo S, Derdak S, Beltran S, Santibañez M, Martinez N et al. Shared Oncogenic Pathways Implicated in Both Virus-Positive and UV-Induced Merkel Cell Carcinomas. J Invest Dermatol. 2017 Jan;137(1):197-206. DOI: 10.1016/j.jid.2016.08.015. Epub 2016 Sep 1

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.