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

详细信息    查看全文

• 作者：Marí ; a del Carmen Gonzá ; lez-Vela¹ ; ² ; ¹⁷ ; Soraya Curiel-Olmo² ; ¹⁷ ; Sophia Derdak³ ; ¹⁴ ; Sergi Beltran³ ; ¹⁴ ; Miguel Santibañ ; ez⁴ ; Nerea Martí ; nez² ; Alfredo Castillo-Trujillo⁵ ; Martha Gut³ ; ¹⁴ ; Roxana Sá ; nchez-Pacheco¹ ; Carmen Almaraz² ; Laura Cereceda² ; Beatriz Llombart⁶ ; Antonio Agraz-Doblas⁷ ; ¹⁶ ; José ; Revert-Arce² ; José ; Antonio Ló ; pez Guerrero⁸ ; Manuela Mollejo⁹ ; Pablo Isidro Marró ; n¹⁰ ; Pablo Ortiz-Romero¹¹ ; Lynnette Fernandez-Cuesta¹² ; ¹⁵ ; Ignacio Varela⁷ ; Ivo Gut³ ; ¹⁴ ; Lorenzo Cerroni¹³ ; Miguel Á ; ngel Piris¹ ; ² ; ¹⁸ ; José ; Pedro Vaqué ; ² ; ⁷ ; ¹⁸ ; ^{vaquej@unican.es}
• 关键词：IHC ; immunohistochemistry ; KEGG ; Kyoto Encyclopedia of Genes and Genomes ; MCC ; Merkel cell carcinoma ; MCPyV ; Merkel cell polyomavirus ; NFAT ; nuclear factor of activated T cells ; P-CREB ; phosphorylated CRE-binding protein ; P-STAT ; phosphorylated signal transducer and activator of transcription ; RB ; retinoblastoma ; RTK ; receptor with tyrosine kinase activity ; SSM ; somatic single-base mutation
• 刊名：Journal of Investigative Dermatology
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：137
• 期：1
• 页码：197-206
• 全文大小：1324 K
• 卷排序：137

文摘

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.