14-3-3 fusion oncogenes in high-grade endometrial stromal sarcoma

• Main Authors: Lee, Cheng-Han (Author), Ou, Wen-Bin (Author), Marino-Enriquez, Adrian (Author), Zhu, Meijun (Author), Mayeda, Mark (Author), Wang, Yuexiang (Author), Guo, Xiangqian (Author), Brunner, Alayne L. (Author), Amant, Frédéric (Author), French, Christopher A. (Author), West, Robert B. (Author), McAlpine, Jessica N. (Author), Gilks, C. Blake (Author), Prentice, Leah M. (Author), Jones, Steven J. M. (Author), Marra, Marco A. (Author), Shah, Sohrab P. (Author), Rijn, Matt van de (Author), Huntsman, David G. (Author), Cin, Paola Dal (Author), Debiec-Rychter, Maria (Author), Nucci, Marisa R. (Author), Fletcher, Jonathan A. (Author), Yaffe, Michael B (Author), McPherson, Andrew (Author)
• Other Authors: Massachusetts Institute of Technology. Department of Biological Engineering (Contributor), Massachusetts Institute of Technology. Department of Biology (Contributor), Koch Institute for Integrative Cancer Research at MIT (Contributor), Yaffe, Michael B. (Contributor)
• Format: Article
• Language: English
• Published: National Academy of Sciences, 2012-09-04T20:11:07Z.
• Subjects: Article
• Online Access: Get fulltext

 14-3-3 proteins are ubiquitously expressed regulators of various cellular functions, including proliferation, metabolism, and differentiation, and altered 14-3-3 expression is associated with development and progression of cancer. We report a transforming 14-3-3 oncoprotein, which we identified through conventional cytogenetics and whole-transcriptome sequencing analysis as a highly recurrent genetic mechanism in a clinically aggressive form of uterine sarcoma: high-grade endometrial stromal sarcoma (ESS). The 14-3-3 oncoprotein results from a t(10;17) genomic rearrangement, leading to fusion between 14-3-3ε (YWHAE) and either of two nearly identical FAM22 family members (FAM22A or FAM22B). Expression of YWHAE-FAM22 fusion oncoproteins was demonstrated by immunoblot in t(10;17)-bearing frozen tumor and cell line samples. YWHAE-FAM22 fusion gene knockdowns were performed with shRNAs and siRNAs targeting various FAM22A exons in an t(10;17)-bearing ESS cell line (ESS1): Fusion protein expression was inhibited, with corresponding reduction in cell growth and migration. YWHAE-FAM22 maintains a structurally and functionally intact 14-3-3ε (YWHAE) protein-binding domain, which is directed to the nucleus by a FAM22 nuclear localization sequence. In contrast to classic ESS, harboring JAZF1 genetic fusions, YWHAE-FAM22 ESS display high-grade histologic features, a distinct gene-expression profile, and a more aggressive clinical course. Fluorescence in situ hybridization analysis demonstrated absolute specificity of YWHAE-FAM22A/B genetic rearrangement for high-grade ESS, with no fusions detected in other uterine and nonuterine mesenchymal tumors (55 tumor types, n = 827). These discoveries reveal diagnostically and therapeutically relevant models for characterizing aberrant 14-3-3 oncogenic functions.