14-3-3 fusion oncogenes in high-grade endometrial stromal sarcoma
Author(s)
Lee, Cheng-Han; Ou, Wen-Bin; Marino-Enriquez, Adrian; Zhu, Meijun; Mayeda, Mark; Wang, Yuexiang; Guo, Xiangqian; Brunner, Alayne L.; Amant, Frédéric; French, Christopher A.; West, Robert B.; McAlpine, Jessica N.; Gilks, C. Blake; Prentice, Leah M.; Jones, Steven J. M.; Marra, Marco A.; Shah, Sohrab P.; Rijn, Matt van de; Huntsman, David G.; Cin, Paola Dal; Debiec-Rychter, Maria; Nucci, Marisa R.; Fletcher, Jonathan A.; Yaffe, Michael B; McPherson, Andrew; ... Show more Show less
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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.
Date issued
2012-01Department
Massachusetts Institute of Technology. Department of Biological Engineering; Massachusetts Institute of Technology. Department of Biology; Koch Institute for Integrative Cancer Research at MITJournal
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Citation
Lee, C.-H. et al. “14-3-3 Fusion Oncogenes in High-grade Endometrial Stromal Sarcoma.” Proceedings of the National Academy of Sciences 109.3 (2012): 929–934. Copyright ©2012 by the National Academy of Sciences
Version: Final published version
ISSN
0027-8424
1091-6490