Title: 14-3-3 fusion oncogenes in high-grade endometrial stromal sarcoma
Authors: Lee, Cheng-Han ×
Ou, Wen-Bin
Mariño-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
Yaffe, Michael B
Prentice, Leah M
McPherson, Andrew
Jones, Steven J M
Marra, Marco A
Shah, Sohrab P
van de Rijn, Matt
Huntsman, David G
Dal Cin, Paola
Debiec-Rychter, Maria
Nucci, Marisa R
Fletcher, Jonathan A #
Issue Date: Jan-2012
Publisher: National Academy of Sciences
Series Title: Proceedings of the National Academy of Sciences of the United States of America vol:109 issue:3 pages:929-934
Abstract: 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.
ISSN: 0027-8424
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
Gynaecological Oncology
Laboratory for Genetics of Malignant Disorders
× corresponding author
# (joint) last author

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