14-3-3 fusion oncogenes in high-grade endometrial stromal sarcoma.
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.
Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
Cheng-Han
CH
Lee
Wen-Bin
WB
Ou
Adrian
A
Mariño-Enriquez
Meijun
M
Zhu
Mark
M
Mayeda
Yuexiang
Y
Wang
Xiangqian
X
Guo
Alayne L
AL
Brunner
Frédéric
F
Amant
Christopher A
CA
French
Robert B
RB
West
Jessica N
JN
McAlpine
C Blake
CB
Gilks
Michael B
MB
Yaffe
Leah M
LM
Prentice
Andrew
A
McPherson
Steven J M
SJ
Jones
Marco A
MA
Marra
Sohrab P
SP
Shah
Matt
M
van de Rijn
David G
DG
Huntsman
Paola
P
Dal Cin
Maria
M
Debiec-Rychter
Marisa R
MR
Nucci
Jonathan A
JA
Fletcher
D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D056970:Co-Repressor Proteins; D020732:Cytogenetic Analysis; D004268:DNA-Binding Proteins; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D015321:Gene Rearrangement / Q000235:genetics; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D060787:Neoplasm Grading; D009363:Neoplasm Proteins / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D018203:Sarcoma, Endometrial Stromal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D017422:Sequence Analysis, DNA; D059467:Transcriptome; D014178:Translocation, Genetic
D048948:14-3-3 Proteins; D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; C430460:JAZF1 protein, human; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; C482983:YWHAE protein, human; C576541:YWHAE-FAM22 fusion protein, human