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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >14-3-3 fusion oncogenes in high-grade endometrial stromal sarcoma
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14-3-3 fusion oncogenes in high-grade endometrial stromal sarcoma

机译：高度子宫内膜间质肉瘤中的14-3-3融合癌基因

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摘要

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 oncopro-tein, 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 oncopro-tein results from a t(10;17) genomic rearrangement leading to fusion between 14-3-3e (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 14-3-3e (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.
机译：14-3-3蛋白是各种细胞功能（包括增殖，代谢和分化）普遍表达的调节剂，而14-3-3表达的改变与癌症的发生和发展有关。我们报告了一种转化型14-3-3癌蛋白，通过常规细胞遗传学和全转录组测序分析，我们确定其为临床上侵袭性子宫肉瘤（高度子宫内膜间质肉瘤（ESS））中的高度复发性遗传机制。 14-3-3癌蛋白由t（10; 17）基因组重排产生，导致14-3-3e（YWHAE）与两个几乎相同的FAM22家族成员（FAM22A或FAM22B）之间融合。 YWHAE-FAM22融合癌蛋白的表达通过免疫印迹在带有t（10; 17）的冷冻肿瘤和细胞系样品中进行了证明。在携带t（10; 17）的ESS细胞系（ESS1）中，使用针对各种FAM22A外显子的shRNA和siRNA进行YWHAE-FAM22融合基因敲低：融合蛋白表达受到抑制，细胞生长和迁移相应减少。 YWHAE-FAM22维持结构上和功能上完整的14-3-3e（YWHAE）蛋白结合结构域，该结构域通过FAM22核定位序列导向细胞核。与具有JAZF1基因融合的经典ESS相比，YWHAE-FAM22 ESS显示出高级的组织学特征，独特的基因表达谱以及更具侵略性的临床过程。荧光原位杂交分析表明，YWHAE-FAM22A / B基因重排对高级ESS具有绝对的特异性，在其他子宫和非子宫间充质肿瘤中未检测到融合（55种肿瘤类型，n = 827）。这些发现揭示了表征异常的14-3-3致癌功能的诊断和治疗相关模型。

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  • 作者

    Cheng-Han Lee; Wen-Bin Ou; Adrian Marino-Enriquez; Meijun Zhu; Mark Mayeda; Yuexiang Wang; Xiangqian Guo; Alayne L. Brunner; Frederic Amant; Christopher A. French; Robert B. West; Jessica N. McAlpine; C. Blake Gilks; Michael B. Yaffe; Leah M. Prentice; Andrew McPherson; Steven J. M. Jones; Marco A. Marra; Sohrab P. Shah; Matt van de Rijn; David G. Huntsman; Paola Dal Cin; Maria Debiec-Rychter; Marisa R. Nucci; Jonathan A. Fletcher;

  • 作者单位

    Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115,Department of Pathology, Vancouver General Hospital, Vancouver, BC,Canada V5Z 4E3;

    Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115;

    Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115;

    Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115;

    Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115;

    Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115;

    Department of Pathology, Stanford University Medical Center, Stanford, CA 94305;

    Department of Pathology, Stanford University Medical Center, Stanford, CA 94305;

    Center for Human Genetics, Catholic University of Leuven, B-3000 Leuven, Belgium;

    Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115;

    Department of Pathology, Stanford University Medical Center, Stanford, CA 94305;

    Department of Gynecology and Obstetrics, University of British Columbia, Vancouver, BC, Canada V5Z 1M9;

    Department of Pathology, Vancouver General Hospital, Vancouver, BC,Canada V5Z 4E3;

    Departments of Biology and Biological Engineering, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139;

    Centre for Translational and Applied Genomics, British Columbia Cancer Agency, Vancouver, BC, Canada V5Z 4E6;

    Centre for Translational and Applied Genomics, British Columbia Cancer Agency, Vancouver, BC, Canada V5Z 4E6;

    Michael Smith Genome Sciences Centre,British Columbia Cancer Agency, Vancouver, BC, Canada V5Z 1L3;

    Michael Smith Genome Sciences Centre,British Columbia Cancer Agency, Vancouver, BC, Canada V5Z 1L3;

    Centre for Translational and Applied Genomics, British Columbia Cancer Agency, Vancouver, BC, Canada V5Z 4E6;

    Department of Pathology, Stanford University Medical Center, Stanford, CA 94305;

    Centre for Translational and Applied Genomics, British Columbia Cancer Agency, Vancouver, BC, Canada V5Z 4E6;

    Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115;

    Center for Human Genetics, Catholic University of Leuven, B-3000 Leuven, Belgium;

    Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115;

    Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    cytogenetic aberration; translocation; uterine neoplasm; NUT; leiomyosarcoma;

    机译：细胞遗传畸变易位子宫肿瘤坚果;平滑肌肉瘤;

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