A RET::GRB2 fusion in pheochromocytoma defies the classic paradigm of RET oncogenic fusions.
A RET::GRB2 fusion in pheochromocytoma defies the classic paradigm of RET oncogenic fusions.
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DOI：
10.1016/j.xcrm.2022.100686
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发表时间：
2022-07-19
影响因子：
14.3
通讯作者：
Dahia, Patricia L. M.
中科院分区：
文献类型：
--
作者：
Estrada-Zuniga, Cynthia M.;Cheng, Zi-Ming;Ethiraj, Purushoth;Guo, Qianjin;Gonzalez-Cantu, Hector;Adderley, Elaina;Lopez, Hector;Landry, Bethany N.;Zainal, Abir;Aronin, Neil;Ding, Yanli;Wang, Xiaojing;Aguiar, Ricardo C. T.;Dahia, Patricia L. M.
RET激酶受体是神经嵴肿瘤（包括嗜铬细胞瘤）突变的靶点，也是上皮癌中致癌融合的靶点。我们报告了一个RET：：GRB 2融合在嗜铬细胞瘤中，其中RET，作为上游合作伙伴，保留其激酶结构域，但失去了关键的C-末端基序，并融合到GRB 2，一个生理RET相互作用蛋白。RET：：GRB 2是一种致癌驱动因子，可导致组成型、配体非依赖性RET信号传导;具有依赖于RET催化功能的转化能力;对RET抑制剂敏感。这些观察结果突出了嗜铬细胞瘤中可能适合RET驱动治疗的新驱动事件。在嗜铬细胞瘤中发现RET：：GRB 2融合体RET保留其激酶结构域，将C尾与GRB 2交换，正常的RET结合伴侣RET：：GRB 2依赖于RET激酶功能进行转化RET：：GRB 2使细胞对RET抑制剂敏感。描述了嗜铬细胞瘤中的RET：：GRB 2融合。在这种重排中，RET独特地位于伴侣基因GRB 2的上游，GRB 2编码天然RET相互作用蛋白。RET：：GRB 2对RET抑制剂具有转化作用和敏感性，支持其驱动作用，并突出了嗜铬细胞瘤靶向治疗的机会。
The RET kinase receptor is a target of mutations in neural crest tumors, including pheochromocytomas, and of oncogenic fusions in epithelial cancers. We report a RET::GRB2 fusion in a pheochromocytoma in which RET, functioning as the upstream partner, retains its kinase domain but loses critical C-terminal motifs and is fused to GRB2, a physiological RET interacting protein. RET::GRB2 is an oncogenic driver that leads to constitutive, ligand-independent RET signaling; has transforming capability dependent on RET catalytic function; and is sensitive to RET inhibitors. These observations highlight a new driver event in pheochromocytomas potentially amenable for RET-driven therapy. A RET::GRB2 fusion was found in a pheochromocytoma RET retains its kinase domain, swaps the C tail with GRB2, a normal RET binding partner RET::GRB2 relies on RET kinase function for transformation RET::GRB2 renders cells sensitive to RET inhibitors Estrada-Zuniga et al. describe a RET::GRB2 fusion in a pheochromocytoma. In this rearrangement, RET is uniquely positioned upstream to the partner gene GRB2, which encodes a natural RET interacting protein. RET::GRB2 is transforming and sensitive to RET inhibitors, supporting its driver role and highlighting opportunities for targeted therapy in pheochromocytomas.
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DOI：
10.1016/j.annonc.2020.10.599
发表时间：
2021-03
期刊：
Annals of oncology : official journal of the European Society for Medical Oncology
影响因子：
--
作者：
Subbiah V;Shen T;Terzyan SS;Liu X;Hu X;Patel KP;Hu M;Cabanillas M;Behrang A;Meric-Bernstam F;Vo PTT;Mooers BHM;Wu J
通讯作者：
Wu J
影响因子：
4.8
作者：
Scott, RP;Eketjäll, S;Ibáñez, CF
通讯作者：
Ibáñez, CF
影响因子：
82.9
作者：
Kohno T;Ichikawa H;Totoki Y;Yasuda K;Hiramoto M;Nammo T;Sakamoto H;Tsuta K;Furuta K;Shimada Y;Iwakawa R;Ogiwara H;Oike T;Enari M;Schetter AJ;Okayama H;Haugen A;Skaug V;Chiku S;Yamanaka I;Arai Y;Watanabe S;Sekine I;Ogawa S;Harris CC;Tsuda H;Yoshida T;Yokota J;Shibata T
通讯作者：
Shibata T
影响因子：
12.3
作者：
Robinson MD;Oshlack A
通讯作者：
Oshlack A
影响因子：
50.3
作者：
Fishbein L;Leshchiner I;Walter V;Danilova L;Robertson AG;Johnson AR;Lichtenberg TM;Murray BA;Ghayee HK;Else T;Ling S;Jefferys SR;de Cubas AA;Wenz B;Korpershoek E;Amelio AL;Makowski L;Rathmell WK;Gimenez-Roqueplo AP;Giordano TJ;Asa SL;Tischler AS;Cancer Genome Atlas Research Network;Pacak K;Nathanson KL;Wilkerson MD
通讯作者：
Wilkerson MD