1. A RET::GRB2 fusion in pheochromocytoma defies the classic paradigm of RET oncogenic fusions
- Author
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Cynthia M. Estrada-Zuniga, Zi-Ming Cheng, Purushoth Ethiraj, Qianjin Guo, Hector Gonzalez-Cantú, Elaina Adderley, Hector Lopez, Bethany N. Landry, Abir Zainal, Neil Aronin, Yanli Ding, Xiaojing Wang, Ricardo C.T. Aguiar, and Patricia L.M. Dahia
- Subjects
Oncogene Proteins ,Mutation ,Proto-Oncogene Proteins c-ret ,Adrenal Gland Neoplasms ,Humans ,Oncogenes ,Pheochromocytoma ,Gene Fusion ,General Biochemistry, Genetics and Molecular Biology ,GRB2 Adaptor Protein - Abstract
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.
- Published
- 2022
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