Novel oncogenic fusion discovered and classified in pheochromocytoma
Pheochromocytoma is a rare tumor that develops in the adrenal glands. To discover novel driver events of the disease, Dr. Patricia Dahia and her team at the University of Texas San Antonio Division of Hematology and Medical Oncology conducted whole transcriptome RNA sequencing of pheochromocytoma tumors. After analyzing the data, the team discovered a novel fusion between RET, a gene commonly mutated in multiple cancers, and GRB2 a known adaptor protein and signaling mediator of the RET protein.
RET is a cellular growth receptor that is found to be mutated in lung, thyroid, colon, prostate, and breast cancers. After conducting whole transcriptome sequencing of 30 pheochromocytoma tumors, Dr. Dahia and her group identified a novel fusion between the N-terminus of the RET gene and the C-terminus of the GRB2 gene, which resulted in production of a RET::GRB2 fusion protein expressed in the tumor cells. Interestingly, GRB2 is known to interact with and regulate the function of RET in normal cells.
The authors of the study then further investigated the function of the newly discovered fusion protein in vitro using multiple assays. Overall, they found that RET::GRB2 fusion protein was activated in the absence of growth factors, promoted transformation of cells, and sensitized cells to RET inhibitors currently in use in the clinic. This study provides insight into how a novel protein transforms cells and explores possible treatments for pheochromocytoma.
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Estrada-Zuniga CM, Cheng ZM, Ethiraj P, Guo Q, Gonzalez-Cantú H, Adderley E, Lopez H, Landry BN, Zainal A, Aronin N, Ding Y, Wang X, Aguiar RCT, Dahia PLM. A RET::GRB2 fusion in pheochromocytoma defies the classic paradigm of RET oncogenic fusions. Cell Rep Med. 2022 Jul 19;3(7):100686. doi: 10.1016/j.xcrm.2022.100686. PMID: 35858593.