Abstract
Following the identification of the BCR-ABL1 (Breakpoint Cluster Region-ABelson murine Leukemia) fusion in chronic myelogenous leukemia, gene fusions generating chimeric oncoproteins have been recognized as common genomic structural variations in human malignancies. This is, in particular, a frequent mechanism in the oncogenic conversion of protein kinases. Gene fusion was the first mechanism identified for the oncogenic activation of the receptor tyrosine kinase RET (REarranged during Transfection), initially discovered in papillary thyroid carcinoma (PTC). More recently, the advent of highly sensitive massive parallel (next generation sequencing, NGS) sequencing of tumor DNA or cell-free (cfDNA) circulating tumor DNA, allowed for the detection of RET fusions in many other solid and hematopoietic malignancies. This review summarizes the role of RET fusions in the pathogenesis of human cancer.
Highlights
This review summarizes the role of RET fusions in the pathogenesis of human cancer
This review addresses, in particular, the role of RET gene fusions in cancer
In the metanalysis reported by Kohno [18], RET fusions were found in 0.7% of total samples, including cancers other than thyroid and lung ones, such as breast (0.00%–0.21%), colon (0.00%–0.26%), esophageal (0.00%–0.17%), ovarian (0.00%–0.17%), prostate (0.08%), and stomach (0.81%) carcinoma, as well as acute myeloid leukemia (0.00%–0.50%) and very rare cancers such as anaplastic ganglioglioma, and Erdheim–Chester Disease
Summary
RET (REarranged during Transfection) was initially isolated as a rearranged oncoprotein upon the transfection of a human lymphoma DNA [1]. 10 (at q11.21) [2] and codes for the functional tyrosine-kinase receptor (RTK) of GDNF (glial cell line-derived neurotrophic factor), Neurturin (NRT), Artemin (ART), and Persephin (PSF) growth factors [3,4,5,6,7]. These growth factors bind to auxiliary membrane-bound co-receptors, named GFRs (GDNF family receptor- [1,2,3,4]), thereby forming a bipartite complex that, in turn, mediates RET dimerization and activation [8]. This is followed by a C-terminal tail that is subject to alternative splicing generating different isoforms, the most abundant being RET9 and RET51 (depending whether they contain 9 or 51 residues starting from glycine 1063 in exon 19) [3]
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