RET Gene Fusions in Malignancies of the Thyroid and Other Tissues

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.

Keywords: kinase; targeted therapy; thyroid cancer; tyrosine kinase inhibitor.

Figure 1

Representative scheme of RET and its fusion partners. (A) Representation of RET fusion protein partners. Arrows indicate the most frequent breakpoint sites in partner proteins. The number under each protein domain refers to the protein domain legend (Table 1). Coiled-coil domains are very numerous and, therefore, are represented as light green boxes without number. (B) Representation of the RET protein. Arrow indicates the most frequent breakpoint site in RET.