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.

Novel Targeted Therapies for Metastatic Thyroid Cancer—A Comprehensive Review

“…The RET/PTC1 rearrangement was a common oncogenic alteration to be observed in childhood thyroid cancer cases after the Chernobyl nuclear power plant accident, which resulted in radiation exposures [47]. Moreover, RET fusions have been observed in almost 50% of atomic bomb survivors with PTCs who had high radiation exposure [48].…”

Thyroid Cancers: From Surgery to Current and Future Systemic Therapies through Their Molecular Identities

“…In PTC, the most prevalent RET alterations are RET/PTC rearrangements. In particular, a RET fusion was found in about 50% of PTC diagnosed in atomic bomb survivors after a high radiation dose exposure and was very common, especially RET/PTC1 and RET/PTC3 , in childhood TC diagnosed after the Chernobyl accident [ 48 , 49 ].…”

Chasing the Target: New Phenomena of Resistance to Novel Selective RET Inhibitors in Lung Cancer. Updated Evidence and Future Perspectives

“…RET/Coiled-Coil Domain Containing 6 (CCDC6) gene fusion is associated in about 80% of cases of sporadic PTC, while the Nuclear Receptor Coactivator 4 (NCOA4) gene, is mainly related to radiation exposure and younger age [ 23 ]. Countless rearrangements have been described in literature being a part of the pathogenesis of PTC [ 24 ]. Although PTCs are the most frequently associated cancers.…”

“…Several other inter-chromosomal rearrangements or translocations have been described, however they represent a small percentage of cases, we have summarized some in Table 1 . [ 24 , 34 ]. Breakpoints in KIF5B are frequently found in the intron 11 at different positions and are involved in transcription of intracytoplasmic segments of RET, however, different introns are rarely involved in fostering the inclusion of the transmembrane dominion [ 35 , 36 ].…”