REToma: a cancer subtype with a shared driver oncogene

Abstract

RET (REarranged during Transfection), which encodes a receptor tyrosine kinase for members of the glial cell line-derived neurotrophic factor, plays a role as driver oncogene in a variety of human cancers. Fusion of RET with several partner genes has been detected in papillary thyroid, lung, colorectal, pancreatic and breast cancers, and tyrosine kinase inhibitors (TKIs) for RET (particularly RET-specific inhibitors) show promising therapeutic effects against such cancers. Oncogenic mutations within the extracellular cysteine-rich and intracellular kinase domains of RET drive medullary thyroid carcinogenesis; the same mutations are also observed in a small subset of diverse cancers such as lung, colorectal and breast cancers. Considering the oncogenic nature of RET mutants, lung, colorectal and breast cancers are predicted to respond to RET TKIs in a manner similar to medullary thyroid cancer. In summary, cancers carrying oncogenic RET alterations as a driver mutation could be collectively termed ‘REToma’ and treated with RET TKIs in a tissue-agnostic manner.

RET Gene Fusions in Malignancies of the Thyroid and Other Tissues

“…As mentioned above, the most typical oncogenic drivers of MTC, a thyroid carcinoma arising from C-cells, are RET point mutations, both in sporadic and familial cases [4][5][6][7][16][17][18]. It is worth noting that RET is normally expressed in C-cells and therefore, its oncogenic conversion does not need the acquisition of a novel transcriptional promoter caused by a gene fusion.…”

“…For a fully comprehensive description of the role played by RET in cancer, the reader is referred to other Reviews published on the topic (see References [4][5][6][7][16][17][18]). Moreover, comprehensive annotation of RET genetic lesions in cancer are provided by TCGA PanCancer, AACR GENIE, and MSKCC projects [19][20][21].…”

“…RET gene fusions are thought to occur secondary to DNA double-strand breaks (DSB) followed by illegitimate repair of the two unrelated genes [13,18,95,96]. DNA repair mechanisms that can be responsible include NHEJ (nonhomologous end joining), which requires no homology or just very short homology sequences and inserts a few nucleotides at the fusion point, and BIR (break-induced replication), that instead requires long homology DNA stretches [95,96].…”

“…RET fusions occur in~10%-20% of sporadic PTCs [15,18]. In the TCGA study, enrolling almost 500 PTC samples,~6.8% of cases harbored a RET fusion [24].…”

“…PDTC (poorly differentiated thyroid carcinoma) and ATC (anaplastic thyroid carcinoma) may derive from pre-existing differentiated carcinomas, including PTC. In the analysis of large databases (more than 60,000 tumor samples), RET fusions were found in 13/560 (2.32%) and 36/500 (7.2 %) PTC cases, 1/107 (0.93%) ATC cases, and 6/134 (4.47%) PDTC cases [18]. Similarly, in a recent study, 5.9% of PDTC but no ATC harbored RET rearrangements, suggesting that RET fusion-positive PTCs rarely progress to ATC [30].…”