This report describes work assessing a CCDC6-RET fusion. Two RET fusion variants, CCDC6-RET and NCOA4-RET, account for >90% of fusions associated with nonmedullary thyroid carcinoma (NMTC); CCDC6-RET fusions are also observed in other cancers, including lung adenocarcinomas (a subtype of non-small-cell lung cancer). RET encodes a cellular tyrosine kinase transmembrane receptor; activation of RET stimulates multiple downstream pathways that promote cell growth, proliferation, survival and differentiation. Little is known about the normal function of CCDC6 (Coiled-coil domain containing 6); it may be involved in the cellular response to DNA damage. The CCDC6-RET fusion is associated with a relatively benign NMTC subtype.
A UAS construct incorporating a fusion of the two human genes, indicated in FlyBase as Hsap\CCDC6::Hsap\RET, was introduced into flies. Different aspects of the functional impact of the fusion were assessed using different GAL4 drivers; broad expression results in lethality. Genetic interactions and sensitivity to clinically relevant drugs were tested. A critical finding was that the CCDC6-RET and NCOA4-RET fusions differed in these assays. (See the human disease model report 'thyroid carcinoma, nonmedullary, NCOA4-RET fusion,' FBhh0000662.)
[updated Nov. 2017 by FlyBase; FBrf0222196]
Nonmedullary thyroid cancer (NMTC) comprises thyroid cancers of follicular cell origin and accounts for more than 95% of all thyroid cancer cases. Papillary thyroid cancer (PTC) is the most common histologic subtype (summary by Vriens et al., 2009; pubmed:20001717). PTCs smaller than 1 cm are referred to as papillary microcarcinomas; these tumors have been identified in up to 35% of individuals at autopsy, suggesting that they may be extremely common, although rarely clinically relevant (summary by Bonora et al., 2010; pubmed:20628519). [from MIM:188550; 2017.11.24]
Two RET fusion isoforms, CCDC6-RET and NCOA4-RET, account for >90% of fusions associated with nonmedullary thyroid carcinoma; CCDC6-RET is associated with a more benign subtype (FBrf0233455).
RET fusion proteins are not localized to the cell membrane (FBrf0233455).
RET (rearranged during transfection proto-oncogene) encodes a cellular tyrosine kinase transmembrane receptor. Activation of RET stimulates multiple downstream pathways that promote cell growth, proliferation, survival and differentiation. These pathways include the mitogen-activated protein kinase (MAPK), the phosphoinositide 3-kinase (PI3K) and protein kinase B, signal transducer and activator of transcription 3, proto-oncogene tyrosine-protein kinase Src1 and focal adhesion kinase pathways (Romei et al., 2016; pubmed:26868437).
There is evidence that CCDC6 is involved in the ATM-mediated cellular response to DNA damage (Merolla et al., 2007; pubmed:17420723). Tong et al. (1997; pubmed:9083029) found that the CCDC6 protein forms a dimer in vivo; the leucine zipper in the N-terminal region is responsible for this dimerization. Constitutive dimerization appears to be essential for CCDC6 transforming activity. [from MIM:601985; 2017.11.27]
One to one: 1 human to 1 Drosophila; additional more distantly related genes in both species.
One to one: 1 human to 1 Drosophila.
