This report describes work assessing an NCOA4-RET fusion. Two RET fusion variants, CCDC6-RET and NCOA4-RET, account for >90% of fusions associated with nonmedullary thyroid carcinoma (NMTC); NCOA4-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. NCOA4 encodes an androgen receptor coactivator; the NCOA4-RET fusion is associated with an aggressive NMTC subtype.
A UAS construct incorporating a fusion of the two human genes, indicated in FlyBase as Hsap\NCOA4::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, CCDC6-RET fusion,' FBhh0000661.)
[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 OMIM:188550; 2017.11.24]
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).
Nuclear receptor coactivator 4 (NCOA4) encodes an androgen receptor coactivator; it interacts with the androgen receptor in a ligand-dependent manner to enhance its transcriptional activity. [Gene Cards, NCOA4; 2017.11.27]
One to one: 1 human to 1 Drosophila; additional more distantly related genes in both species.
No gene orthologous to NCOA4 has been identified in Drosophila.