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General Information
Name
thyroid carcinoma, nonmedullary, NCOA4-RET fusion
FlyBase ID
FBhh0000662
OMIM
Overview

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]

Disease Summary Information
Parent Disease Summary: thyroid carcinoma, nonmedullary
Symptoms and phenotype

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]

Specific Disease Summary: thyroid carcinoma, nonmedullary, NCOA4-RET fusion
OMIM report
Human gene(s) implicated
Symptoms and phenotype
Genetics

Two RET fusion isoforms, CCDC6-RET and NCOA4-RET, account for >90% of fusions associated with nonmedullary thyroid carcinoma; NCOA4-RET is associated with a more aggressive and malignant subtype (FBrf0233455).

Cellular phenotype and pathology

RET fusion proteins are not localized to the cell membrane (FBrf0233455).

Molecular information

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]

External links
Disease synonyms
PTC
Ortholog Information
Human gene(s) in FlyBase
Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)

One to one: 1 human to 1 Drosophila; additional more distantly related genes in both species.

Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)

No gene orthologous to NCOA4 has been identified in Drosophila.

Other mammalian ortholog(s) used
    D. melanogaster Gene Information (0)
    Other Genes Used: Viral, Bacterial, Synthetic (0)
      Summary of Physical Interactions (0 groups)
      Alleles Reported to Model Human Disease (Disease Ontology) (1 alleles)
      Models Based on Experimental Evidence ( 1 )
      Modifiers Based on Experimental Evidence ( 0 )
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      Disease
      Interaction
      References
      Alleles Representing Disease-Implicated Variants
      Genetic Tools, Stocks and Reagents
      Sources of Stocks
      Contact lab of origin for a reagent not available from a public stock center.
      Bloomington Stock Center Disease Page
      Selected mammalian transgenes
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      Transgene
      Publicly Available Stocks
      Selected Drosophila transgenes
      Allele
      Transgene
      Publicly Available Stocks
      RNAi constructs available
      Allele
      Transgene
      Publicly Available Stocks
      Selected Drosophila classical alleles
      Allele
      Allele class
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      Publicly Available Stocks
      References (12)