RET Fusion as a Novel Driver of Medullary Thyroid Carcinoma

Grubbs, Elizabeth G.; Ng, Patrick Kwok Shing; Bui, Jacquelin H.; Busaidy, Naifa L.; Chen, Ken; Lee, Jeffrey E.; Lu, Xinyan; Lu, Hengyu; Meric‐Bernstam, Funda; Mills, Gordon B.; Palmer, Gary A.; Perrier, Nancy D.; Scott, Kenneth L.; Shaw, Kenna; Waguespack, Steven G.; Williams, Michelle D.; Yelensky, Roman; Cote, Gilbert J.

doi:10.1210/jc.2014-4153

Cited by 65 publications

(42 citation statements)

References 22 publications

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“…Somatic RET mutations are the most common drivers in sporadic medullary thyroid carcinoma, followed by RAS mutations and RET or ALK fusions. 68–70 The clinical aggressiveness of hereditary or sporadic medullary thyroid carcinoma is related to the RET mutation.…”

Section: Medullary Thyroid Carcinomamentioning

confidence: 99%

Biologic and Clinical Perspectives on Thyroid Cancer

2016

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Section: Medullary Thyroid Carcinomamentioning

confidence: 99%

Biologic and Clinical Perspectives on Thyroid Cancer

2016

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“…For example, individual cases of myeloid neoplasms driven by fusions involving JAK2 and FLT3 are sensitive to JAK inhibitor (ruxolitinib) (8) and tyrosine kinase inhibitor (sorafenib) (9), respectively. Likewise, we recently reported an oncogenic fusion involving the RET kinase in a single medullary thyroid carcinoma patient whose activity is highly sensitive to multiple tyrosine kinase inhibitors (10). Together, these examples highlight the importance of identifying the subset of rare, oncogenic gene fusions and assessing their sensitivity to therapeutics.…”

Section: Introductionmentioning

confidence: 97%

Engineering and Functional Characterization of Fusion Genes Identifies Novel Oncogenic Drivers of Cancer

Villafañe

Dogruluk

et al. 2017

Cancer Research

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Oncogenic gene fusions drive many human cancers, but tools to more quickly unravel their functional contributions are needed. Here we describe methodology permitting fusion gene construction for functional evaluation. Using this strategy, we engineered the known fusion oncogenes, BCR-ABL1, EML4-ALK, and ETV6-NTRK3, as well as 20 previously uncharacterized fusion genes identified in TCGA datasets. In addition to confirming oncogenic activity of the known fusion oncogenes engineered by our construction strategy, we validated five novel fusion genes involving MET, NTRK2, and BRAF kinases that exhibited potent transforming activity and conferred sensitivity to FDA-approved kinase inhibitors. Our fusion construction strategy also enabled domain-function studies of BRAF fusion genes. Our results confirmed other reports that the transforming activity of BRAF fusions results from truncation-mediated loss of inhibitory domains within the N-terminus of the BRAF protein. BRAF mutations residing within this inhibitory region may provide a means for BRAF activation in cancer, therefore we leveraged the modular design of our fusion gene construction methodology to screen N-terminal domain mutations discovered in tumors that are wild-type at the BRAF mutation hotspot, V600. We identified an oncogenic mutation, F247L, whose expression robustly activated the MAPK pathway and sensitized cells to BRAF and MEK inhibitors. When applied broadly, these tools will facilitate rapid fusion gene construction for subsequent functional characterization and translation into personalized treatment strategies.

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“…These RET fusion proteins frequently contain coiled-coil domains (CCDs) within their partner genes and result in aberrant activation of RET kinase by their CCD-dependent homodimerization [2, 19, 20]. RET dimerization and autophosphorylation via intracellular tyrosine residues 1062 (pY1062) and pY1096 (in the RET51 isoform only) recruit adaptor and signaling proteins to stimulate multiple downstream molecules [6].…”

Section: Introductionmentioning

confidence: 99%

Identification of a novel partner gene, KIAA1217, fused to RET: Functional characterization and inhibitor sensitivity of two isoforms in lung adenocarcinoma

et al. 2016

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REarranged during Transfection (RET) fusion genes are detected in approximately 1% of lung adenocarcinomas and known primarily as oncogenic driver factors. Here, we found a novel RET fusion gene, KIAA1217-RET, and examined the functional differences of RET51 and RET9 protein, fused with KIAA1217 in cancer progression and drug response. KIAA1217-RET, resulting from the rearrangement of chromosome 10, was generated by the fusion of KIAA1217 exon 11 and RET exon 11 from a non-small cell lung cancer patient. Expression of this gene led to increased cell growth and invasive properties through activations of the PI3K/AKT and ERK signaling pathways and subsequently enabled oncogenic transformation of lung cells. We observed that cells expressing KIAA1217-RET9 fusion protein were more sensitive to vandetanib than those expressing KIAA1217-RET51 and both isoforms attenuated cellular growth via cell cycle arrest. These results demonstrated that KIAA1217-RET fusion represents a novel oncogenic driver gene, the products of which are sensitive to vandetanib treatment, and suggested that the KIAA1217-RET-fusion gene is a promising target for lung cancer treatment.

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RET Fusion as a Novel Driver of Medullary Thyroid Carcinoma

Cited by 65 publications

References 22 publications

Biologic and Clinical Perspectives on Thyroid Cancer

Biologic and Clinical Perspectives on Thyroid Cancer

Engineering and Functional Characterization of Fusion Genes Identifies Novel Oncogenic Drivers of Cancer

Identification of a novel partner gene, KIAA1217, fused to RET: Functional characterization and inhibitor sensitivity of two isoforms in lung adenocarcinoma

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