RET fusion as a novel driver of medullary thyroid carcinoma

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

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Introduction: Oncogenic RET tyrosine kinase gene fusions and activating mutations have recently been identified in lung cancers, prompting initiation of targeted therapy trials in this disease. Although RET point mutation has been identified as a driver of tumorigenesis in medullary thyroid carcinoma (MTC), no fusions have been described to date. Objective: We evaluated the role of RET fusion as an oncogenic driver in MTC. Methods: We describe a patient who died from aggressive sporadic MTC < 10 months after diagnosis. Her tumor was evaluated by means of next-generation sequencing, including an intronic capture strategy. Results: Areciprocal translocation involving RET intron 12 was identified. The fusion was validated using a targeted break apart fluorescence in situ hybridization probe, and RNA sequencing confirmed the existence of an in-frame fusion transcript joining MYH13 exon 35 with RET exon 12. Ectopic expression of fusion product in a murine Ba/F3 cell reporter model established strong oncogenicity. Three tyrosine kinase inhibitors currently used to treat MTC in clinical practice blocked tumorigenic cell growth. Conclusion: This finding represents the report of a novel RET fusion, the first of its kind described in MTC. The finding of this potential novel oncogenic mechanism has clear implications for sporadic MTC, which in the majority of cases has no driver mutation identified. The presence of a RET fusion also provides a plausible target for RET tyrosine kinase inhibitor therapies.

Original languageEnglish (US)
Pages (from-to)788-793
Number of pages6
JournalJournal of Clinical Endocrinology and Metabolism
Volume100
Issue number3
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

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Fusion reactions
Protein-Tyrosine Kinases
Exons
RNA Sequence Analysis
Mutation
Gene Fusion
RNA Probes
Fluorescence In Situ Hybridization
Point Mutation
Introns
Medullary Thyroid cancer
Lung Neoplasms
Carcinogenesis
Cell growth
Joining
Tumors
Genes
Fluorescence
Therapeutics
Growth

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

Cite this

Grubbs, E. G., Ng, P. K. S., Bui, J., Busaidy, N. L., Chen, K., Lee, J. E., ... Cote, G. J. (2015). RET fusion as a novel driver of medullary thyroid carcinoma. Journal of Clinical Endocrinology and Metabolism, 100(3), 788-793. https://doi.org/10.1210/jc.2014-4153

RET fusion as a novel driver of medullary thyroid carcinoma. / Grubbs, Elizabeth G.; Ng, Patrick Kwok Shing; Bui, Jacquelin; Busaidy, Naifa L.; Chen, Ken; Lee, Jeffrey E.; Lu, Xinyan; Lu, Hengyu; Meric-Bernstam, Funda; Mills, Gordon; Palmer, Gary; Perrier, Nancy D.; Scott, Kenneth L.; Shaw, Kenna R.; Waguespack, Steven G.; Williams, Michelle D.; Yelensky, Roman; Cote, Gilbert J.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 100, No. 3, 01.01.2015, p. 788-793.

Research output: Contribution to journalArticle

Grubbs, EG, Ng, PKS, Bui, J, Busaidy, NL, Chen, K, Lee, JE, Lu, X, Lu, H, Meric-Bernstam, F, Mills, G, Palmer, G, Perrier, ND, Scott, KL, Shaw, KR, Waguespack, SG, Williams, MD, Yelensky, R & Cote, GJ 2015, 'RET fusion as a novel driver of medullary thyroid carcinoma', Journal of Clinical Endocrinology and Metabolism, vol. 100, no. 3, pp. 788-793. https://doi.org/10.1210/jc.2014-4153
Grubbs, Elizabeth G. ; Ng, Patrick Kwok Shing ; Bui, Jacquelin ; Busaidy, Naifa L. ; Chen, Ken ; Lee, Jeffrey E. ; Lu, Xinyan ; Lu, Hengyu ; Meric-Bernstam, Funda ; Mills, Gordon ; Palmer, Gary ; Perrier, Nancy D. ; Scott, Kenneth L. ; Shaw, Kenna R. ; Waguespack, Steven G. ; Williams, Michelle D. ; Yelensky, Roman ; Cote, Gilbert J. / RET fusion as a novel driver of medullary thyroid carcinoma. In: Journal of Clinical Endocrinology and Metabolism. 2015 ; Vol. 100, No. 3. pp. 788-793.
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AU - Ng, Patrick Kwok Shing

AU - Bui, Jacquelin

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AU - Chen, Ken

AU - Lee, Jeffrey E.

AU - Lu, Xinyan

AU - Lu, Hengyu

AU - Meric-Bernstam, Funda

AU - Mills, Gordon

AU - Palmer, Gary

AU - Perrier, Nancy D.

AU - Scott, Kenneth L.

AU - Shaw, Kenna R.

AU - Waguespack, Steven G.

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AU - Yelensky, Roman

AU - Cote, Gilbert J.

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