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J Clin Endocrinol Metab. 2015 Mar;100(3):788-93. doi: 10.1210/jc.2014-4153. Epub 2014 Dec 29.

RET fusion as a novel driver of medullary thyroid carcinoma.

Author information

1
Departments of Surgical Oncology (E.G.G., J.B., J.E.L., F.M.-B., N.D.P.), Institute of Personalized Cancer Therapy (P.K.-S.N., K.R.S.), Endocrine Neoplasia and Hormonal Disorders (N.L.B., S.G.W., G.J.C.), Bioinformatics and Computational Biology (K.C.), Hematopathology (X.L.), Investigational Cancer Therapeutics (F.M.-B.), Systems Biology (G.B.M.), and Pathology (M.D.W.), University of Texas MD Anderson Cancer Center, Houston, Texas 77030; Foundation Medicine (G.P., R.Y.), Cambridge, Massachusetts 02141; and Integrative Molecular and Biomedical Sciences Graduate Program (H.L., K.L.S.), Baylor College of Medicine, Houston, Texas 77030.

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:

A reciprocal 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.

PMID:
25546157
PMCID:
PMC4333032
DOI:
10.1210/jc.2014-4153
[Indexed for MEDLINE]
Free PMC Article

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