Targetable gene fusions identified in radioactive iodine refractory advanced thyroid carcinoma

in European Journal of Endocrinology
Correspondence should be addressed to H Morreau; Email:
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Gene alterations leading to activation of the MAPK pathway are of interest for targeted therapy in patients with advanced radioactive iodine refractory (RAI-R) thyroid carcinoma. Due to technical reasons gene fusion analysis in RNA isolated from formalin-fixed tumor tissues has till now been limited. The objective of the present study was to identify targetable gene rearrangements in RNA isolated from formalin-fixed RAI-R thyroid carcinomas.


Retrospective study in 132 patients with RAI-R thyroid carcinoma (59 papillary-, 24 follicular-, 35 Hürthle cell- and 14 anaplastic thyroid carcinoma).


Total nucleic acid (undivided DNA and RNA) was isolated from formalin-fixed tissue. Extensive gene fusion analysis was performed in all samples that tested negative for pathogenic BRAF, NRAS, HRAS and KRAS variants.


Seven targetable gene fusions were identified in the remaining 60 samples without known DNA variants. This includes frequently reported gene fusions such as CCDC6/RET (PTC1), PRKAR1A/RET (PTC2) and ETV6/NTRK3 , and gene fusions that are less common in thyroid cancer (TPM3/NTRK1, EML4/ALK and EML4/NTRK3). Of note, most gene fusions were detected in papillary thyroid carcinoma and MAPK-associated alterations in Hürthle cell carcinomas are rare (2/35).


Targetable gene fusions were found in 12% of RAI-R thyroid carcinoma without DNA variants and can be effectively identified in formalin-fixed tissue. These gene fusions might provide a preclinical rationale to include specific kinase inhibitors in the treatment regimen for these patients. The latter intends to restore iodine transport and/or take advantage of the direct effect on tumor cell vitality once progressive disease is seen.

Downloadable materials

  • Supplemental Table 1 | Study population characteristics
  • Supplemental Table 2 | Identified RAS variants in RAI-R DTC
  • Supplemental Figure 1 | Kaplan-Meier curves overall survival
  • Supplemental Figure 2 | ALK immunohistochemical staining


     European Society of Endocrinology

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    Flow chart of study population. In total, 132 RAI-R thyroid carcinomas with valid results for gene fusion and/or DNA variant analysis were included. We identified 45 BRAF, 27 RAS pathogenic variant(s) and 7 targetable gene fusions. FTC, follicular thyroid carcinoma; FVPTC, follicular variant PTC; HCC, Hürthle cell carcinoma; MAPK, mitogen-activated protein kinase pathway; PTC, papillary thyroid carcinoma; RAI-R, radioactive iodine refractory.


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