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  • Author: Frederik J Hes x
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Karin van der Tuin, Marina Ventayol, Willem Corver, Midia Khalifa, Dina Ruano, E P Corssmit, Frederik J Hes, Thera P Links, Jan Smit, Theo S. Plantinga, E Kapiteijn, Ton Van Wezel and Hans Morreau

OBJECTIVE: 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.

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

METHODS: 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.

RESULTS: 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 (n=2), 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).

CONCLUSION: 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 fusionsmight 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.

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Nicolasine D Niemeijer, Johannes A Rijken, Karin Eijkelenkamp, Anouk N A van der Horst-Schrivers, Michiel N Kerstens, Carli M J Tops, Anouk van Berkel, Henri J L M Timmers, Henricus P M Kunst, C René Leemans, Peter H Bisschop, Koen M A Dreijerink, Marieke F van Dooren, Jean-Pierre Bayley, Alberto M Pereira, Jeroen C Jansen, Frederik J Hes, Erik F Hensen and Eleonora P M Corssmit

Objective

Succinate dehydrogenase B subunit (SDHB) gene germline mutations predispose to pheochromocytomas, sympathetic paragangliomas, head and neck paragangliomas and non-paraganglionic tumors (e.g. renal cell carcinoma, gastrointestinal stromal tumor and pituitary neoplasia). The aim of this study was to determine phenotypical characteristics of a large Dutch cohort of SDHB germline mutation carriers and assess differences in clinical phenotypes related to specific SDHB mutations.

Design

Retrospective descriptive study.

Methods

Retrospective descriptive study in seven academic centers.

Results

We included 194 SDHB mutation carriers consisting 65 (33.5%) index patients and 129 (66.5%) relatives. Mean age was 44.8 ± 16.0 years. Median duration of follow-up was 2.6 years (range: 0–36). Sixty persons (30.9%) carried the exon 3 deletion and 46 (23.7%) the c.423 + 1G > A mutation. Fifty-four mutation carriers (27.8%) had one or multiple head and neck paragangliomas, 4 (2.1%) had a pheochromocytoma and 26 (13.4%) had one or more sympathetic paragangliomas. Fifteen patients (7.7%) developed metastatic paraganglioma and 17 (8.8%) developed non-paraganglionic tumors. At study close, there were 111 (57.2%) unaffected mutation carriers. Statistical analyses showed no significant differences in the number and location of head and neck paragangliomas, sympathetic paragangliomas or pheochromocytomas, nor in the occurrence of metastatic disease or other tumors between carriers of the two founder SDHB mutations (exon 3 deletion vs c.423+ 1G > A).

Conclusions

In this nationwide study of disease-affected and unaffected SDHB mutation carriers, we observed a lower rate of metastatic disease and a relatively high number of head and neck paragangliomas compared with previously reported referral-based cohorts.