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  • Thyroid cancer - basic and translational x
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Hyun-Jin Lee Department of Otorhinolaryngology-Head and Neck Surgery, Gyeongsang National University College of Medicine, Jinju, South Korea
Department of Otorhinolaryngology-Head and Neck Surgery, Chung-Ang University College of Medicine, Seoul, South Korea

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Young-Sool Hah Biomedical Research Institute, Gyeongsang National University Hospital, Jinju, South Korea

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So Young Cheon Biomedical Research Institute, Gyeongsang National University Hospital, Jinju, South Korea

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Seong Jun Won Department of Otorhinolaryngology-Head and Neck Surgery, Gyeongsang National University College of Medicine, Jinju, South Korea
Department of Otorhinolaryngology-Head and Neck Surgery, Gyeongsang National University Hospital, Jinju, South Korea
Institute of Health Sciences, Gyeongsang National University, Jinju, South Korea

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Chae Dong Yim Department of Otorhinolaryngology-Head and Neck Surgery, Gyeongsang National University College of Medicine, Jinju, South Korea
Department of Otorhinolaryngology-Head and Neck Surgery, Gyeongsang National University Hospital, Jinju, South Korea
Institute of Health Sciences, Gyeongsang National University, Jinju, South Korea

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Somi Ryu Department of Otorhinolaryngology-Head and Neck Surgery, Gyeongsang National University College of Medicine, Jinju, South Korea
Department of Otorhinolaryngology-Head and Neck Surgery, Gyeongsang National University Hospital, Jinju, South Korea
Institute of Health Sciences, Gyeongsang National University, Jinju, South Korea

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Seung-Jun Lee Department of Convergence of Medical Sciences, Gyeongsang National University, Jinju, South Korea

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Ji Hyun Seo Institute of Health Sciences, Gyeongsang National University, Jinju, South Korea
Department of Pediatrics, Gyeongsang National University College of Medicine, Jinju, South Korea

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Jung Je Park Department of Otorhinolaryngology-Head and Neck Surgery, Gyeongsang National University College of Medicine, Jinju, South Korea
Biomedical Research Institute, Gyeongsang National University Hospital, Jinju, South Korea
Department of Otorhinolaryngology-Head and Neck Surgery, Gyeongsang National University Hospital, Jinju, South Korea
Institute of Health Sciences, Gyeongsang National University, Jinju, South Korea

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Objective

This study examined the effect of sirtuin 4 (SIRT4), a NAD+-dependent deacetylase, on the proliferation and progression of papillary thyroid carcinoma (PTC).

Methods

Data from The Cancer Genome Atlas (TCGA) were analyzed to identify SIRT4 expression in thyroid cancer. Subsequently, the correlation between SIRT4 expression and clinical characteristics was examined in 205 PTC tissue samples. In vitro assays using three human thyroid cancer cell lines (B-CPAP, TPC-1, and SNU-790) were conducted to assess the effects of regulated SIRT4 expression on cell growth, apoptosis, invasion, and migration. Furthermore, in vivo experiments were performed in a xenograft mouse model.

Results

Gene Expression Omnibus (GEO) and TCGA data indicated that SIRT4 expression is lower in thyroid cancer and SIRT4 downregulation is associated with poor overall survival. In PTC tissues, positive SIRT4 expression was associated with decreased extracapsular extension. In in vitro experiments using three human thyroid cancer cell lines, overexpression of SIRT4 decreased cell survival, clonogenic potential, and invasion and migratory capabilities, as well as inducing apoptosis and increasing reactive oxygen species levels. SIRT4 overexpression upregulated E-cadherin and downregulated N-cadherin, suggesting its potential involvement in the regulation of epithelial–mesenchymal transition. These findings were confirmed in vivo using a xenograft mouse model.

Conclusion

This study provides novel insight into the potential contribution of SIRT4 to the regulation of the pathological progression of PTC. The data suggest that SIRT4 plays a tumor-suppressive role in PTC by inhibiting growth, survival, and invasive potential. Future research should investigate the molecular mechanisms underlying these effects of SIRT4.

Open access
Fabio Hecht Université Paris-Saclay, Orsay, France
UMR 9019 CNRS F-94805 Villejuif, France
Gustave Roussy, Villejuif, France

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Laura Valerio Université Paris-Saclay, Orsay, France
UMR 9019 CNRS F-94805 Villejuif, France
Gustave Roussy, Villejuif, France

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Carlos Frederico Lima Gonçalves Université Paris-Saclay, Orsay, France
UMR 9019 CNRS F-94805 Villejuif, France
Gustave Roussy, Villejuif, France

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Marylin Harinquet Université Paris-Saclay, Orsay, France
UMR 9019 CNRS F-94805 Villejuif, France
Gustave Roussy, Villejuif, France

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Rabii Ameziane El Hassani Laboratoire de Biologie des Pathologies Humaines ‘BioPatH’, Université Mohammed V de Rabat, Faculté des Sciences, BP1014 Rabat, 10001, Morocco

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Denise P Carvalho Laboratório de Fisiologia Endócrina Doris Rosenthal, nstituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

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Stephane Koundrioukoff UMR 9019 CNRS F-94805 Villejuif, France
Gustave Roussy, Villejuif, France
Sorbonne Université, Paris, France

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Jean-Charles Cadoret Université Paris Cité, CNRS, Institut Jacques Monod, Paris, France

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Corinne Dupuy Université Paris-Saclay, Orsay, France
UMR 9019 CNRS F-94805 Villejuif, France
Gustave Roussy, Villejuif, France

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Objective

Ionizing radiation generates genomic instability by promoting the accumulation of chromosomal rearrangements. The oncogenic translocation RET/PTC1 is present in more than 70% of radiation-induced thyroid cancers. Both RET and CCDC6, the genes implicated in RET/PTC1, are found within common fragile sites – chromosomal regions prone to DNA breakage during slight replication stress. Given that irradiated cells become more susceptible to genomic destabilization due to the accumulation of replication-stress-related double-strand breaks (DSBs), we explored whether RET and CCDC6 exhibit DNA breakage under replicative stress several days post-irradiation of thyroid cells.

Methods

We analyzed the dynamic of DNA replication in human thyroid epithelial cells (HThy-ori-3.1) 4 days post a 5-Gy exposure using molecular DNA combing. The DNA replication schedule was evaluated through replication-timing experiments. We implemented a ChIP-qPCR assay to determine whether the RET and CCDC6 genes break following irradiation.

Results

Our study indicates that replicative stress, occurring several days post-irradiation in thyroid cells, primarily causes DSBs in the RET gene. We discovered that both the RET and CCDC6 genes undergo late replication in thyroid cells. However, only RET’s replication rate is notably delayed after irradiation.

Conclusion

The findings suggest that post-irradiation in the RET gene causes a breakage in the replication fork, which could potentially invade another genomic area, including CCDC6. As a result, this could greatly contribute to the high prevalence of chromosomal RET/PTC rearrangements seen in patients exposed to external radiation.

Open access
Zhaoqi Zhang Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria
Department of Nuclear Medicine, The Fourth hospital of Hebei Medical University, Shijiazhuang, Hebei, China

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Josef Yu Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria

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Eva Rainer Department of Biomedical Imaging and Image-guided Therapy, Division of General and Pediatric Radiology, Medical University of Vienna, Vienna, Austria

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Lindsay Hargitai Department of General Surgery, Medical University of Vienna, Vienna, Austria

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Zewen Jiang Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria

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Georgios Karanikas Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria

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Tatjana Traub-Weidinger Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria

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Richard Crevenna Department of Physical Medicine, Rehabilitation and Occupational Medicine, Medical University of Vienna, Vienna, Austria.

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Marcus Hacker Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria

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Shuren Li Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria

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Objective

Correct diagnosis and prognostic evaluation of medullary thyroid cancer (MTC) are crucial to treat patients. The purpose of this study was to evaluate the diagnostic and prognostic value of [18F]F-DOPA PET/CT in patients with MTC.

Methods

We reviewed MTC patients who underwent [18F]F-DOPA PET/CT from June 2008 to November 2023. Clinical characteristics, follow-up data, and the following [18F]F-DOPA PET/CT parameters were recorded: maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), metabolic tumor volume (MTV), and SUVmean of multiple organs. The diagnostic value of PET/CT for the detection of tumor lesions was calculated. Serum basal calcitonin (bCt) and stimulated calcitonin (sCt) were determined. Receiver operating characteristics, Kaplan–Meier, and Cox regression analyses were performed.

Results

In total, 109 patients (50 women, 59 men; average age, 55 ± 14 years) were included in the analysis. The patient-related sensitivity, specificity, and accuracy of [18F]F-DOPA PET/CT were 95%, 93%, and 94%, respectively. The lesion-related sensitivity, specificity, and accuracy were 65%, 99%, and 72%, respectively. The optimal cutoff values of bCt, sCt, and CEA to obtain positive [18F]F-DOPA PET/CT results were 64 pg/mL, 1808 pg/mL, and 4 µg/L, respectively. Patients with negative [18F]F-DOPA PET/CT had longer overall survival than patients with positive [18F]F-DOPA PET/CT results (P = 0.017). Significant positive correlations were found between bCt, sCt, and CEA with SUVmax, SUVmean, and MTV of [18F]F-DOPA PET/CT (P < 0.001). [18F]F-DOPA PET/CT results and MTV may be useful for the evaluation of the prognosis of patients with recurrent MTC, while age and MTV were independent prognostic factors in patients with primary MTC. For all patients, SUVmean of the left kidney, liver, aorta, and pancreas might be used to independently predict OS.

Conclusion

[18F]F-DOPA PET/CT had great value for diagnosis and prognostic assessment in patients with MTC. The DOPA PET/CT parameter SUVmean and MTV showed significant association with OS.

Open access
Carla Colombo Endocrine Oncology Unit, Department of Endocrine and Metabolic Diseases, Istituto Auxologico Italiano IRCCS, Milan, Italy
Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy

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Daniele Ceruti Department of Biotechnology and Translational Medicine, University of Milan, Milan, Italy

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Massimiliano Succi Department of Biotechnology and Translational Medicine, University of Milan, Milan, Italy

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Simone De Leo Endocrine Oncology Unit, Department of Endocrine and Metabolic Diseases, Istituto Auxologico Italiano IRCCS, Milan, Italy

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Matteo Trevisan Endocrine Oncology Unit, Department of Endocrine and Metabolic Diseases, Istituto Auxologico Italiano IRCCS, Milan, Italy
Department of Biotechnology and Translational Medicine, University of Milan, Milan, Italy

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Claudia Moneta Department of Biotechnology and Translational Medicine, University of Milan, Milan, Italy

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Laura Fugazzola Endocrine Oncology Unit, Department of Endocrine and Metabolic Diseases, Istituto Auxologico Italiano IRCCS, Milan, Italy
Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy

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Background

Fatigue is a frequent adverse event during systemic treatments for advanced thyroid cancer, often leading to reduction, interruption, or discontinuation. We were the first group to demonstrate a correlation between fatigue and primary adrenal insufficiency (PAI).

Aim

The objective was to assess the entire adrenal function in patients on systemic treatments.

Methods

ACTH, cortisol and all the hormones produced by the adrenal gland were evaluated monthly in 36 patients (25 on lenvatinib, six on vandetanib, and five on selpercatinib). ACTH stimulation tests were performed in 26 cases.

Results

After a median treatment period of 7 months, we observed an increase in ACTH values in 80–100% of patients and an impaired cortisol response to the ACTH test in 19% of cases. Additionally, dehydroepiandrosterone sulphate, ∆-4-androstenedione and 17-OH progesterone levels were below the median of normal values in the majority of patients regardless of the drug used. Testosterone in females and oestradiol in males were below the median of normal values in the majority of patients on lenvatinib and vandetanib. Finally, aldosterone was below the median of the normal values in most cases, whilst renin levels were normal. Metanephrines and normetanephrines were always within the normal range. Replacement therapy with cortisone acetate improved fatigue in 14/17 (82%) patients with PAI.

Conclusion

Our data confirm that systemic treatments for advanced thyroid cancer can lead to impaired cortisol secretion. A reduction in the other hormones secreted by the adrenal cortex has been first reported and should be considered in the more appropriate management of these fragile patients.

Open access
Abdul Rehman Syed University of Calgary, Calgary, Alberta, Canada

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Aakash Gorana Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Alberta, Canada

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Erik Nohr Alberta Precision Laboratories, Molecular Pathology Program, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada

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Xiaoli-Kat Yuan Precision Oncology Hub Laboratory, Tom Baker Cancer Centre, Calgary, Alberta, Canada

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Parthiv Amin MASc Department of Radiology, Cumming School of Medicine, University of Calgary, Calgary Alberta, Canada

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Sana Ghaznavi Arnie Charbonneau Cancer Institute, Department of Medicine, Section of Endocrinology, University of Calgary, Calgary, Alberta, Canada

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Debbie Lamb Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Alberta, Canada

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John McIntyre Precision Oncology Hub Laboratory, Tom Baker Cancer Centre, Calgary, Alberta, Canada

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Markus Eszlinger Department of Oncology, Cumming School of Medicine, and Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada

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Ralf Paschke Departments of Medicine, Section of Endocrinology, Oncology, Pathology and Laboratory Medicine, Biochemistry and Molecular Biology and Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada

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Context

Two-thirds of metastatic differentiated thyroid cancer (DTC) patients have radioiodine (RAI)-resistant disease, resulting in poor prognosis and high mortality. For rare NTRK and RET fusion-positive metastatic, RAI-resistant thyroid cancers, variable success of re-induction of RAI avidity during treatment with NTRK or RET inhibitors has been reported.

Case presentation and results

We report two cases with RAI-resistant lung metastases treated with larotrectinib: an 83-year-old male presenting with an ETV6::NTRK3 fusion-positive tumor with the TERT promoter mutation c.-124C>T, and a 31-year-old female presenting with a TPR::NTRK1 fusion-positive tumor (and negative for TERT promoter mutation). Post larotrectinib treatment, diagnostic I-123 whole body scan revealed unsuccessful RAI-uptake re-induction in the TERT-positive tumor, with a thyroid differentiation score (TDS) of −0.287. In contrast, the TERT-negative tumor exhibited successful I-131 reuptake with a TDS of −0.060.

Conclusion

As observed for RAI-resistance associated with concurrent TERT and BRAF mutations, the co-occurrence of TERT mutations and NTRK fusions may also contribute to re-sensitization failure.

Open access
Hélène Théodon Department of Thyroid and Endocrine Tumors, Sorbonne Université, GRC n°16, GRC Tumeurs Thyroïdiennes, Pitié-Salpêtrière Hospital, Paris, France

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Erell Guillerm Department of Oncogenetic, Sorbonne Université, GRC n°16, GRC Tumeurs Thyroïdiennes, Pitié-Salpêtrière Hospital, Paris, France

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Johanna Wassermann Department of Oncology, Sorbonne Université, GRC n°16, GRC Tumeurs Thyroïdiennes, Pitié-Salpêtrière Hospital, Paris, France

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Gabrielle Deniziaut Department of Pathology, Sorbonne Université, GRC n°16, GRC Tumeurs Thyroïdiennes, Pitié-Salpêtrière Hospital, Paris, France

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Loïc Jaffrelot Department of Oncology, Sorbonne Université, GRC n°16, GRC Tumeurs Thyroïdiennes, Pitié-Salpêtrière Hospital, Paris, France

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Jérome Denis Department of Endocrine and Oncology Biochemistry, Sorbonne Université, Pitié-Salpêtrière Hospital, Paris, France

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Nathalie Chereau Department of Endocrine Surgery, Sorbonne Université, GRC n°16, GRC Tumeurs Thyroïdiennes, Pitié-Salpêtrière Hospital, Paris, France

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Claude Bigorgne Department of Pathology, Sorbonne Université, GRC n°16, GRC Tumeurs Thyroïdiennes, Pitié-Salpêtrière Hospital, Paris, France

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Wiame Potonnier Department of Pathology, Sorbonne Université, GRC n°16, GRC Tumeurs Thyroïdiennes, Pitié-Salpêtrière Hospital, Paris, France

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Florence Coulet Department of Oncogenetic, Sorbonne Université, GRC n°16, GRC Tumeurs Thyroïdiennes, Pitié-Salpêtrière Hospital, Paris, France

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Laurence Leenhardt Department of Thyroid and Endocrine Tumors, Sorbonne Université, GRC n°16, GRC Tumeurs Thyroïdiennes, Pitié-Salpêtrière Hospital, Paris, France

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Camille Buffet Department of Thyroid and Endocrine Tumors, Sorbonne Université, GRC n°16, GRC Tumeurs Thyroïdiennes, Pitié-Salpêtrière Hospital, Paris, France

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Objective

Tumor molecular genotyping plays a key role in improving the management of advanced thyroid cancers. Molecular tests are classically performed on formalin-fixed, paraffin-embedded (FFPE) carcinoma tissue. However alternative molecular testing strategies are needed when FFPE tumoral tissue is unavailable. The objective of our study was to retrospectively assess the performance of targeted DNA and RNA-based next-generation sequencing (NGS) on the fine needle aspirate from thyroid cancer cervical recurrences to determine if this strategy is efficient in clinical practice.

Design/Methods

A retrospective study of 33 patients who had had DNA and/or RNA-based NGS on ultrasound (US)-guided fine needle aspirates of cervical thyroid cancer recurrences in our Department from July 2019 to September 2022.

Results

In total, 34 DNA and 32 RNA-based NGS analyses were performed. Out of the 34 DNA-based NGS performed, 27 (79%) were conclusive allowing the identification of an oncogenic driver for 18 patients (53%). The most common mutation (n = 13) was BRAF c.1799T>A. Out of the 32 RNA-based NGS performed, 26 were interpretable (81%) and no gene fusion was found. The identification of a BRAFV600E mutation was decisive for one patient in our series, who was prescribed dabrafenib and trametinib.

Conclusion

NGS performed on fine needle aspirates of neck lymph node metastases enabled the identification of an oncogenic driver alteration in 53% of the cases in our series of advanced thyroid cancer patients and could significantly alter patient management.

Significance statement

This paper shows that thyroid cancer genotyping on the fine needle aspirate (FNA) of a metastatic neck lymph node recurrence can be performed efficiently. This strategy of genotyping appears particularly effective and safe when FFPE tissue is unavailable and when the spread of the disease requires systemic treatment. To the best of our knowledge, our data regarding DNA and RNA next generation sequencing on FNA of metastatic neck recurrences are the first ever published.

Open access
Markus Eszlinger Department of Oncology and Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Heritage Medical Research Building, Calgary, Alberta, Canada, and Institute of Pathology, University Hospital Halle, Halle, Germany

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Alexandra Stephenson Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Heritage Medical Research Building, Calgary, Alberta, Canada

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Shideh Mirhadi Program in Cell Biology, Hospital for Sick Children, and Department of Molecular Genetics, University of Toronto, Peter Gilgan Centre for Research and Learning, Toronto, Ontario, Canada

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Konrad Patyra Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Turku, Finland

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Michael F Moran Program in Cell Biology, Hospital for Sick Children, and Department of Molecular Genetics, University of Toronto, Peter Gilgan Centre for Research and Learning, Toronto, Ontario, Canada

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Moosa Khalil Department of Pathology and Laboratory Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada

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Jukka Kero Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Turku, Finland
Department of Pediatrics, Turku University Hospital, Turku, Finland

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Ralf Paschke Department of Oncology and Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Heritage Medical Research Building, Calgary, Alberta, Canada, and Institute of Pathology, University Hospital Halle, Halle, Germany
Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Heritage Medical Research Building, Calgary, Alberta, Canada
Department of Pathology and Laboratory Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
Department of Medicine, Cumming School of Medicine, University of Calgary, Heritage Medical Research Building, Calgary, Alberta, Canada

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Objective

Nonautoimmune hyperthyroidism (NAH) is rare and occurs due to a constitutively activating thyroid stimulating hormone receptor (TSHR) mutation. In contrast to other thyroid nodules, no further evaluation for malignancy is recommended for hot thyroid nodules. In the first model for NAH in mice nearly all homozygous mice had developed papillary thyroid cancer by 12 months of age.

Methods

To further evaluate these mice, whole exome sequencing and phosphoproteome analysis were employed in a further generation of mice to identify any other mutations potentially responsible and to identify the pathways involved in thyroid carcinoma development.

Results

Only three genes (Nrg1, Rrs1, Rasal2) were mutated in all mice examined, none of which were known primary drivers of papillary thyroid cancer development. Wild-type and homozygous TSHR D633H knockin mice showed distinct phosphoproteome profiles with an enrichment of altered phosphosites found in ERK/mitogen-activated protein kinase (MAPK) signaling. Most importantly, phosphosites with known downstream effects included BRAF p.S766, which forms an inhibitory site: a decrease of phosphorylation at this site suggests an increase in MEK/ERK pathway activation. The decreased phosphorylation at BRAF p.S766 would suggest decreased AMP-activated protein kinase (AMPK) signaling, which is supported by the decreased phosphorylation of STIM1 p.S257, a downstream AMPK target.

Conclusion

The modified phosphoproteome profile of the homozygous mice in combination with human literature suggests a potential signaling pathway from constitutive TSHR signaling and cAMP activation to the activation of ERK/MAPK signaling. This is the first time that a specific mechanism has been identified for a possible involvement of TSH signaling in thyroid carcinoma development.

Open access
Joachim N Nilsson Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
Department of Medical Radiation Physics and Nuclear Medicine, Karolinska University Hospital, Stockholm, Sweden

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Jonathan Siikanen Department of Medical Radiation Physics and Nuclear Medicine, Karolinska University Hospital, Stockholm, Sweden
Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

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Vincenzo Condello Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

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Kenbugul Jatta Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
Department of Pathology and Cancer Diagnostics, Karolinska University Hospital, Stockholm, Sweden

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Ravi Saini Department of Pathology and Cancer Diagnostics, Karolinska University Hospital, Stockholm, Sweden

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Christel Hedman Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
Stockholms Sjukhem Foundation's Research and Development Department, Stockholm, Sweden
Department of Clinical Sciences Lund, Lund University, Lund, Sweden

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Catharina Ihre Lundgren Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
Department of Breast, Endocrine Tumours and Sarcoma, Karolinska University Hospital, Stockholm, Sweden

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C Christofer Juhlin Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
Department of Pathology and Cancer Diagnostics, Karolinska University Hospital, Stockholm, Sweden

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Background

Successful radioiodine treatment of differentiated thyroid cancer requires iodine avidity: that is, the concentration and retention of iodine in cancer tissue. Several parameters have previously been linked with lower iodine avidity. However, a comprehensive analysis of which factors best predict iodine avidity status, and the magnitude of their impact, is lacking.

Methods

Quantitative measurements of iodine avidity in surgical specimens (primary tumour and lymph node metastases) of 28 patients were compared to immunohistochemical expression of the thyroid-stimulating hormone receptor, thyroid peroxidase (TPO), pendrin, sodium–iodide symporter (NIS) and mutational status of BRAF and the TERT promoter. Regression analysis was used to identify independent predictors of poor iodine avidity.

Results

Mutations in BRAF and the TERT promoter were significantly associated with lower iodine avidity for lymph node metastases (18-fold and 10-fold, respectively). Membranous NIS localisation was found only in two cases but was significantly associated with high iodine avidity. TPO expression was significantly correlated with iodine avidity (r = 0.44). The multivariable modelling showed that tumour tissue localisation (primary tumour or lymph node metastasis), histological subtype, TPO and NIS expression and TERT promoter mutation were each independent predictors of iodine avidity that could explain 68% of the observed variation of iodine avidity.

Conclusions

A model based on histological subtype, TPO and NIS expression and TERT promoter mutation, all evaluated on initial surgical material, can predict iodine avidity in thyroid cancer tissue ahead of treatment. This could inform early adaptation with respect to expected treatment effect.

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Ségolène Hescot Department of Drug Development and Innovation (D3i), Institut Curie, Paris, France

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Julien Masliah-Planchon Department of Genetics, Institut Curie, Paris, France

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Pauline du Rusquec Department of Drug Development and Innovation (D3i), Institut Curie, Paris, France

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Célia Dupain Department of Drug Development and Innovation (D3i), Institut Curie, Paris, France

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Maud Kamal Department of Drug Development and Innovation (D3i), Institut Curie, Paris, France

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Vincent Servois Department of Radiology, Institut Curie, Paris, France

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Ivan Bieche Department of Genetics, Institut Curie, Paris, France

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Markus Eszlinger Departments of Oncology, Pathology and Laboratory Medicine, Biochemistry and Molecular Biology, and Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Heritage Medical Research Building, Calgary, Alberta, Canada
Institute of Pathology, University Hospital Halle (Saale), Halle (Saale), Germany

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Paul Stewardson Department of Medical Science and Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada

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John B McIntyre Precision Oncology Hub Laboratory, Alberta Health Services, Tom Baker Cancer Centre, Calgary, Alberta, Canada

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Adrian Box Department of Pathology and Laboratory Medicine, Cumming School of Medicine, University of Calgary, Calgary, Canada

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Moosa Khalil Department of Pathology and Laboratory Medicine, Cumming School of Medicine, University of Calgary, Calgary, Canada

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Martin Hyrcza Department of Pathology and Laboratory Medicine, Cumming School of Medicine, University of Calgary, Calgary, Canada

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Konstantin Koro Department of Pathology and Laboratory Medicine, Cumming School of Medicine, University of Calgary, Calgary, Canada

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Dean Ruether Section of Medical Oncology, Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, Canada

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Jiahui Wu Department of Medical Science and Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada

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Ralf Paschke Departments of Medicine, Oncology, Pathology and Laboratory Medicine, Biochemistry and Molecular Biology, and Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Heritage Medical Research Building, Calgary, Alberta, Canada

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Objective

The aim of the study was to identify patients with NTRK fusion-positive or RET fusion/mutation-positive thyroid cancers, who could benefit from neurotrophic tyrosine kinase receptor (NTRK) or receptor tyrosine kinase (RET) inhibitors.

Methods

Patients were identified in the Calgary prospective thyroid cancer database (N= 482). Patients were ‘pre-screened’ with clinically available MassARRAY® BRAF test, Colon Panel, Melanoma Panel, or ThyroSPEC™. Mutation-negative tumors were ‘screened’ for NTRK fusions and RET fusions/mutations with the Oncomine™ Comprehensive Assay v3 (OCAv3).

Results

A total of 86 patients were included in 1 of 2 separate analyses. Analysis A included 42 patients with radioactive iodine (RAI)-resistant distant metastases. After pre-screening, 20 BRAF and RAS mutation-negative patients underwent OCAv3 screening, resulting in the detection of 4 patients with NTRKfusions and 4 patients with RET fusions (8/20, 40% of analyzed patients). Analysis B included 44 patients, 42 with American Thyroid Association (ATA) high and intermediate risk of recurrence and 2 with medullary thyroid carcinoma. During pre-screening, 1 patient with an NTRK fusion, 1 patient with a RET fusion, and 30 patients with BRAF mutations were identified. The remaining 9 patients received OCAv3 screening, resulting in detection of 1 patient with an NTRKfusion and 1 with a RET fusion (4/11, 36% of analyzed patients).

Conclusions

Our findings indicate a higher rate of NTRK fusions and RETfusions in patients with thyroid cancer with RAI-resistant distant metastases and ATA high or intermediate risk of recurrence. This highlights the importance of early screening to enable intervention with a NTRK or RET inhibitor.

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