Thyroid cancer - basic and translational
You are looking at 1 - 10 of 14 items
Lerner Research Institute, Cleveland Clinic,
Search for other papers by Shovan Dutta in
Google Scholar
PubMed
Lerner Research Institute, Cleveland Clinic,
Department of Otolaryngology-Head & Neck Surgery, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University,
Search for other papers by Jeffrey A Knauf in
Google Scholar
PubMed
The development of mouse models for thyroid cancer has significantly advanced over the years, enhancing our understanding of thyroid tumorigenesis, molecular pathways and treatment responses. The earliest mouse models of thyroid cancer relied on hormone, radiation or chemical carcinogenesis to induce tumors. However, as our understanding of the genetic alterations driving thyroid cancer has expanded, more sophisticated genetic engineering techniques have been employed to create models with thyroid-specific expression of these driver mutations. While driver mutations can initiate tumorigenesis, they are often insufficient to sustain cancer progression and invasion, which significantly limits their usefulness in studying advanced thyroid cancers. Recent studies exploring the genomic landscape of advanced thyroid cancer have identified several cooperating mutations, which are secondary genetic alterations that work alongside driver mutations to promote thyroid tumor progression. Indeed, mice with a combination of oncogenic drivers and common cooperating alterations have been developed, demonstrating that these alterations function in conjunction with the oncogenic driver to promote the progression to advanced thyroid cancer. These models provide important preclinical tools to explore how cooperating alterations influence the response to therapies, particularly those targeting the oncogenic driver. This review will focus on recent publications that broaden the scope of advanced thyroid cancer models by combining thyroid-specific oncogenic driver expression with various cooperating mutations.
Search for other papers by Wiame Potonnier in
Google Scholar
PubMed
Search for other papers by Erell Guillerm in
Google Scholar
PubMed
Search for other papers by Claude Bigorgne in
Google Scholar
PubMed
Search for other papers by Cécile Ghander in
Google Scholar
PubMed
Search for other papers by Malanie Roy in
Google Scholar
PubMed
Search for other papers by Florence Coulet in
Google Scholar
PubMed
Search for other papers by François Ansart in
Google Scholar
PubMed
Search for other papers by Fabrice Menegaux in
Google Scholar
PubMed
Search for other papers by Laurence Leenhardt in
Google Scholar
PubMed
Search for other papers by Isabelle Brocheriou in
Google Scholar
PubMed
Search for other papers by Gabrielle Deniziaut in
Google Scholar
PubMed
Search for other papers by Camille Buffet in
Google Scholar
PubMed
Objective
Fine-needle aspiration (FNA) cytological analysis fails to confirm the benignity or malignancy of Bethesda III, IV and V thyroid nodules. Molecular tests performed on FNA samples have demonstrated interesting results in improving the diagnosis of these nodules. The aim of this study was to assess the performance of a large next-generation sequencing (NGS) panel in thyroid nodules with indeterminate cytology (Bethesda III, IV and V).
Methods
Retrospective, monocentric study including 121 patients with cytologically indeterminate thyroid nodules (Bethesda III, IV and V) who underwent a routine FNA procedure for molecular testing using the AmpliSeq general cancer NGS panel, with an available final histological diagnosis. The main objective was to estimate the negative predictive value (NPV) of malignancy of the AmpliSeq panel in Bethesda III and IV thyroid nodules. Performance assessment (sensitivity, specificity, positive predictive value (PPV) and NPV) was carried out in the grouped categories III and IV, in the overall cohort and in each Bethesda category. The final histological diagnosis was used as the designated gold standard.
Results
Histologically, 86 nodules were benign and 35 nodules were malignant. Molecular analysis yielded a positive result in 40 nodules. Panel performances assessed in the grouped categories Bethesda III and IV demonstrated a 55.0% (95% CI: 31.5; 76.9) sensitivity, a 76.9% (95% CI: 66.0; 85.7) specificity, a 37.9% (95% CI: 25.7; 51.9) PPV and an 87.0% (95% CI: 80.2; 91.7) NPV, considering a 20% prevalence of malignancy.
Conclusions
The performances of the AmpliSeq panel are promising; however, the NPV is not sufficient to avoid diagnostic surgery in cytologically indeterminate thyroid nodules.
Significance statement
Different ancillary molecular tests have been marketed in the USA and are integrated into the management of thyroid nodules with indeterminate cytology. Unfortunately, none of these molecular tests are currently available in France and clinicians lack effective tools for the management of these nodules. The aim of this work was to assess the performance of a large general-cancer targeted NGS panel in a series of thyroid nodules with indeterminate cytology (i.e. Bethesda III and IV categories and, to some extent, the Bethesda V category), managed in a French university medical center referral for thyroid tumors.
Integrative Tumor Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health,
Search for other papers by Olivia W Lee in
Google Scholar
PubMed
Search for other papers by Danielle M Karyadi in
Google Scholar
PubMed
Search for other papers by Stephen W Hartley in
Google Scholar
PubMed
Search for other papers by Weyin Zhou in
Google Scholar
PubMed
Search for other papers by Mitchell J Machiela in
Google Scholar
PubMed
Search for other papers by Shahriar A Zamani in
Google Scholar
PubMed
Search for other papers by Liudmyla Yu Zurnadzhy in
Google Scholar
PubMed
Search for other papers by John N Weinstein in
Google Scholar
PubMed
Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University,
Search for other papers by Young Joo Park in
Google Scholar
PubMed
Precision Medicine Institute, Macrogen Inc,
Search for other papers by Jeong-Sun Seo in
Google Scholar
PubMed
Search for other papers by Gerry A Thomas in
Google Scholar
PubMed
Search for other papers by Tetiana I Bogdanova in
Google Scholar
PubMed
Search for other papers by Mykola D Tronko in
Google Scholar
PubMed
Search for other papers by Lindsay M Morton in
Google Scholar
PubMed
Search for other papers by Stephen J Chanock in
Google Scholar
PubMed
Deletion of the long q arm of chromosome 22 (22qDEL) is the most frequently identified recurrent somatic copy number alteration observed in papillary thyroid carcinoma (PTC). Since its role in PTC is not fully understood, we conducted a pooled analysis of genomic characteristics and clinical correlates in 1094 primary tumors from four published PTC genomic studies. The majority of PTC cases with 22qDEL exhibited arm-level loss of heterozygosity (86%); nearly all PTC cases with 22qDEL had losses in 22q12 and 13, which together constitute 70% of the q arm. Our analysis confirmed that 22qDEL occurs more frequently with RAS point mutations (50.4%), particularly HRAS (70.3%), compared with other PTC drivers (9.3%), supporting the conclusion that 22qDEL is unlikely to be a solitary driver of PTC but possibly an important co-factor in carcinogenesis, particularly in PTCs with RAS driver mutations. Differential RNA expression analyses revealed downregulation of most genes located on chromosome 22 in cases with 22qDEL compared to those without 22qDEL. Many differentially expressed genes are drawn from immune response and regulation pathways. These findings highlight the value of further investigations into the contributions of 22qDEL events to PTC, perhaps mediated through immune perturbations.
Search for other papers by Vincenzo Condello in
Google Scholar
PubMed
Department of Pathology and Cancer Diagnostics, Karolinska University Hospital,
Search for other papers by C Christofer Juhlin in
Google Scholar
PubMed
In recent years, germline mutations in the microRNA (miRNA) processor genes DICER1 and DGCR8 have been coupled to the development of thyroid follicular nodular disease (TFND), thereby casting new light on the etiology of this enigmatic, benign condition in non-iodine-deficient regions. Moreover, DICER1 and DGCR8 mutations have also been reported in rare subsets of follicular cell-derived thyroid carcinomas. Specifically, truncating germline or missense somatic DICER1 mutations have been reported in small subsets of pediatric and adolescent follicular thyroid carcinoma (FTC) and poorly differentiated thyroid carcinoma (PDTC). Similarly, a recurrent somatic mutation of the DGCR8 gene has been observed in highly aggressive FTCs and in some indolent cases of encapsulated follicular variant of papillary thyroid carcinoma. The reason why identical mutations in the same miRNA processor gene can lead to such a myriad of thyroid conditions, ranging from benign TFND to FTCs and PDTCs, remains unclear. This review highlights key features of miRNA regulator gene mutations in thyroid disease and explores their potential roles as drivers or progression events in tumor development.
Department of Otorhinolaryngology-Head and Neck Surgery, Chung-Ang University College of Medicine, Seoul, South Korea
Search for other papers by Hyun-Jin Lee in
Google Scholar
PubMed
Search for other papers by Young-Sool Hah in
Google Scholar
PubMed
Search for other papers by So Young Cheon in
Google Scholar
PubMed
Department of Otorhinolaryngology-Head and Neck Surgery, Gyeongsang National University Hospital, Jinju, South Korea
Institute of Health Sciences, Gyeongsang National University, Jinju, South Korea
Search for other papers by Seong Jun Won in
Google Scholar
PubMed
Department of Otorhinolaryngology-Head and Neck Surgery, Gyeongsang National University Hospital, Jinju, South Korea
Institute of Health Sciences, Gyeongsang National University, Jinju, South Korea
Search for other papers by Chae Dong Yim in
Google Scholar
PubMed
Department of Otorhinolaryngology-Head and Neck Surgery, Gyeongsang National University Hospital, Jinju, South Korea
Institute of Health Sciences, Gyeongsang National University, Jinju, South Korea
Search for other papers by Somi Ryu in
Google Scholar
PubMed
Search for other papers by Seung-Jun Lee in
Google Scholar
PubMed
Department of Pediatrics, Gyeongsang National University College of Medicine, Jinju, South Korea
Search for other papers by Ji Hyun Seo in
Google Scholar
PubMed
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
Search for other papers by Jung Je Park in
Google Scholar
PubMed
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.
UMR 9019 CNRS F-94805 Villejuif, France
Gustave Roussy, Villejuif, France
Search for other papers by Fabio Hecht in
Google Scholar
PubMed
UMR 9019 CNRS F-94805 Villejuif, France
Gustave Roussy, Villejuif, France
Search for other papers by Laura Valerio in
Google Scholar
PubMed
UMR 9019 CNRS F-94805 Villejuif, France
Gustave Roussy, Villejuif, France
Search for other papers by Carlos Frederico Lima Gonçalves in
Google Scholar
PubMed
UMR 9019 CNRS F-94805 Villejuif, France
Gustave Roussy, Villejuif, France
Search for other papers by Marylin Harinquet in
Google Scholar
PubMed
Search for other papers by Rabii Ameziane El Hassani in
Google Scholar
PubMed
Search for other papers by Denise P Carvalho in
Google Scholar
PubMed
Gustave Roussy, Villejuif, France
Sorbonne Université, Paris, France
Search for other papers by Stephane Koundrioukoff in
Google Scholar
PubMed
Search for other papers by Jean-Charles Cadoret in
Google Scholar
PubMed
UMR 9019 CNRS F-94805 Villejuif, France
Gustave Roussy, Villejuif, France
Search for other papers by Corinne Dupuy in
Google Scholar
PubMed
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.
Department of Nuclear Medicine, The Fourth hospital of Hebei Medical University, Shijiazhuang, Hebei, China
Search for other papers by Zhaoqi Zhang in
Google Scholar
PubMed
Search for other papers by Josef Yu in
Google Scholar
PubMed
Search for other papers by Eva Rainer in
Google Scholar
PubMed
Search for other papers by Lindsay Hargitai in
Google Scholar
PubMed
Search for other papers by Zewen Jiang in
Google Scholar
PubMed
Search for other papers by Georgios Karanikas in
Google Scholar
PubMed
Search for other papers by Tatjana Traub-Weidinger in
Google Scholar
PubMed
Search for other papers by Richard Crevenna in
Google Scholar
PubMed
Search for other papers by Marcus Hacker in
Google Scholar
PubMed
Search for other papers by Shuren Li in
Google Scholar
PubMed
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.
Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
Search for other papers by Carla Colombo in
Google Scholar
PubMed
Search for other papers by Daniele Ceruti in
Google Scholar
PubMed
Search for other papers by Massimiliano Succi in
Google Scholar
PubMed
Search for other papers by Simone De Leo in
Google Scholar
PubMed
Department of Biotechnology and Translational Medicine, University of Milan, Milan, Italy
Search for other papers by Matteo Trevisan in
Google Scholar
PubMed
Search for other papers by Claudia Moneta in
Google Scholar
PubMed
Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
Search for other papers by Laura Fugazzola in
Google Scholar
PubMed
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.
Search for other papers by Abdul Rehman Syed in
Google Scholar
PubMed
Search for other papers by Aakash Gorana in
Google Scholar
PubMed
Search for other papers by Erik Nohr in
Google Scholar
PubMed
Search for other papers by Xiaoli-Kat Yuan in
Google Scholar
PubMed
Search for other papers by Parthiv Amin MASc in
Google Scholar
PubMed
Search for other papers by Sana Ghaznavi in
Google Scholar
PubMed
Search for other papers by Debbie Lamb in
Google Scholar
PubMed
Search for other papers by John McIntyre in
Google Scholar
PubMed
Search for other papers by Markus Eszlinger in
Google Scholar
PubMed
Search for other papers by Ralf Paschke in
Google Scholar
PubMed
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.
Search for other papers by Hélène Théodon in
Google Scholar
PubMed
Search for other papers by Erell Guillerm in
Google Scholar
PubMed
Search for other papers by Johanna Wassermann in
Google Scholar
PubMed
Search for other papers by Gabrielle Deniziaut in
Google Scholar
PubMed
Search for other papers by Loïc Jaffrelot in
Google Scholar
PubMed
Search for other papers by Jérome Denis in
Google Scholar
PubMed
Search for other papers by Nathalie Chereau in
Google Scholar
PubMed
Search for other papers by Claude Bigorgne in
Google Scholar
PubMed
Search for other papers by Wiame Potonnier in
Google Scholar
PubMed
Search for other papers by Florence Coulet in
Google Scholar
PubMed
Search for other papers by Laurence Leenhardt in
Google Scholar
PubMed
Search for other papers by Camille Buffet in
Google Scholar
PubMed
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.