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Open AccessEditorial

Advances in Thyroid Carcinoma

by Iñigo Landa

Cancers 2022, 14(12), 2908; https://doi.org/10.3390/cancers14122908 - 13 Jun 2022

Cited by 1 | Viewed by 1902

Abstract

“Thyroid cancer” encompasses a heterogeneous group of tumors that range from the predominant papillary thyroid cancer (PTC) subtype, which shows excellent survival rates, to the poorly differentiated (PDTC) and anaplastic thyroid cancer (ATC) forms, accounting for most of the disease-related morbidity and mortality [...] Read more.

“Thyroid cancer” encompasses a heterogeneous group of tumors that range from the predominant papillary thyroid cancer (PTC) subtype, which shows excellent survival rates, to the poorly differentiated (PDTC) and anaplastic thyroid cancer (ATC) forms, accounting for most of the disease-related morbidity and mortality [...] Full article

(This article belongs to the Special Issue Advances in Thyroid Carcinoma)

Research

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21 pages, 2874 KiB

Open AccessArticle

Medullary Thyroid Carcinoma Mutational Spectrum Update and Signaling-Type Inference by Transcriptional Profiles: Literature Meta-Analysis and Study of Tumor Samples

by Emanuela Minna, Paola Romeo, Matteo Dugo, Loris De Cecco, Antonella Aiello, Federico Pistore, Andrea Carenzo, Angela Greco and Maria Grazia Borrello

Cancers 2022, 14(8), 1951; https://doi.org/10.3390/cancers14081951 - 13 Apr 2022

Cited by 14 | Viewed by 3052

Abstract

Medullary thyroid carcinoma (MTC) is a rare but aggressive tumor. Although RET and RAS genes are recognized drivers in MTC, associated downstream signaling pathways are largely unknown. In this study, we report 17 sporadic MTCs, collected at our institution, comprising patient-matched primary and [...] Read more.

Medullary thyroid carcinoma (MTC) is a rare but aggressive tumor. Although RET and RAS genes are recognized drivers in MTC, associated downstream signaling pathways are largely unknown. In this study, we report 17 sporadic MTCs, collected at our institution, comprising patient-matched primary and lymph node metastatic tumors investigated for mutational and transcriptional profiles. As we identified two uncommon RET deletions (D898_E901del and E632_L633del), we also performed a literature review and meta-analysis to assess the occurrence of unconventional alterations in MTC, focusing on next-generation sequencing studies. We found that new gene alterations are emerging, along with the known RET/RAS drivers, involving not only RET by multiple concurrent mutations or deletions but also other previously underestimated cancer-related genes, especially in sporadic MTCs. In our MTC gene profiles, we found transcriptome similarity between patient-matched tissues and expression of immune genes only by a few samples. Furthermore, we defined a gene signature able to stratify samples into two distinct signaling types, termed MEN2B-like and MEN2A-like. We provide an updated overview of the MTC mutational spectrum and describe how transcriptional profiles can be used to define distinct MTC signaling subtypes that appear to be shared by various gene drivers, including the unconventional ones. Full article

(This article belongs to the Special Issue Advances in Thyroid Carcinoma)

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15 pages, 1499 KiB

Open AccessArticle

APOBEC SBS13 Mutational Signature—A Novel Predictor of Radioactive Iodine Refractory Papillary Thyroid Carcinoma

by Sarah Siraj, Tariq Masoodi, Abdul K. Siraj, Saud Azam, Zeeshan Qadri, Sandeep K. Parvathareddy, Rong Bu, Khawar S. Siddiqui, Saif S. Al-Sobhi, Mohammed AlDawish and Khawla S. Al-Kuraya

Cancers 2022, 14(6), 1584; https://doi.org/10.3390/cancers14061584 - 21 Mar 2022

Cited by 6 | Viewed by 2948

Abstract

Standard surgery followed by radioactive iodine (¹³¹I, RAI) therapy are not curative for 5–20% of papillary thyroid carcinoma (PTC) patients with RAI refractory disease. Early predictors indicating therapeutic response to RAI therapy in PTC are yet to be elucidated. Whole-exome sequencing [...] Read more.

Standard surgery followed by radioactive iodine (¹³¹I, RAI) therapy are not curative for 5–20% of papillary thyroid carcinoma (PTC) patients with RAI refractory disease. Early predictors indicating therapeutic response to RAI therapy in PTC are yet to be elucidated. Whole-exome sequencing was performed (at median depth 198x) on 66 RAI-refractory and 92 RAI-avid PTCs with patient-matched germline. RAI-refractory tumors were significantly associated with distinct aggressive clinicopathological features, including positive surgical margins (p = 0.016) and the presence of lymph node metastases at primary diagnosis (p = 0.012); higher nonsilent tumor mutation burden (p = 0.011); TERT promoter (TERTp) mutation (p < 0.0001); and the enrichment of the APOBEC-related single-base substitution (SBS) COSMIC mutational signatures 2 (p = 0.030) and 13 (p < 0.001). Notably, SBS13 (odds ratio [OR] 30.4, 95% confidence intervals [CI] 1.43–647.22) and TERTp mutation (OR 41.3, 95% CI 4.35–391.60) were revealed to be independent predictors of RAI refractoriness in PTC (p = 0.029 and 0.001, respectively). Although SBS13 and TERTp mutations alone highly predicted RAI refractoriness, when combined, they significantly increased the likelihood of predicting RAI refractoriness in PTC. This study highlights the APOBEC SBS13 mutational signature as a novel independent predictor of RAI refractoriness in a distinct subgroup of PTC. Full article

(This article belongs to the Special Issue Advances in Thyroid Carcinoma)

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14 pages, 2024 KiB

Open AccessArticle

Multiple ETS Factors Participate in the Transcriptional Control of TERT Mutant Promoter in Thyroid Cancers

by Caitlin E. M. Thornton, Jingzhu Hao, Prasanna P. Tamarapu and Iñigo Landa

Cancers 2022, 14(2), 357; https://doi.org/10.3390/cancers14020357 - 12 Jan 2022

Cited by 12 | Viewed by 2301

Abstract

Hotspot mutations in the TERT (telomerase reverse transcriptase) gene are key determinants of thyroid cancer progression. TERT promoter mutations (TPM) create de novo consensus binding sites for the ETS (“E26 transformation specific”) family of transcription factors. In this study, we systematically knocked down [...] Read more.

Hotspot mutations in the TERT (telomerase reverse transcriptase) gene are key determinants of thyroid cancer progression. TERT promoter mutations (TPM) create de novo consensus binding sites for the ETS (“E26 transformation specific”) family of transcription factors. In this study, we systematically knocked down each of the 20 ETS factors expressed in thyroid tumors and screened their effects on TERT expression in seven thyroid cancer cell lines with defined TPM status. We observed that, unlike in other TPM-carrying cancers such as glioblastomas, ETS factor GABPA does not unambiguously regulate transcription from the TERT mutant promoter in thyroid specimens. In fact, multiple members of the ETS family impact TERT expression, and they typically do so in a mutation-independent manner. In addition, we observe that partial inhibition of MAPK, a central pathway in thyroid cancer transformation, is more effective at suppressing TERT transcription in the absence of TPMs. Taken together, our results show a more complex scenario of TERT regulation in thyroid cancers compared with other lineages and suggest that compensatory mechanisms by ETS and other regulators likely exist and advocate for the need for a more comprehensive understanding of the mechanisms of TERT deregulation in thyroid tumors before eventually exploring TPM-specific therapeutic strategies. Full article

(This article belongs to the Special Issue Advances in Thyroid Carcinoma)

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17 pages, 4829 KiB

Open AccessArticle

MiRNA Deregulation Distinguishes Anaplastic Thyroid Carcinoma (ATC) and Supports Upregulation of Oncogene Expression

by Danny Misiak, Marcus Bauer, Jana Lange, Jacob Haase, Juliane Braun, Kerstin Lorenz, Claudia Wickenhauser and Stefan Hüttelmaier

Cancers 2021, 13(23), 5913; https://doi.org/10.3390/cancers13235913 - 24 Nov 2021

Cited by 7 | Viewed by 2757

Abstract

Anaplastic thyroid carcinoma (ATC) is the most fatal and rapidly evolving endocrine malignancy invading the head and neck region and accounts for up to 50% of thyroid cancer-associated deaths. Deregulation of the microRNA (miRNA) expression promotes thyroid carcinoma progression by modulating the reorganization [...] Read more.

Anaplastic thyroid carcinoma (ATC) is the most fatal and rapidly evolving endocrine malignancy invading the head and neck region and accounts for up to 50% of thyroid cancer-associated deaths. Deregulation of the microRNA (miRNA) expression promotes thyroid carcinoma progression by modulating the reorganization of the ATC transcriptome. Here, we applied comparative miRNA–mRNA sequencing on a cohort of 28 thyroid carcinomas to unravel the association of deregulated miRNA and mRNA expression. This identified 85 miRNAs significantly deregulated in ATC. By establishing a new analysis pipeline, we unraveled 85 prime miRNA–mRNA interactions supporting the downregulation of candidate tumor suppressors and the upregulation of bona fide oncogenes such as survivin (BIRC5) in ATC. This miRNA-dependent reprogramming of the ATC transcriptome provided an mRNA signature comprising 65 genes sharply distinguishing ATC from other thyroid carcinomas. The validation of the deregulated protein expression in an independent thyroid carcinoma cohort demonstrates that miRNA-dependent oncogenes comprised in this signature, the transferrin receptor TFRC (CD71) and the E3-ubiquitin ligase DTL, are sharply upregulated in ATC. This upregulation is sufficient to distinguish ATC even from poorly differentiated thyroid carcinomas (PDTC). In sum, these findings provide new diagnostic tools and a robust resource to explore the key miRNA–mRNA regulation underlying the progression of thyroid carcinoma. Full article

(This article belongs to the Special Issue Advances in Thyroid Carcinoma)

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9 pages, 576 KiB

Open AccessArticle

Differentiated Thyroid Cancer with Biochemical Incomplete Response: Clinico-Pathological Characteristics and Long Term Disease Outcomes

by Miriam Steinschneider, Jacob Pitaro, Shlomit Koren, Yuval Mizrakli, Carlos Benbassat and Limor Muallem Kalmovich

Cancers 2021, 13(21), 5422; https://doi.org/10.3390/cancers13215422 - 29 Oct 2021

Cited by 12 | Viewed by 2617

Abstract

Although most patients with differentiated thyroid cancer (DTC) and biochemical incomplete response (BIR) follow a good clinical outcome, progression to structural disease may occur in 8–17% of patients. We aimed to identify factors that could predict the long-term outcomes of BIR patients. To [...] Read more.

Although most patients with differentiated thyroid cancer (DTC) and biochemical incomplete response (BIR) follow a good clinical outcome, progression to structural disease may occur in 8–17% of patients. We aimed to identify factors that could predict the long-term outcomes of BIR patients. To this end, we conducted a retrospective review study of 1049 charts from our Differential Thyroid Cancer registry of patients who were initially treated with total thyroidectomy between 1962 and 2019. BIR was defined as suppressed thyroglobulin (Tg) > 1 ng/mL, stimulated Tg > 10 ng/mL or rising anti-Tg antibodies, who did not have structural evidence of disease, and who were assessed 12–24 months after initial treatment. We found 83 patients (7.9%) matching the definition of BIR. During a mean follow-up of 12 ± 6.6 years, 49 (59%) patients remained in a state of BIR or reverted to no evidence of disease, while 34 (41%) progressed to structural disease. At the last follow-up, three cases (3.6%) were recorded as disease-related death. The American Thyroid Association (ATA) Initial Risk Stratification system and/or AJCC/TNM (8th ed.) staging system at diagnosis predicted the shift from BIR to structural disease, irrespective of their postoperative Tg levels. We conclude that albeit 41% of BIR patients may shift to structural disease, and most have a rather indolent disease. Specific new individual data enable the Response to Therapy reclassification to become a dynamic system to allow for the better management of BIR patients in the long term. Full article

(This article belongs to the Special Issue Advances in Thyroid Carcinoma)

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24 pages, 4065 KiB

Open AccessArticle

RAC1 Alterations Induce Acquired Dabrafenib Resistance in Association with Anaplastic Transformation in a Papillary Thyroid Cancer Patient

by Rozita Bagheri-Yarmand, Naifa L. Busaidy, Elena McBeath, Brian P. Danysh, Kurt W. Evans, Tyler J. Moss, Argun Akcakanat, Patrick K. S. Ng, Christina M. Knippler, Jalyn A. Golden, Michelle D. Williams, Asha S. Multani, Maria E. Cabanillas, Kenna R. Shaw, Funda Meric-Bernstam, Manisha H. Shah, Matthew D. Ringel and Marie Claude Hofmann

Cancers 2021, 13(19), 4950; https://doi.org/10.3390/cancers13194950 - 30 Sep 2021

Cited by 18 | Viewed by 3410

Abstract

BRAF-activating mutations are the most frequent driver mutations in papillary thyroid cancer (PTC). Targeted inhibitors such as dabrafenib have been used in advanced BRAF-mutated PTC; however, acquired resistance to the drug is common and little is known about other effectors that [...] Read more.

BRAF-activating mutations are the most frequent driver mutations in papillary thyroid cancer (PTC). Targeted inhibitors such as dabrafenib have been used in advanced BRAF-mutated PTC; however, acquired resistance to the drug is common and little is known about other effectors that may play integral roles in this resistance. In addition, the induction of PTC dedifferentiation into highly aggressive KRAS-driven anaplastic thyroid cancer (ATC) has been reported. We detected a novel RAC1 (P34R) mutation acquired during dabrafenib treatment in a progressive metastatic lesion with ATC phenotype. To identify a potential functional link between this novel mutation and tumor dedifferentiation, we developed a cell line derived from the metastatic lesion and compared its behavior to isogenic cell lines and primary tumor samples. Our data demonstrated that RAC1 mutations induce changes in cell morphology, reorganization of F-actin almost exclusively at the cell cortex, and changes in cell adhesion properties. We also established that RAC1 amplification, with or without mutation, is sufficient to drive cell proliferation and resistance to BRAF inhibition. Further, we identified polyploidy of chromosome 7, which harbors RAC1, in both the metastatic lesion and its derived cell line. Copy number amplification and overexpression of other genes located on this chromosome, such as TWIST1, EGFR, and MET were also detected, which might also lead to dabrafenib resistance. Our study suggests that polyploidy leading to increased expression of specific genes, particularly those located on chromosome 7, should be considered when analyzing aggressive thyroid tumor samples and in further treatments. Full article

(This article belongs to the Special Issue Advances in Thyroid Carcinoma)

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14 pages, 3070 KiB

Open AccessArticle

DNA Methylation Age Drift Is Associated with Poor Outcomes and De-Differentiation in Papillary and Follicular Thyroid Carcinomas

by Tiantian Liu, Jiansheng Wang, Yuchen Xiu, Yujiao Wu and Dawei Xu

Cancers 2021, 13(19), 4827; https://doi.org/10.3390/cancers13194827 - 27 Sep 2021

Cited by 7 | Viewed by 2401

Abstract

Alterations in global DNA methylation play a critical role in both aging and cancer, and DNA methylation (DNAm) age drift has been implicated in cancer risk and pathogenesis. In the present study, we analyzed the TCGA cohort of papillary and follicular thyroid carcinoma [...] Read more.

Alterations in global DNA methylation play a critical role in both aging and cancer, and DNA methylation (DNAm) age drift has been implicated in cancer risk and pathogenesis. In the present study, we analyzed the TCGA cohort of papillary and follicular thyroid carcinoma (PTC and FTC) for their DNAm age and association with clinic-pathological features. In 54 noncancerous thyroid (NT) samples, DNAm age was highly correlated with patient chronological age (R² = 0.928, p = 2.6 × 10⁻³¹), but drifted to younger than chronological age in most specimens, especially those from patients >50 years old. DNAm age in 502 tumors was also correlated with patient chronological age, but to a much lesser extent (R² = 0.403). Highly drifted DNAm age (HDDA) was identified in 161 tumors, among which were 101 with DNAm age acceleration while 60 with DNAm age deceleration. Tumors with HDDA were characterized by the robust aberrations in metabolic activities, extracellular microenvironment components and inflammation/immunology responses, and dedifferentiation. Importantly, HDDA in tumors independently predicted shorter disease-free survival of patients. Collectively, NT thyroids from TC patients have younger DNAm age, while HDDA frequently occurs in TCs, and contributes to the TC progression and poor patient outcomes. HDDA may serve as a new prognostic factor for TCs. Full article

(This article belongs to the Special Issue Advances in Thyroid Carcinoma)

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21 pages, 4221 KiB

Open AccessArticle

Secreted Factors by Anaplastic Thyroid Cancer Cells Induce Tumor-Promoting M2-like Macrophage Polarization through a TIM3-Dependent Mechanism

by Cinthia Carolina Stempin, Romina Celeste Geysels, Sunmi Park, Luz Maria Palacios, Ximena Volpini, Claudia Cristina Motran, Eva Virginia Acosta Rodríguez, Juan Pablo Nicola, Sheue-yann Cheng, Claudia Gabriela Pellizas and Laura Fozzatti

Cancers 2021, 13(19), 4821; https://doi.org/10.3390/cancers13194821 - 26 Sep 2021

Cited by 19 | Viewed by 4083

Abstract

Anaplastic thyroid cancer (ATC) is a highly aggressive type of thyroid cancer (TC). Currently, no effective target treatments are available that can improve overall survival, with ATC representing a major clinical challenge because of its remarkable lethality. Tumor-associated macrophages (TAMs) are the most [...] Read more.

Anaplastic thyroid cancer (ATC) is a highly aggressive type of thyroid cancer (TC). Currently, no effective target treatments are available that can improve overall survival, with ATC representing a major clinical challenge because of its remarkable lethality. Tumor-associated macrophages (TAMs) are the most evident cells in ATCs, and their high density is correlated with a poor prognosis. However, the mechanisms of how TAMs promote ATC progression remain poorly characterized. Here, we demonstrated that the treatment of human monocytes (THP-1 cells) with ATC cell-derived conditioned media (CM) promoted macrophage polarization, showing high levels of M2 markers. Furthermore, we found that STAT3 was activated, and this was correlated with an increased expression and secretion of the inflammatory cytokine interleukin-6. Remarkably, the M2-like macrophages obtained revealed tumor-promoting activity. A cytokine array analysis demonstrated that M2-like macrophage-derived CM contained high levels of TIM3, which is an important immune regulatory molecule. Consistently, TIM3 expression was up-regulated in THP-1 cells cultured with ATC cell-derived CM. Moreover, TIM3 blockade significantly reversed the polarization of THP-1 cells induced by ATC cell-secreted soluble factors. We validated the clinical significance of the TIM3 in human TC by analyzing public datasets and found that the expression of TIM3 and its ligand galectin 9 was significantly higher in human TC tissue samples than in normal thyroid tissues. Taken together, our findings identified a new mechanism by which TIM3 induces tumor-promoting M2-like macrophage polarization in TC. Furthermore, TIM3 interference might be a potential tool for treatment of patients with ATC. Full article

(This article belongs to the Special Issue Advances in Thyroid Carcinoma)

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21 pages, 4982 KiB

Open AccessArticle

Evidence of Cooperation between Hippo Pathway and RAS Mutation in Thyroid Carcinomas

by Thaise Nayane Ribeiro Carneiro, Larissa Valdemarin Bim, Vanessa Candiotti Buzatto, Vanessa Galdeno, Paula Fontes Asprino, Eunjung Alice Lee, Pedro Alexandre Favoretto Galante and Janete Maria Cerutti

Cancers 2021, 13(10), 2306; https://doi.org/10.3390/cancers13102306 - 12 May 2021

Cited by 6 | Viewed by 3546

Abstract

Thyroid cancer incidences have been steadily increasing worldwide and are projected to become the fourth leading cancer diagnosis by 2030. Improved diagnosis and prognosis predictions for this type of cancer depend on understanding its genetic bases and disease biology. RAS mutations have been [...] Read more.

Thyroid cancer incidences have been steadily increasing worldwide and are projected to become the fourth leading cancer diagnosis by 2030. Improved diagnosis and prognosis predictions for this type of cancer depend on understanding its genetic bases and disease biology. RAS mutations have been found in a wide range of thyroid tumors, from benign to aggressive thyroid carcinomas. Based on that and in vivo studies, it has been suggested that RAS cooperates with other driver mutations to induce tumorigenesis. This study aims to identify genetic alterations or pathways that cooperate with the RAS mutation in the pathogenesis of thyroid cancer. From a cohort of 120 thyroid carcinomas, 11 RAS-mutated samples were identified. The samples were subjected to RNA-Sequencing analyses. The mutation analysis in our eleven RAS-positive cases uncovered that four genes that belong to the Hippo pathway were mutated. The gene expression analysis revealed that this pathway was dysregulated in the RAS-positive samples. We additionally explored the mutational status and expression profiling of 60 RAS-positive papillary thyroid carcinomas (PTC) from The Cancer Genome Atlas (TCGA) cohort. Altogether, the mutational landscape and pathway enrichment analysis (gene set enrichment analysis (GSEA) and Kyoto Encyclopedia of Genes and Genome (KEGG)) detected the Hippo pathway as dysregulated in RAS-positive thyroid carcinomas. Finally, we suggest a crosstalk between the Hippo and other signaling pathways, such as Wnt and BMP. Full article

(This article belongs to the Special Issue Advances in Thyroid Carcinoma)

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16 pages, 1688 KiB

Open AccessArticle

Genetic Determinants for Prediction of Outcome of Patients with Papillary Thyroid Carcinoma

by Antónia Afonso Póvoa, Elisabete Teixeira, Maria Rosa Bella-Cueto, Rui Batista, Ana Pestana, Miguel Melo, Thalita Alves, Mafalda Pinto, Manuel Sobrinho-Simões, Jorge Maciel and Paula Soares

Cancers 2021, 13(9), 2048; https://doi.org/10.3390/cancers13092048 - 23 Apr 2021

Cited by 23 | Viewed by 2884

Abstract

Papillary thyroid carcinoma (PTC) usually presents an excellent prognosis, but some patients present with aggressive metastatic disease. BRAF, RAS, and TERT promoter (TERTp) genes are altered in PTC, and their impact on patient outcomes remains controversial. We aimed to determine the role of [...] Read more.

Papillary thyroid carcinoma (PTC) usually presents an excellent prognosis, but some patients present with aggressive metastatic disease. BRAF, RAS, and TERT promoter (TERTp) genes are altered in PTC, and their impact on patient outcomes remains controversial. We aimed to determine the role of genetic alterations in PTC patient outcomes (recurrent/persistent disease, structural disease, and disease-specific mortality (DSM)). The series included 241 PTC patients submitted to surgery, between 2002–2015, in a single hospital. DNA was extracted from tissue samples of 287 lesions (primary tumors and metastases). Molecular alterations were detected by Sanger sequencing. Primary tumors presented 143 BRAF, 16 TERTp, and 13 RAS mutations. Isolated TERTp^mut showed increased risk of structural disease (HR = 7.0, p < 0.001) and DSM (HR = 10.1, p = 0.001). Combined genotypes, BRAF^wt/TERTp^mut (HR = 6.8, p = 0.003), BRAF^mut/TERTp^mut (HR = 3.2, p = 0.056) and BRAF^mut/TERTp^wt (HR = 2.2, p = 0.023) showed increased risk of recurrent/persistent disease. Patients with tumors BRAF^wt/TERTp^mut (HR = 24.2, p < 0.001) and BRAF^mut/TERTp^mut (HR = 11.5, p = 0.002) showed increased risk of structural disease. DSM was significantly increased in patients with TERTp^mut regardless of BRAF status (BRAF^mut/TERTp^mut, log-rank p < 0.001; BRAF^wt/TERTp^mut, log-rank p < 0.001). Our results indicate that molecular markers may have a role in predicting PTC patients’ outcome. BRAF^mut/TERTp^wt tumors were prone to associate with local aggressiveness (recurrent/persistent disease), whereas TERTp^mut tumors were predisposed to recurrent structural disease and DSM. Full article

(This article belongs to the Special Issue Advances in Thyroid Carcinoma)

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17 pages, 4241 KiB

Open AccessArticle

Development of Novel Follicular Thyroid Cancer Models Which Progress to Poorly Differentiated and Anaplastic Thyroid Cancer

by Caitlin O. Caperton, Lee Ann Jolly, Nicole Massoll, Andrew J. Bauer and Aime T. Franco

Cancers 2021, 13(5), 1094; https://doi.org/10.3390/cancers13051094 - 4 Mar 2021

Cited by 10 | Viewed by 2397

Abstract

Recent developments in thyroid cancer research have been hindered by a lack of validated in vitro models, allowing for preclinical experimentation and the screening of prospective therapeutics. The goal of this work is to develop and characterize three novel follicular thyroid cancer (FTC) [...] Read more.

Recent developments in thyroid cancer research have been hindered by a lack of validated in vitro models, allowing for preclinical experimentation and the screening of prospective therapeutics. The goal of this work is to develop and characterize three novel follicular thyroid cancer (FTC) cell lines developed from relevant animal models. These cell lines recapitulate the genetics and histopathological features of FTC, as well as progression to a poorly differentiated state. We demonstrate that these cell lines can be used for a variety of in vitro applications and maintain the potential for in vivo transplantation into immunocompetent hosts. Further, cell lines exhibit differing degrees of dysregulated growth and invasive behavior that may help define mechanisms of pathogenesis underlying the heterogeneity present in the patient population. We believe these novel cell lines will provide powerful tools for investigating the molecular basis of thyroid cancer progression and lead to the development of more personalized diagnostic and treatment strategies. Full article

(This article belongs to the Special Issue Advances in Thyroid Carcinoma)

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11 pages, 1355 KiB

Open AccessArticle

Genetic Profiles of Aggressive Variants of Papillary Thyroid Carcinomas

by Meihua Jin, Dong Eun Song, Jonghwa Ahn, Eyun Song, Yu-Mi Lee, Tae-Yon Sung, Tae Yong Kim, Won Bae Kim, Young Kee Shong, Min Ji Jeon and Won Gu Kim

Cancers 2021, 13(4), 892; https://doi.org/10.3390/cancers13040892 - 20 Feb 2021

Cited by 17 | Viewed by 3719

Abstract

Aggressive variants of papillary thyroid carcinoma (PTC) have been described with increasing frequency and are associated with unfavorable clinical outcomes. However, limited data exist on the comprehensive genetic profile of these variants. We performed targeted next-generation sequencing in 36 patients with aggressive variants [...] Read more.

Aggressive variants of papillary thyroid carcinoma (PTC) have been described with increasing frequency and are associated with unfavorable clinical outcomes. However, limited data exist on the comprehensive genetic profile of these variants. We performed targeted next-generation sequencing in 36 patients with aggressive variants of PTC and compared it to PTC from The Cancer Genome Atlas (TCGA) project and poorly differentiated thyroid cancers (PDTCs)/anaplastic thyroid cancers (ATCs) from the Memorial Sloan Kettering Cancer Center (MSKCC). BRAF mutation was the most prevalent (89%) in aggressive variants of PTC compared to that in other thyroid cancers. RAS mutation was identified in one patient (3%), which was less frequent than in others. TERT promoter mutation (17%) ranged between that of PTCs (9%) and PDTCs (40%). Tumor suppressor genes, ZFHX3, TP53, and CHEK2, were mutated in 14%, 3%, and 6% of aggressive variants of PTC, respectively. The mutation rate of TP53 (3%) was significantly higher than that of PTCs (0.7%) and lower than that of ATCs (73%). Mutations in three functional groups, histone methyl transferases, SWI/SNF chromatin remodeling complex, and the PI3K/AKT/mTOR pathway, were present in 11%, 14%, and 11% of samples, respectively. In conclusion, aggressive variants of PTC had higher BRAF and lower NRAS mutation prevalence than other thyroid cancers. The prevalence of mutations in the TERT promoter, TP53, and genes encoding three functional groups ranged between that of PTCs and PDTCs/ATCs. Full article

(This article belongs to the Special Issue Advances in Thyroid Carcinoma)

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13 pages, 1259 KiB

Open AccessArticle

Annual Hazard Rate of Recurrence in Middle Eastern Papillary Thyroid Cancer over a Long-Term Follow-Up

by Abdul K. Siraj, Sandeep Kumar Parvathareddy, Zeeshan Qadri, Khawar Siddiqui, Saif S. Al-Sobhi, Fouad Al-Dayel and Khawla S. Al-Kuraya

Cancers 2020, 12(12), 3624; https://doi.org/10.3390/cancers12123624 - 3 Dec 2020

Cited by 15 | Viewed by 2014

Abstract

Predicting the pattern of recurrence in papillary thyroid cancer (PTC) is necessary to establish optimal surveillance and treatment strategies. We analyzed changes in hazard rate (HR) for tumor recurrence over time in 1201 unselected Middle Eastern PTC patients. The changes in risk were [...] Read more.

Predicting the pattern of recurrence in papillary thyroid cancer (PTC) is necessary to establish optimal surveillance and treatment strategies. We analyzed changes in hazard rate (HR) for tumor recurrence over time in 1201 unselected Middle Eastern PTC patients. The changes in risk were further analyzed according to clinical variables predictive of early (≤5 years) and late (>5 years) recurrence using Cox regression analysis to identify patient populations that remain at risk. Tumor recurrence was noted in 18.4% (221/1201) patients. The annualized hazard of PTC recurrence was highest during the first 5 years (2.8%), peaking between 1 and 2 years (3.7%), with a second smaller peak between 13 and 14 years (3.2%). Patients receiving radioactive iodine (RAI) therapy had lower recurrence hazard compared to those who did not (1.5% vs. 2.7%, p = 0.0001). Importantly, this difference was significant even in intermediate-risk PTC patients (0.7% vs. 2.3%; p = 0.0001). Interestingly, patients aged ≥55 years and having lymph node metastasis were at persistent risk for late recurrence. In conclusion, we confirmed the validity of the double-peaked time-varying pattern for recurrence risk in Middle Eastern PTC patients and our findings could help in formulating individualized treatment and surveillance plans. Full article

(This article belongs to the Special Issue Advances in Thyroid Carcinoma)

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Review

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21 pages, 7206 KiB

Open AccessReview

Gene Editing with CRISPR/Cas Methodology and Thyroid Cancer: Where Are We?

by Cesar Seigi Fuziwara, Diego Claro de Mello and Edna Teruko Kimura

Cancers 2022, 14(3), 844; https://doi.org/10.3390/cancers14030844 - 8 Feb 2022

Cited by 6 | Viewed by 3700

Abstract

Important advances on the role of genetic alterations in thyroid cancer have been achieved in the last two decades. One key reason is linked to the development of technical approaches that allowed for the mimicking of genetic alterations in vitro and in vivo [...] Read more.

Important advances on the role of genetic alterations in thyroid cancer have been achieved in the last two decades. One key reason is linked to the development of technical approaches that allowed for the mimicking of genetic alterations in vitro and in vivo and, more recently, the gene editing methodology. The CRISPR/Cas methodology has emerged as a tangible tool for editing virtually any DNA sequence in the genome. To induce a double-strand break and programmable gene editing, Cas9 endonuclease is guided by a single-guide RNA (sgRNA) that is complementary to the target sequence in DNA. The gene editing per se occurs as the cells repair the broken DNA and may erroneously change the original DNA sequence. In this review, we explore the principles of the CRISPR/Cas system to facilitate an understanding of the mainstream technique and its applications in gene editing. Furthermore, we explored new applications of CRISPR/Cas for gene modulation without changing the DNA sequence and provided a Dry Lab experience for those who are interested in starting “CRISPRing” any given gene. In the last section, we will discuss the progress in the knowledge of thyroid cancer biology fostered by the CRISPR/Cas gene editing tools. Full article

(This article belongs to the Special Issue Advances in Thyroid Carcinoma)

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25 pages, 1679 KiB

Open AccessReview

Nanoparticles: Promising Auxiliary Agents for Diagnosis and Therapy of Thyroid Cancers

by Eleonore Fröhlich and Richard Wahl

Cancers 2021, 13(16), 4063; https://doi.org/10.3390/cancers13164063 - 12 Aug 2021

Cited by 10 | Viewed by 4087

Abstract

Cancers of the endocrine system are rare. The majority are not highly malignant tumors. Thyroid cancer (TC) is the most common endocrine cancer, with differentiated papillary and follicular tumors occurring more frequently than the more aggressive poorly differentiated and anaplastic TC. Nanoparticles (NP) [...] Read more.

Cancers of the endocrine system are rare. The majority are not highly malignant tumors. Thyroid cancer (TC) is the most common endocrine cancer, with differentiated papillary and follicular tumors occurring more frequently than the more aggressive poorly differentiated and anaplastic TC. Nanoparticles (NP) (mainly mesoporous silica, gold, carbon, or liposomes) have been developed to improve the detection of biomarkers and routine laboratory parameters (e.g., thyroid stimulating hormone, thyroglobulin, and calcitonin), tumor imaging, and drug delivery in TC. The majority of drug-loaded nanocarriers to be used for treatment was developed for anaplastic tumors because current treatments are suboptimal. Further, doxorubicin, sorafenib, and gemcitabine treatment can be improved by nanotherapy due to decreased adverse effects. Selective delivery of retinoic acid to TC cells might improve the re-differentiation of de-differentiated TC. The use of carbon NPs for the prevention of parathyroid damage during TC surgery does not show a clear benefit. Certain technologies less suitable for the treatment of deeply located cancers may have some potential for unresectable anaplastic carcinomas, namely those based on low-intensity focused ultrasound and near-infrared irradiation. Although some of these approaches yielded promising results in animal studies, results from clinical trials are currently lacking. Full article

(This article belongs to the Special Issue Advances in Thyroid Carcinoma)

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17 pages, 969 KiB

Open AccessReview

Translational Utility of Liquid Biopsies in Thyroid Cancer Management

by Ayanthi A. Wijewardene, Marthe Chehade, Matti L. Gild, Roderick J. Clifton-Bligh and Martyn Bullock

Cancers 2021, 13(14), 3443; https://doi.org/10.3390/cancers13143443 - 9 Jul 2021

Cited by 15 | Viewed by 4204

Abstract

Liquid biopsies are a novel technique to assess for either circulating tumor cells (CTC) or circulating tumor DNA (ctDNA and microRNA (miRNA)) in peripheral blood samples of cancer patients. The diagnostic role of liquid biopsy in oncology has expanded in recent years, particularly [...] Read more.

Liquid biopsies are a novel technique to assess for either circulating tumor cells (CTC) or circulating tumor DNA (ctDNA and microRNA (miRNA)) in peripheral blood samples of cancer patients. The diagnostic role of liquid biopsy in oncology has expanded in recent years, particularly in lung, colorectal and breast cancer. In thyroid cancer, the role of liquid biopsy in either diagnosis or prognosis is beginning to translate from the lab to the clinic. In this review, we describe the evolution of liquid biopsies in detecting CTC, ctDNA and miRNA in thyroid cancer patients, together with its limitations and future directions in clinical practice. Full article

(This article belongs to the Special Issue Advances in Thyroid Carcinoma)

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17 pages, 930 KiB

Open AccessReview

Clinical Indications for Treatment with Multi-Kinase Inhibitors in Patients with Radioiodine-Refractory Differentiated Thyroid Cancer

by Naoki Fukuda and Shunji Takahashi

Cancers 2021, 13(9), 2279; https://doi.org/10.3390/cancers13092279 - 10 May 2021

Cited by 14 | Viewed by 3873

Abstract

Differentiated thyroid cancer is usually a slow-growing disease, even if the patients develop distant metastasis. For recurrent or metastatic disease, radioactive iodine therapy is a standard treatment. However, the disease gradually progresses in some of the patients and can ultimately develop into life-threatening [...] Read more.

Differentiated thyroid cancer is usually a slow-growing disease, even if the patients develop distant metastasis. For recurrent or metastatic disease, radioactive iodine therapy is a standard treatment. However, the disease gradually progresses in some of the patients and can ultimately develop into life-threatening conditions. For patients with progressive radioactive iodine-refractory differentiated thyroid cancer (RR-DTC), multi-kinase inhibitors (MKIs) including sorafenib and lenvatinib prolonged progression-free survival compared with placebo in pivotal randomized phase 3 trials, although the benefit in overall survival has not been clearly confirmed, possibly because the patients who received placebo were permitted to cross-over to lenvatinib upon disease progression. Moreover, the adverse events related to MKIs were not negligible. Therefore, the optimal timing of MKI initiation has long been controversial, and physicians should consider various patient and disease factors. Herein, we comprehensively review the clinical factors that can be helpful in determining the initiation of MKIs for patients with RR-DTC. Full article

(This article belongs to the Special Issue Advances in Thyroid Carcinoma)

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21 pages, 2664 KiB

Open AccessReview

Radio-Iodide Treatment: From Molecular Aspects to the Clinical View

by Antonio De la Vieja and Garcilaso Riesco-Eizaguirre

Cancers 2021, 13(5), 995; https://doi.org/10.3390/cancers13050995 - 27 Feb 2021

Cited by 28 | Viewed by 7691

Abstract

Thyroid radio-iodide therapy (RAI) is one of the oldest known and used targeted therapies. In thyroid cancer, it has been used for more than eight decades and is still being used to improve thyroid tumor treatment to eliminate remnants after thyroid surgery, and [...] Read more.

Thyroid radio-iodide therapy (RAI) is one of the oldest known and used targeted therapies. In thyroid cancer, it has been used for more than eight decades and is still being used to improve thyroid tumor treatment to eliminate remnants after thyroid surgery, and tumor metastases. Knowledge at the molecular level of the genes/proteins involved in the process has led to improvements in therapy, both from the point of view of when, how much, and how to use the therapy according to tumor type. The effectiveness of this therapy has spread into other types of targeted therapies, and this has made sodium/iodide symporter (NIS) one of the favorite theragnostic tools. Here we focus on describing the molecular mechanisms involved in radio-iodide therapy and how the alteration of these mechanisms in thyroid tumor progression affects the diagnosis and results of therapy in the clinic. We analyze basic questions when facing treatment, such as: (1) how the incorporation of radioiodine in normal, tumor, and metastatic thyroid cells occurs and how it is regulated; (2) the pros and cons of thyroid hormonal deprivation vs. recombinant human Thyroid Stimulating Hormone (rhTSH) in radioiodine residence time, treatment efficacy, thyroglobulin levels and organification, and its influence on diagnostic imaging tests and metastasis treatment; and (3) the effect of stunning and the possible causes. We discuss the possible incorporation of massive sequencing data into clinical practice, and we conclude with a socioeconomical and clinical vision of the above aspects. Full article

(This article belongs to the Special Issue Advances in Thyroid Carcinoma)

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