Special Issue "Molecular Alterations in Thyroid Cancer – with Special Focus on Diagnosis, Prognosis and Treatment"

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: 30 June 2021.

Special Issue Editors

Dr. Christofer Juhlin
Website
Guest Editor
1. Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
2. Department of Pathology and Cytology, Karolinska University Hospital, Stockholm, Sweden
Interests: follicular thyroid cancer; anaplastic thyroid cancer; endocrine neoplasia; endocrine pathology; next-generation sequencing; histopathology; diagnostic and prognostic markers
Dr. Adam Stenman
Website
Guest Editor
1. Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
2. Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
3. Department of Breast, Endocrine Tumors and Sarcoma, Karolinska University Hospital, Stockholm, Sweden
Interests: papillary thyroid cancer; follicular thyroid cancer; endocrine surgery; next-generation sequencing; genetic aberrations in endocrine neoplasia; prognostic markers
Prof. Dr. Jan Zedenius
Website
Guest Editor
1. Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
2. Department of Breast, Endocrine Tumors and Sarcoma, Karolinska University Hospital, Stockholm, Sweden
Interests: medullary thyroid cancer; anaplastic thyroid cancer; hereditary syndromes; translational research; therapeutics; endocrine surgery

Special Issue Information

Dear Colleagues,

Thyroid cancer is the most common endocrine malignancy with an annual incidence of about 60,000 cases in the US and shows an increased incidence globally. The disease entity is multifaceted, and although the majority of well-differentiated forms of thyroid cancer (papillary thyroid cancer, PTC, and follicular thyroid cancer, FTC) exhibit good prognosis, other forms of thyroid cancer are often associated with dismal outcomes (poorly differentiated thyroid cancer, PDTC, and anaplastic thyroid cancer, ATC). The underlying genetic mechanisms driving thyroid cancer is only partly understood, but the advent of next-generation sequencing techniques has greatly facilitated the detection of recurrent genomic alterations of importance for disease development—of which some could be of direct clinical value.

This Special Issue will focus on molecular studies aimed at providing aid to three commonly encountered clinical dilemmas, namely (1) the diagnostic predicaments in thyroid cancer (most notably―but not limited to―the distinction of benign and malignant follicular thyroid tumors), (2) the enablement to prognosticate thyroid cancer (for example, to pinpoint the subset of thyroid cancer that recur and/or spread to distant sites) and (3) the therapeutic quandaries regarding metastatic thyroid cancer and less differentiated forms of the disease (PDTC, ATC). Further, submissions aimed at increasing our understanding of inherited forms of thyroid cancer are also warmly welcome.

Dr. Carl Christofer Juhlin
Dr. Adam Stenman
Prof. Dr. Jan Zedenius
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2200 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Papillary thyroid carcinoma
  • Follicular thyroid carcinoma
  • Medullary thyroid carcinoma
  • Anaplastic thyroid carcinoma
  • Thyroid tumors
  • Diagnosis
  • Prognostication
  • Treatment
  • Molecular genetics
  • Next-generation sequencing
  • Mutation
  • Omics
  • Clinical biomarker

Published Papers (6 papers)

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Research

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Open AccessArticle
RAS Subcellular Localization Inversely Regulates Thyroid Tumor Growth and Dissemination
Cancers 2020, 12(9), 2588; https://doi.org/10.3390/cancers12092588 - 10 Sep 2020
Abstract
RAS mutations are the second most common genetic alteration in thyroid tumors. However, the extent to which they are associated with the most aggressive phenotypes is still controversial. Regarding their malignancy, the majority of RAS mutant tumors are classified as undetermined, which complicates [...] Read more.
RAS mutations are the second most common genetic alteration in thyroid tumors. However, the extent to which they are associated with the most aggressive phenotypes is still controversial. Regarding their malignancy, the majority of RAS mutant tumors are classified as undetermined, which complicates their clinical management and can lead to undesired under- or overtreatment. Using the chick embryo spontaneous metastasis model, we herein demonstrate that the aggressiveness of HRAS-transformed thyroid cells, as determined by the ability to extravasate and metastasize at distant organs, is orchestrated by HRAS subcellular localization. Remarkably, aggressiveness inversely correlates with tumor size. In this respect, we also show that RAS site-specific capacity to regulate tumor growth and dissemination is dependent on VEGF-B secretion. Furthermore, we have identified the acyl protein thioesterase APT-1 as a determinant of thyroid tumor growth versus dissemination. We show that alterations in APT-1 expression levels can dramatically affect the behavior of thyroid tumors, based on its role as a regulator of HRAS sublocalization at distinct plasma membrane microdomains. In agreement, APT-1 emerges in thyroid cancer clinical samples as a prognostic factor. As such, APT-1 levels could serve as a biomarker that could help in the stratification of HRAS mutant thyroid tumors based on their aggressiveness. Full article
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Open AccessArticle
Cytochrome C Oxidase Subunit 4 (COX4): A Potential Therapeutic Target for the Treatment of Medullary Thyroid Cancer
Cancers 2020, 12(9), 2548; https://doi.org/10.3390/cancers12092548 - 08 Sep 2020
Abstract
The nuclear-encoded subunit 4 of cytochrome c oxidase (COX4) plays a role in regulation of oxidative phosphorylation and contributes to cancer progression. We sought to determine the role of COX4 in differentiated (DTC) and medullary (MTC) thyroid cancers. We examined the expression of [...] Read more.
The nuclear-encoded subunit 4 of cytochrome c oxidase (COX4) plays a role in regulation of oxidative phosphorylation and contributes to cancer progression. We sought to determine the role of COX4 in differentiated (DTC) and medullary (MTC) thyroid cancers. We examined the expression of COX4 in human thyroid tumors by immunostaining and used shRNA-mediated knockdown of COX4 to evaluate its functional contributions in thyroid cancer cell lines. In human thyroid tissue, the expression of COX4 was higher in cancers than in either normal thyroid (p = 0.0001) or adenomas (p = 0.001). The level of COX4 expression correlated with tumor size (p = 0.04) and lymph-node metastases (p = 0.024) in patients with MTCs. COX4 silencing had no effects on cell signaling activation and mitochondrial respiration in DTC cell lines (FTC133 and BCPAP). In MTC-derived TT cells, COX4 silencing inhibited p70S6K/pS6 and p-ERK signaling, and was associated with decreased oxygen consumption and ATP production. Treatment with potassium cyanide had minimal effects on FTC133 and BCPAP, but inhibited mitochondrial respiration and induced apoptosis in MTC-derived TT cells. Our data demonstrated that metastatic MTCs are characterized by increased expression of COX4, and MTC-derived TT cells are vulnerable to COX4 silencing. These data suggest that COX4 can be considered as a novel molecular target for the treatment of MTC. Full article
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Open AccessArticle
PLEKHS1 Over-Expression is Associated with Metastases and Poor Outcomes in Papillary Thyroid Carcinoma
Cancers 2020, 12(8), 2133; https://doi.org/10.3390/cancers12082133 - 31 Jul 2020
Cited by 1
Abstract
Pleckstrin homology domain containing S1 (PLEKHS1) is a poorly characterized factor, although its promoter mutations were identified in human malignancies including thyroid carcinoma (TC). This study was designed to determine PLEKHS1 promoter hotspot mutations in papillary and anaplastic thyroid carcinomas (PTCs and ATCs) [...] Read more.
Pleckstrin homology domain containing S1 (PLEKHS1) is a poorly characterized factor, although its promoter mutations were identified in human malignancies including thyroid carcinoma (TC). This study was designed to determine PLEKHS1 promoter hotspot mutations in papillary and anaplastic thyroid carcinomas (PTCs and ATCs) and to evaluate if PLEKHS1 expression influences clinical outcome. The PLEKHS1 promoter mutation was observed in 1/93 of PTCs and none of 18 ATCs in our cohort; however, PLEKHS1 expression was aberrantly up-regulated in TCs compared to adjacent non-tumorous thyroid tissues. ATC tumors, an undifferentiated TC, exhibited the highest PLEKHS1 expression. In both TCGA and present cohorts of PTCs, PLEKHS1 gene methylation density was inversely correlated with its mRNA expression and demethylation at the PLEKHS1 locus occurred at two CpGs. Higher PLEKHS1 expression was associated with lymph node and distant metastases, and shorter overall and disease-free survival in our cohort of PTC patients. Importantly, PLEKHS1 over-expression predicted shorter patient survival in PTCs lacking TERT promoter mutations. Cellular experiments showed that PLEKHS1 over-expression enhanced AKT phosphorylation and invasiveness. Collectively, the PLEKHS1 gene demethylation causes its over-expression in PTCs. PLEKHS1 promotes aggressive behavior of TCs possibly by increasing AKT activity, and its over-expression predicts poor patient outcomes. Full article
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Open AccessArticle
Clinical Routine TERT Promoter Mutational Screening of Follicular Thyroid Tumors of Uncertain Malignant Potential (FT-UMPs): A Useful Predictor of Metastatic Disease
Cancers 2019, 11(10), 1443; https://doi.org/10.3390/cancers11101443 - 26 Sep 2019
Cited by 13
Abstract
Mutations of the Telomerase reverse transcriptase (TERT) gene promoter are recurrently found in follicular thyroid carcinoma (FTC) and follicular tumors of uncertain malignant potential (FT-UMP), but nearly never in follicular thyroid adenoma (FTA). We, therefore, believe these mutations could signify malignant [...] Read more.
Mutations of the Telomerase reverse transcriptase (TERT) gene promoter are recurrently found in follicular thyroid carcinoma (FTC) and follicular tumors of uncertain malignant potential (FT-UMP), but nearly never in follicular thyroid adenoma (FTA). We, therefore, believe these mutations could signify malignant potential. At our department, postoperative TERT promoter mutational testing of FT-UMPs was implemented in 2014, with a positive mutation screening leading to vigilant follow-up and sometimes adjuvant treatment. To date, we screened 51 FT-UMPs and compared outcomes to 40 minimally invasive FTCs (miFTCs) with known TERT genotypes. Eight FT-UMPs (16%) displayed TERT promoter mutations, of which four cases underwent a completion lobectomy at the discretion of the patient, and a single patient also opted in for radioiodine (RAI) treatment. Three mutation-positive patients developed distant metastases, registered in one patient receiving a completion lobectomy and in two patients with no additional treatment. Three out of four patients who received additional surgery, including the RAI-treated patient, are still without metastatic disease. We conclude that FT-UMPs with TERT promoter mutations harbor malignant potential and exhibit at least similar recurrence rates to TERT-promoter-mutated miFTCs. Mutational screening should constitute a cornerstone analysis in the histopathological work-up of FT-UMPs. Full article
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Open AccessArticle
Association between Circulating Fibroblast Growth Factor 21 and Aggressiveness in Thyroid Cancer
Cancers 2019, 11(8), 1154; https://doi.org/10.3390/cancers11081154 - 12 Aug 2019
Cited by 4
Abstract
Fibroblast growth factor 21 (FGF21) plays important roles in regulating glucose, lipid, and energy metabolism; however, its effects in tumors remain poorly understood. To understand the role of FGF21 in regulating tumor aggressiveness in thyroid cancer, serum levels of FGF21 were measured in [...] Read more.
Fibroblast growth factor 21 (FGF21) plays important roles in regulating glucose, lipid, and energy metabolism; however, its effects in tumors remain poorly understood. To understand the role of FGF21 in regulating tumor aggressiveness in thyroid cancer, serum levels of FGF21 were measured in healthy subjects and patients with papillary thyroid cancer (PTC), and expression levels of FGF21, FGF receptors (FGFRs), and β-klotho (KLB) were investigated in human thyroid tissues. The cell viability, migrating cells, and invading cells were measured in PTC cells after treatment with recombinant FGF21. Higher serum levels of FGF21 were found in patients with thyroid cancer than in control participants, and were significantly associated with body mass index (BMI), fasting glucose levels, triglyceride levels, tumor stage, lymphovascular invasion, and recurrence. Serum FGF21 levels were positively correlated with the BMI in patients with PTC, and significantly associated with recurrence. Recombinant FGF21 led to tumor aggressiveness via activation of the FGFR signaling axis and epithelial-to-mesenchymal transition (EMT) signaling in PTC cells, and AZD4547, an FGFR tyrosine kinase inhibitor, attenuated the effects of FGF21. Hence, FGF21 may be a new biomarker for predicting tumor progression, and targeting FGFR may be a novel therapy for the treatment of obese patients with PTC. Full article
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Review

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Open AccessReview
Molecular Markers Guiding Thyroid Cancer Management
Cancers 2020, 12(8), 2164; https://doi.org/10.3390/cancers12082164 - 04 Aug 2020
Abstract
The incidence of thyroid cancer is rapidly increasing, mostly due to the overdiagnosis and overtreatment of differentiated thyroid cancer (TC). The increasing use of potent preclinical models, high throughput molecular technologies, and gene expression microarrays have provided a deeper understanding of molecular characteristics [...] Read more.
The incidence of thyroid cancer is rapidly increasing, mostly due to the overdiagnosis and overtreatment of differentiated thyroid cancer (TC). The increasing use of potent preclinical models, high throughput molecular technologies, and gene expression microarrays have provided a deeper understanding of molecular characteristics in cancer. Hence, molecular markers have become a potent tool also in TC management to distinguish benign from malignant lesions, predict aggressive biology, prognosis, recurrence, as well as for identification of novel therapeutic targets. In differentiated TC, molecular markers are mainly used as an adjunct to guide management of indeterminate nodules on fine needle aspiration biopsies. In contrast, in advanced thyroid cancer, molecular markers enable targeted treatments of affected signalling pathways. Identification of the driver mutation of targetable kinases in advanced TC can select treatment with mutation targeted tyrosine kinase inhibitors (TKI) to slow growth and reverse adverse effects of the mutations, when traditional treatments fail. This review will outline the molecular landscape and discuss the impact of molecular markers on diagnosis, surveillance and treatment of differentiated, poorly differentiated and anaplastic follicular TC. Full article
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