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13 pages, 2481 KiB

Open AccessArticle

Pan-Genomic Sequencing Reveals Actionable CDKN2A/2B Deletions and Kataegis in Anaplastic Thyroid Carcinoma

by Adam Stenman, Minjun Yang, Johan O. Paulsson, Jan Zedenius, Kajsa Paulsson and C. Christofer Juhlin

Cancers 2021, 13(24), 6340; https://doi.org/10.3390/cancers13246340 - 17 Dec 2021

Cited by 19 | Viewed by 3213

Abstract

Anaplastic thyroid carcinoma (ATC) is a lethal malignancy characterized by poor response to conventional therapies. Whole-genome sequencing (WGS) analyses of this tumor type are limited, and we therefore interrogated eight ATCs using WGS and RNA sequencing. Five out of eight cases (63%) displayed [...] Read more.

Anaplastic thyroid carcinoma (ATC) is a lethal malignancy characterized by poor response to conventional therapies. Whole-genome sequencing (WGS) analyses of this tumor type are limited, and we therefore interrogated eight ATCs using WGS and RNA sequencing. Five out of eight cases (63%) displayed cyclin-dependent kinase inhibitor 2A (CDKN2A) abnormalities, either copy number loss (n = 4) or truncating mutations (n = 1). All four cases with loss of the CDKN2A locus (encoding p16 and p14arf) also exhibited loss of the neighboring CDKN2B gene (encoding p15ink4b), and displayed reduced CDKN2A/2B mRNA levels. Mutations in established ATC-related genes were observed, including TP53, BRAF, ARID1A, and RB1, and overrepresentation of mutations were also noted in 13 additional cancer genes. One of the more predominant mutational signatures was intimately coupled to the activity of Apolipoprotein B mRNA-editing enzyme, the catalytic polypeptide-like (APOBEC) family of cytidine deaminases implied in kataegis, a focal hypermutation phenotype, which was observed in 4/8 (50%) cases. We corroborate the roles of CDKN2A/2B in ATC development and identify kataegis as a recurrent phenomenon. Our findings pinpoint clinically relevant alterations, which may indicate response to CDK inhibitors, and focal hypermutational phenotypes that may be coupled to improved responses using immune checkpoint inhibitors. Full article

(This article belongs to the Special Issue Molecular Alterations in Thyroid Cancer – with Special Focus on Diagnosis, Prognosis and Treatment)

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14 pages, 1470 KiB

Open AccessArticle

Pre-Therapeutic Measurements of Iodine Avidity in Papillary and Poorly Differentiated Thyroid Cancer Reveal Associations with Thyroglobulin Expression, Histological Variants and Ki-67 Index

by Joachim N. Nilsson, Jonathan Siikanen, Christel Hedman, C. Christofer Juhlin and Catharina Ihre Lundgren

Cancers 2021, 13(14), 3627; https://doi.org/10.3390/cancers13143627 - 20 Jul 2021

Cited by 12 | Viewed by 2696

Abstract

Papillary thyroid cancer (PTC) and poorly differentiated thyroid cancer (PDTC) are treated with radioiodine to reduce recurrence and to treat the spread of disease. Adequate iodine accumulation in cancer tissue, iodine avidity, is important for treatment effect. This study investigated which clinical and [...] Read more.

Papillary thyroid cancer (PTC) and poorly differentiated thyroid cancer (PDTC) are treated with radioiodine to reduce recurrence and to treat the spread of disease. Adequate iodine accumulation in cancer tissue, iodine avidity, is important for treatment effect. This study investigated which clinical and histological tumour characteristics correlate with avidity. To quantify avidity in cancer tissue, tracer amounts of iodine-131 were given to 45 patients with cytologically confirmed thyroid cancer. At pathology grossing, representative samples of tumour and lymph nodes were taken and subjected to radioactivity quantification ex vivo to determine avidity. Afterwards, samples underwent extended pathology work-up and analysis. We found that tumoural Tg expression and Ki-67 index were correlated with avidity, whereas tumour size and pT stage were not. The histological variant of thyroid cancer was also correlated with iodine avidity. Variants associated with worse clinical prognoses displayed lower avidity than variants with better prognoses. This work provides new information on which tumours have low iodine avidity. Lower avidity in aggressive histological PTC variants may explain their overall poorer prognoses. Our findings also suggest that radioiodine dosage could be adapted to Tg expression, Ki-67 index or histological variant instead of pT stage, potentially improving the efficacy of radioiodine therapy. Full article

(This article belongs to the Special Issue Molecular Alterations in Thyroid Cancer – with Special Focus on Diagnosis, Prognosis and Treatment)

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17 pages, 3883 KiB

Open AccessArticle

RAS Subcellular Localization Inversely Regulates Thyroid Tumor Growth and Dissemination

by Yaiza García-Ibáñez, Garcilaso Riesco-Eizaguirre, Pilar Santisteban, Berta Casar and Piero Crespo

Cancers 2020, 12(9), 2588; https://doi.org/10.3390/cancers12092588 - 10 Sep 2020

Cited by 3 | Viewed by 2248

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

(This article belongs to the Special Issue Molecular Alterations in Thyroid Cancer – with Special Focus on Diagnosis, Prognosis and Treatment)

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15 pages, 2576 KiB

Open AccessArticle

Cytochrome C Oxidase Subunit 4 (COX4): A Potential Therapeutic Target for the Treatment of Medullary Thyroid Cancer

by Athanasios Bikas, Kirk Jensen, Aneeta Patel, John Costello, Sarah M. Reynolds, Maria Cecilia Mendonca-Torres, Shilpa Thakur, Joanna Klubo-Gwiezdzinska, Dorina Ylli, Leonard Wartofsky, Kenneth Burman and Vasyl Vasko

Cancers 2020, 12(9), 2548; https://doi.org/10.3390/cancers12092548 - 08 Sep 2020

Cited by 19 | Viewed by 3365

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

(This article belongs to the Special Issue Molecular Alterations in Thyroid Cancer – with Special Focus on Diagnosis, Prognosis and Treatment)

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18 pages, 3892 KiB

Open AccessArticle

PLEKHS1 Over-Expression is Associated with Metastases and Poor Outcomes in Papillary Thyroid Carcinoma

by Xiangling Xing, Ninni Mu, Xiaotian Yuan, Na Wang, C. Christofer Juhlin, Klas Strååt, Catharina Larsson and Dawei Xu

Cancers 2020, 12(8), 2133; https://doi.org/10.3390/cancers12082133 - 31 Jul 2020

Cited by 14 | Viewed by 3021

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

(This article belongs to the Special Issue Molecular Alterations in Thyroid Cancer – with Special Focus on Diagnosis, Prognosis and Treatment)

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10 pages, 860 KiB

Open AccessArticle

Clinical Routine TERT Promoter Mutational Screening of Follicular Thyroid Tumors of Uncertain Malignant Potential (FT-UMPs): A Useful Predictor of Metastatic Disease

by Martin Hysek, Johan O. Paulsson, Kenbugul Jatta, Ivan Shabo, Adam Stenman, Anders Höög, Catharina Larsson, Jan Zedenius and Carl Christofer Juhlin

Cancers 2019, 11(10), 1443; https://doi.org/10.3390/cancers11101443 - 26 Sep 2019

Cited by 29 | Viewed by 3353

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

(This article belongs to the Special Issue Molecular Alterations in Thyroid Cancer – with Special Focus on Diagnosis, Prognosis and Treatment)

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18 pages, 3115 KiB

Open AccessArticle

Association between Circulating Fibroblast Growth Factor 21 and Aggressiveness in Thyroid Cancer

by Yea Eun Kang, Jung Tae Kim, Mi Ae Lim, Chan Oh, Lihua Liu, Seung-Nam Jung, Ho-Ryun Won, Kyungmin Lee, Jae Won Chang, Hyon-Seung Yi, Hyun Jin Kim, Bon Jeong Ku, Minho Shong and Bon Seok Koo

Cancers 2019, 11(8), 1154; https://doi.org/10.3390/cancers11081154 - 12 Aug 2019

Cited by 23 | Viewed by 4269

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

(This article belongs to the Special Issue Molecular Alterations in Thyroid Cancer – with Special Focus on Diagnosis, Prognosis and Treatment)

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Review

Jump to: Research

26 pages, 2092 KiB

Open AccessReview

Molecular Markers Guiding Thyroid Cancer Management

by Carolina Nylén, Robert Mechera, Isabella Maréchal-Ross, Venessa Tsang, Angela Chou, Anthony J. Gill, Roderick J. Clifton-Bligh, Bruce G. Robinson, Mark S. Sywak, Stan B. Sidhu and Anthony R. Glover

Cancers 2020, 12(8), 2164; https://doi.org/10.3390/cancers12082164 - 04 Aug 2020

Cited by 36 | Viewed by 6045

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

(This article belongs to the Special Issue Molecular Alterations in Thyroid Cancer – with Special Focus on Diagnosis, Prognosis and Treatment)

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