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Thyroid Cancer: Genetics and Targeted Therapies

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A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (21 September 2019) | Viewed by 55965

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Special Issue Editors

Dr. Dora Dias-Santagata

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Guest Editor

Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA

Dr. Lori J. Wirth

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Guest Editor

Department of Hematology-Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02109, USA

Special Issue Information

Dear Colleagues,

We write to invite you to contribute to a Special Issue in Genes that will focus on Thyroid Cancer Genetics and Therapies. Thyroid cancer is the most prevalent endocrine malignancy. It affects women three times more frequently than men and ranks as the 5th most common cancer in women in the United States. The number of newly diagnosed thyroid cancers has more than tripled over the past four decades, and the worldwide incidence of the disease continues to steadily rise.

Significant advances in the molecular characterization of thyroid cancer have dramatically improved our understanding of the genetic mechanisms underlying disease development and progression. Genetic testing of thyroid specimens has demonstrated clinical utility in addressing some of the most critical challenges in the field. Molecular analysis of fine needle aspirates (FNA) is having a major impact on the pre-operative diagnosis of thyroid nodules with indeterminate cytology, by helping to discriminate between high-risk cancerous lesions, intermediate/low-risk tumors, and benign thyroid nodules. This molecularly-based risk stratification is being used alongside imaging studies and cytological analyses to guide patient management, which can range from total thyroidectomy with lymph node dissection for high-risk cancer, to periodic observation, thus sparing patients with benign nodules from unnecessary surgery. In the setting of advanced-stage, progressive disease, genetic testing of thyroid tumors is directing systemic treatment decisions by identifying relevant molecular markers associated with response to specific targeted therapies.

In this Special Issue of Genes, we welcome reviews, mini-reviews, new methods, and original research articles that highlight our current knowledge and advance our understanding of thyroid cancer. We welcome studies on all forms of thyroid cancer, including papillary thyroid carcinoma, the most prevalent type, as well as rare tumors, including follicular thyroid carcinoma, Hürthle cell thyroid cancer, poorly differentiated and anaplastic thyroid carcinoma, and medullary thyroid cancer. Topics of interest include but are not limited to the role of genetic and epigenetic alterations, pathological features, and environmental factors in thyroid cancer biology and evolution, and their potential clinical implications for diagnosis, prognosis, and in predicting therapeutic efficacies and outcomes. We also welcome studies that highlight new technologies and non-invasive approaches to monitoring treatment response, early detection of primary disease or recurrence, and identification of mechanisms of acquired resistance to therapy.

We look forward to your contributions.

Dr. Dora Dias-Santagata
Dr. Lori J. Wirth
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 submissions that pass pre-check are 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. Genes 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 2600 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

thyroid cancer
thyroid carcinoma
genetic abnormalities
genetic markers
molecular testing
fine needle aspiration
targeted cancer therapy
systemic therapy
adjuvant therapy
oncogenic mutations
gene rearrangements

Published Papers (10 papers)

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Research

Jump to: Review

15 pages, 2631 KiB

Open AccessArticle

NOP53 as A Candidate Modifier Locus for Familial Non-Medullary Thyroid Cancer

by Aida Orois, Sudheer K. Gara, Mireia Mora, Irene Halperin, Sandra Martínez, Rocio Alfayate, Electron Kebebew and Josep Oriola

Genes 2019, 10(11), 899; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10110899 - 07 Nov 2019

Cited by 18 | Viewed by 2447

Abstract

Nonsyndromic familial non-medullary thyroid cancer (FNMTC) represents 3–9% of thyroid cancers, but the susceptibility gene(s) remain unknown. We designed this multicenter study to analyze families with nonsyndromic FNMTC and identify candidate susceptibility genes. We performed exome sequencing of DNA from four affected individuals from one kindred, with five cases of nonsyndromic FNMTC. Single Nucleotide Variants, and insertions and deletions that segregated with all the affected members, were analyzed by Sanger sequencing in 44 additional families with FNMTC (37 with two affected members, and seven with three or more affected members), as well as in an independent control group of 100 subjects. We identified the germline variant p. Asp31His in NOP53 gene (rs78530808, MAF 1.8%) present in all affected members in three families with nonsyndromic FNMTC, and not present in unaffected spouses. Our functional studies of NOP53 in thyroid cancer cell lines showed an oncogenic function. Immunohistochemistry exhibited increased NOP53 protein expression in tumor samples from affected family members, compared with normal adjacent thyroid tissue. Given the relatively high frequency of the variant in the general population, these findings suggest that instead of a causative gene, NOP53 is likely a low-penetrant gene implicated in FNMTC, possibly a modifier. Full article

(This article belongs to the Special Issue Thyroid Cancer: Genetics and Targeted Therapies)

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Graphical abstract

12 pages, 636 KiB

Open AccessArticle

Twenty-Five Years Experience on RET Genetic Screening on Hereditary MTC: An Update on The Prevalence of Germline RET Mutations

by Rossella Elisei, Alessia Tacito, Teresa Ramone, Raffaele Ciampi, Valeria Bottici, Virginia Cappagli, David Viola, Antonio Matrone, Loredana Lorusso, Laura Valerio, Carlotta Giani, Cristina Campopiano, Alessandro Prete, Laura Agate, Eleonora Molinaro and Cristina Romei

Genes 2019, 10(9), 698; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10090698 - 10 Sep 2019

Cited by 53 | Viewed by 5644

Abstract

Background: Pathogenic germline mutations affecting the RET proto-oncogene underlie the development of hereditary medullary thyroid carcinoma (MTC). The aims of this study were to evaluate the prevalence of germline RET mutations in a large series of MTC, collected over the last 25 years, and to reappraise their clinical significance. Methods: We performed RET genetic screening in 2031 Italian subjects: patients who presented with sporadic (n = 1264) or hereditary (n = 117) MTC, plus 650 relatives. Results: A RET germline mutation was found in 115/117 (98.3%) hereditary and in 78/1264 (6.2%) apparently sporadic cases: in total, 42 distinct germline variants were found. The V804M mutation was the most prevalent in our cohort, especially in cases that presented as sporadic, while mutations affecting cysteine residues were the most frequent in the group of clinically hereditary cases. All M918T mutations were “de novo” and exclusively associated with MEN2B. Several variants of unknown significance (VUS) were also found. Conclusions: a) RET genetic screening is informative in both hereditary and sporadic MTC; b) the prevalence of different mutations varies with V804M being the most frequent; c) the association genotype–phenotype is confirmed; d) by RET screening, some VUS can be found but their pathogenic role must be demonstrated before screening the family. Full article

(This article belongs to the Special Issue Thyroid Cancer: Genetics and Targeted Therapies)

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31 pages, 800 KiB

Open AccessArticle

Thyroid Cancer: The Quest for Genetic Susceptibility Involving DNA Repair Genes

by Luís S. Santos, Bruno Costa Gomes, Hélder N. Bastos, Octávia M. Gil, Ana Paula Azevedo, Teresa C. Ferreira, Edward Limbert, Susana N. Silva and José Rueff

Genes 2019, 10(8), 586; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10080586 - 01 Aug 2019

Cited by 10 | Viewed by 3315

Abstract

The incidence of thyroid cancer (TC), particularly well-differentiated forms (DTC), has been rising and remains the highest among endocrine malignancies. Although ionizing radiation (IR) is well established on DTC aetiology, other environmental and genetic factors may also be involved. DNA repair single nucleotide polymorphisms (SNPs) could be among the former, helping in explaining the high incidence. To further clarify the role of DNA repair SNPs in DTC susceptibility, we analyzed 36 SNPs in 27 DNA repair genes in a population of 106 DTCs and corresponding controls with the aim of interpreting joint data from previously studied isolated SNPs in DNA repair genes. Significant associations with DTC susceptibility were observed for XRCC3 rs861539, XPC rs2228001, CCNH rs2230641, MSH6 rs1042821 and ERCC5 rs2227869 and for a haplotype block on chromosome 5q. From 595 SNP-SNP combinations tested and 114 showing relevance, 15 significant SNP combinations (p < 0.01) were detected on paired SNP analysis, most of which involving CCNH rs2230641 and mismatch repair variants. Overall, a gene-dosage effect between the number of risk genotypes and DTC predisposition was observed. In spite of the volume of data presented, new studies are sought to provide an interpretability of the role of SNPs in DNA repair genes and their combinations in DTC susceptibility. Full article

(This article belongs to the Special Issue Thyroid Cancer: Genetics and Targeted Therapies)

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8 pages, 226 KiB

Open AccessArticle

Association of Vitamin D Pathway Genetic Variation and Thyroid Cancer

by Isabel S. Carvalho, Catarina I. Gonçalves, Joana T. Almeida, Teresa Azevedo, Teresa Martins, Fernando J. Rodrigues and Manuel C. Lemos

Genes 2019, 10(8), 572; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10080572 - 28 Jul 2019

Cited by 10 | Viewed by 3467

Abstract

Vitamin D is mostly known for its role in bone and calcium metabolism. However, studies have suggested that it also has inhibitory effects on tumor development and progression. Genetic variants close to genes that encode crucial enzymes for the synthesis (DHCR7 rs12785878), metabolism (CYP2R1 rs2060793) and degradation (CYP24A1 rs6013897) of vitamin D have been associated with serum levels of vitamin D. The aim of this case-control study was to determine the effect of these variants in the vitamin D pathway on the susceptibility to thyroid cancer. Five hundred patients with differentiated thyroid cancer and 500 controls were genotyped for the DHCR7 rs12785878, CYP2R1 rs2060793, and CYP24A1 rs6013897 variants. Genotype and allele frequencies were compared between patients and controls. The DHCR7 rs12785878 minor allele was associated with thyroid cancer under an additive (OR 1.38, 95% CI 1.15–1.65, p = 0.0004) and codominant (OR 1.88, 95% CI 1.30–2.74, p = 0.0021) model. These findings suggest that DHCR7 polymorphisms may be associated with an increased risk of thyroid cancer due to an effect of this gene on circulating vitamin D levels. Full article

(This article belongs to the Special Issue Thyroid Cancer: Genetics and Targeted Therapies)

Review

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17 pages, 792 KiB

Open AccessEditor’s ChoiceReview

RET Gene Fusions in Malignancies of the Thyroid and Other Tissues

by Massimo Santoro, Marialuisa Moccia, Giorgia Federico and Francesca Carlomagno

Genes 2020, 11(4), 424; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11040424 - 15 Apr 2020

Cited by 72 | Viewed by 8122

Abstract

Following the identification of the BCR-ABL1 (Breakpoint Cluster Region-ABelson murine Leukemia) fusion in chronic myelogenous leukemia, gene fusions generating chimeric oncoproteins have been recognized as common genomic structural variations in human malignancies. This is, in particular, a frequent mechanism in the oncogenic conversion of protein kinases. Gene fusion was the first mechanism identified for the oncogenic activation of the receptor tyrosine kinase RET (REarranged during Transfection), initially discovered in papillary thyroid carcinoma (PTC). More recently, the advent of highly sensitive massive parallel (next generation sequencing, NGS) sequencing of tumor DNA or cell-free (cfDNA) circulating tumor DNA, allowed for the detection of RET fusions in many other solid and hematopoietic malignancies. This review summarizes the role of RET fusions in the pathogenesis of human cancer. Full article

(This article belongs to the Special Issue Thyroid Cancer: Genetics and Targeted Therapies)

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27 pages, 2341 KiB

Open AccessReview

Influencers on Thyroid Cancer Onset: Molecular Genetic Basis

by Berta Luzón-Toro, Raquel María Fernández, Leticia Villalba-Benito, Ana Torroglosa, Guillermo Antiñolo and Salud Borrego

Genes 2019, 10(11), 913; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10110913 - 08 Nov 2019

Cited by 25 | Viewed by 5658

Abstract

Thyroid cancer, a cancerous tumor or growth located within the thyroid gland, is the most common endocrine cancer. It is one of the few cancers whereby incidence rates have increased in recent years. It occurs in all age groups, from children through to seniors. Most studies are focused on dissecting its genetic basis, since our current knowledge of the genetic background of the different forms of thyroid cancer is far from complete, which poses a challenge for diagnosis and prognosis of the disease. In this review, we describe prevailing advances and update our understanding of the molecular genetics of thyroid cancer, focusing on the main genes related with the pathology, including the different noncoding RNAs associated with the disease. Full article

(This article belongs to the Special Issue Thyroid Cancer: Genetics and Targeted Therapies)

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17 pages, 2359 KiB

Open AccessReview

The Role of Molecular Testing for the Indeterminate Thyroid FNA

by Esther Diana Rossi, Liron Pantanowitz and William C. Faquin

Genes 2019, 10(10), 736; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10100736 - 23 Sep 2019

Cited by 44 | Viewed by 4346

Abstract

Thyroid nodules are common in the adult population where a majority are benign and only 4.0% to 6.5% are malignant. Fine needle aspiration (FNA) is a key method used in the early stages to evaluate and triage patients with thyroid nodules. While a definitive cytological diagnosis is provided in more than 70–75% of all thyroid FNA cases, the group of indeterminate lesions offers a challenge in terms of interpretation and clinical management. Molecular testing platforms have been developed, are recognized as an option by the 2015 American Thyroid Association Guidelines, and are frequently used in conjunction with FNA as an integral part of the cytologic evaluation. In this review, the utility of molecular testing options for nodules assigned to the group of indeterminate thyroid FNAs is described. Full article

(This article belongs to the Special Issue Thyroid Cancer: Genetics and Targeted Therapies)

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20 pages, 356 KiB

Open AccessReview

Thyroid Cancer in the Pediatric Population

by Vera A. Paulson, Erin R. Rudzinski and Douglas S. Hawkins

Genes 2019, 10(9), 723; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10090723 - 18 Sep 2019

Cited by 138 | Viewed by 9688

Abstract

Thyroid cancer is rare in the pediatric population, but thyroid carcinomas occurring in children carry a unique set of clinical, pathologic, and molecular characteristics. In comparison to adults, children more often present with aggressive, advanced stage disease. This is at least in part due to the underlying biologic and molecular differences between pediatric and adult thyroid cancer. Specifically, papillary thyroid carcinoma (which accounts for approximately 90% of pediatric thyroid cancer) has a high rate of gene fusions which influence the histologic subtypes encountered in pediatric thyroid tumors, are associated with more extensive extrathyroidal disease, and offer unique options for targeted medical therapies. Differences are also seen in pediatric follicular thyroid cancer, although there are few studies of non-papillary pediatric thyroid tumors published in the literature due to their rarity, and in medullary carcinoma, which is most frequently diagnosed in the pediatric population in the setting of prophylactic thyroidectomies for known multiple endocrine neoplasia syndromes. The overall shift in the spectrum of histotypes and underlying molecular alterations common in pediatric thyroid cancer is important to recognize as it may directly influence diagnostic test selection and therapeutic recommendations. Full article

(This article belongs to the Special Issue Thyroid Cancer: Genetics and Targeted Therapies)

33 pages, 5156 KiB

Open AccessReview

Molecular Alterations in Thyroid Cancer: From Bench to Clinical Practice

by Elena Tirrò, Federica Martorana, Chiara Romano, Silvia Rita Vitale, Gianmarco Motta, Sandra Di Gregorio, Michele Massimino, Maria Stella Pennisi, Stefania Stella, Adriana Puma, Fiorenza Gianì, Marco Russo, Livia Manzella and Paolo Vigneri

Genes 2019, 10(9), 709; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10090709 - 13 Sep 2019

Cited by 65 | Viewed by 6637

Abstract

Thyroid cancer comprises different clinical and histological entities. Whereas differentiated (DTCs) malignancies are sensitive to radioiodine therapy, anaplastic (ATCs) and medullary (MTCs) tumors do not uptake radioactive iodine and display aggressive features associated with a poor prognosis. Moreover, in a majority of DTCs, disease evolution leads to the progressive loss of iodine sensitivity. Hence, iodine-refractory DTCs, along with ATCs and MTCs, require alternative treatments reflective of their different tumor biology. In the last decade, the molecular mechanisms promoting thyroid cancer development and progression have been extensively studied. This has led to a better understanding of the genomic landscape, displayed by thyroid malignancies, and to the identification of novel therapeutic targets. Indeed, several pharmacological compounds have been developed for iodine-refractory tumors, with four multi-target tyrosine kinase inhibitors already available for DTCs (sorafenib and lenvatinib) and MTCs (cabozantib and vandetanib), and a plethora of drugs currently being evaluated in clinical trials. In this review, we will describe the genomic alterations and biological processes intertwined with thyroid cancer development, also providing a thorough overview of targeted drugs already tested or under investigation for these tumors. Furthermore, given the existing preclinical evidence, we will briefly discuss the potential role of immunotherapy as an additional therapeutic strategy for the treatment of thyroid cancer. Full article

(This article belongs to the Special Issue Thyroid Cancer: Genetics and Targeted Therapies)

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14 pages, 533 KiB

Open AccessReview

Current Knowledge of Germline Genetic Risk Factors for the Development of Non-Medullary Thyroid Cancer

by Kinga Hińcza, Artur Kowalik and Aldona Kowalska

Genes 2019, 10(7), 482; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10070482 - 26 Jun 2019

Cited by 57 | Viewed by 5841

Abstract

The thyroid is the most common site of endocrine cancer. One type of thyroid cancer, non-medullary thyroid cancer (NMTC), develops from follicular cells and represents approximately 90% of all thyroid cancers. Approximately 5%–15% of NMTC cases are thought to be of familial origin (FNMTC), which is defined as the occurrence of the disease in three or more first-degree relatives of the patient. It is often divided into two groups: Syndrome-associated and non-syndromic. The associated syndromes include Cowden syndrome, familial adenomatous polyposis, Gardner syndrome, Carney complex and Werner syndrome. The hereditary factors contributing to the unfavorable course of FNMTC remain poorly understood; therefore, considerable effort is being expended to identify contributing loci. Research carried out to date identifies fourteen genes (DICER1, FOXE1, PTCSC2, MYH9, SRGAP1, HABP2, BRCA1, CHEK2, ATM, RASAL1, SRRM2, XRCC1, TITF-1/NKX2.1, PTCSC3) associated with vulnerability to FNMTC that are not related to hereditary syndromes. In this review, we summarize FNMTC studies to date, and provide information on genes involved in the development of non-syndromic familial non-medullary thyroid cancers, and the significance of mutations in these genes as risk factors. Moreover, we discuss whether the genetic polymorphism rs966423 in DIRC3 has any potential as a prognostic factor of papillary thyroid cancer. Full article

(This article belongs to the Special Issue Thyroid Cancer: Genetics and Targeted Therapies)

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