Special Issue "Thyroid Cancer: Genetics and Targeted Therapies"

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

Deadline for manuscript submissions: 21 September 2019.

Special Issue Editors

Guest Editor
Dr. Dora Dias-Santagata Website E-Mail
Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
Guest Editor
Dr. Lori J. Wirth E-Mail
Department of Hematology-Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 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 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. 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 1800 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 (6 papers)

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Research

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Open AccessArticle
Twenty-Five Years Experience on RET Genetic Screening on Hereditary MTC: An Update on The Prevalence of Germline RET Mutations
Genes 2019, 10(9), 698; https://doi.org/10.3390/genes10090698 - 10 Sep 2019
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, [...] Read more.
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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Open AccessArticle
Thyroid Cancer: The Quest for Genetic Susceptibility Involving DNA Repair Genes
Genes 2019, 10(8), 586; https://doi.org/10.3390/genes10080586 - 01 Aug 2019
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 [...] Read more.
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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Open AccessArticle
Association of Vitamin D Pathway Genetic Variation and Thyroid Cancer
Genes 2019, 10(8), 572; https://doi.org/10.3390/genes10080572 - 28 Jul 2019
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), [...] Read more.
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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Open AccessReview
Thyroid Cancer in the Pediatric Population
Genes 2019, 10(9), 723; https://doi.org/10.3390/genes10090723 - 18 Sep 2019
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 [...] Read more.
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)
Open AccessReview
Molecular Alterations in Thyroid Cancer: From Bench to Clinical Practice
Genes 2019, 10(9), 709; https://doi.org/10.3390/genes10090709 - 13 Sep 2019
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, [...] Read more.
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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Open AccessReview
Current Knowledge of Germline Genetic Risk Factors for the Development of Non-Medullary Thyroid Cancer
Genes 2019, 10(7), 482; https://doi.org/10.3390/genes10070482 - 26 Jun 2019
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 [...] Read more.
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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