Current Genomics (v.12, #8)

This issue of Current genomics is devoted to a broad spectrum of thyroid disorders which occur in the population with ahigh frequency and represent an important clinical problem to thyroid specialists all over the world. Understanding the diseasepathophysiology represents an important tool for clinicians confronting various diagnostic and therapeutic challenges inmanaging patients. In the last decade we have been facing a tremendous advance in our knowledge and numerous evidence of asusceptibility to various thyroid disorders. All this is helping us to understand the mechanisms, offering promises for preventionand even having an impact on the way we treat patients. It is now clear that a certain genotype in combination with a properenvironmental trigger is crucial for the disease development, but several steps from this point to the clinical disease remain tobe elucidated. This special focus issue summarizes current knowledge of thyroid genetics, emphasizing the importance ofgenetic contribution to a distinctive clinical outcome in thyroid autoimmune disease and in thyroid neoplasm.In thyroid autoimmune disease, the evidence on genetic susceptibility obtained by epidemiological, family and twin studieshas been confirmed using the whole genome and candidate gene approaches. Those studies helped to uncover major candidategenes, some of them being thyroid specific, while others are being involved in the immune regulation. Brand and Goughcomprehensively reviewed immunogenetic mechanisms of thyroid autoimmunity and genotyping technologies, illustrating bothhistorical and recent aspects as well as future challenges. In spite of shared genetic predisposal factors, different immunogeneticpathways lead to specific subtypes of thyroid autoimmunity, such as Graves' disease, Graves' ophthalmopathy andHashimoto's thyroiditis. Detailed up-date on the current knowledge of genetic markers associated with Graves' disease,presented by Ploski and colleagues, also explains a functional significance of observed associations and genotype-phenotypecorrelations. Immunogenetics of Graves' ophthalmopathy, being clinically detected in up to 50% of patients with Graves'disease, is reviewed by Khalilzadeh and colleagues, emphasizing both genetic background and putative events in immuneactivation in the orbit. In contrast to Graves' disease, where humoral immune response predominates, cell-mediated immuneresponse is characteristic for Hashimoto's thyroiditis. Zaletel and Gaberek provided an extensive overview of the possibletriggers as well as putative mechanisms leading to the clinical disease.When discussing thyroid tumors, thyroid nodule is a frequent finding in adults, especially in those undergoing thyroidultrasound examinations. Taking into account a high prevalence and most frequently a benign nature, diagnosing of thyroidcarcinoma seems like looking for a needle in a haystack. Although fine needle aspiration biopsy is a convenient and the bestnon-surgical diagnostic tool for distinguishing between benign and malignant thyroid lesion, its accuracy varies with thehistological subtype of thyroid nodule and in a high percentage of specimen indeterminate cytology is reported. The article ofCerutti is a detailed review of all different approaches used in recent years to overcome a problem of differentiation of benignfrom malignant thyroid tumors, emphasizing molecular markers that may improve diagnostic accuracy and help to avoidunnecessary treatment of benign tumors. Detection of specific genetic alterations in thyroid cancer seems to be useful not onlyfor the diagnosis, but also for the prognosis of the disease. While the author Gomez Saez described different geneticabnormalities focusing on differentiated histological subtypes of thyroid carcinoma, Soares and co-workers reviewed the mostrelevant genetic alterations in aggressive poorly differentiated and undifferentiated thyroid carcinomas. The current knowledgeand approaches in medullary thyroid carcinoma are summarized by Taccaliti and colleagues, focusing on the central role ofRET proto-oncogene in management of patients and their families. In the recent years, the rapidly growing knowledge of themolecular pathways in thyroid cancer enabled the development of new therapeutic agents. Antonelli and co-workerscontributed a timely review of this relevant topic, providing both an overview on molecular pathways being explored astherapeutic targets and detailed information on new targeted therapies for thyroid carcinoma.Hopefully, the selected topics of this thematic issue will offer critically summarized and timely information from the field ofthyroid pathology relevant to physicians, clinical researchers and basic scientists. I would especially like to thank the reviewersfor their valuable time, comments, and suggestions that contributed to an even better quality of the reviews. Finally, let methank Editor-in-Chief, Dr. Christian Neri, and his co-workers for the trust and support during the process of preparing thisspecial focus issue.

The autoimmune thyroid diseases (AITD) include Graves' disease (GD) and Hashimoto's thyroiditis (HT),which are characterised by a breakdown in immune tolerance to thyroid antigens. Unravelling the genetic architecture ofAITD is vital to better understanding of AITD pathogenesis, required to advance therapeutic options in both diseasemanagement and prevention. The early whole-genome linkage and candidate gene association studies provided the firstevidence that the HLA region and CTLA-4 represented AITD risk loci. Recent improvements in; high throughputgenotyping technologies, collection of larger disease cohorts and cataloguing of genome-scale variation have facilitatedgenome-wide association studies and more thorough screening of candidate gene regions. This has allowed identificationof many novel AITD risk genes and more detailed association mapping. The growing number of confirmed AITDsusceptibility loci, implicates a number of putative disease mechanisms most of which are tightly linked with aspects ofimmune system function. The unprecedented advances in genetic study will allow future studies to identify further noveldisease risk genes and to identify aetiological variants within specific gene regions, which will undoubtedly lead to abetter understanding of AITD patho-physiology.

The Genetic Basis of Graves' Disease by Rafal Ploski, Konrad Szymanski, Tomasz Bednarczuk (542-563).
The presented comprehensive review of current knowledge about genetic factors predisposing to Graves'disease (GD) put emphasis on functional significance of observed associations. In particular, we discuss recent effortsaimed at refining diseases associations found within the HLA complex and implicating HLA class I as well as HLADPB1loci. We summarize data regarding non-HLA genes such as PTPN22, CTLA4, CD40, TSHR and TG which havebeen extensively studied in respect to their role in GD. We review recent findings implicating variants of FCRL3 (gene forFC receptor-like-3 protein), SCGB3A2 (gene for secretory uteroglobin-related protein 1- UGRP1) as well as otherunverified possible candidate genes for GD selected through their documented association with type 1 diabetes mellitus:Tenr-IL2-IL21, CAPSL (encoding calcyphosine-like protein), IFIH1(gene for interferon-induced helicase C domain 1),AFF3, CD226 and PTPN2. We also review reports on association of skewed X chromosome inactivation and fetalmicrochimerism with GD. Finally we discuss issues of genotype-phenotype correlations in GD.

Graves' Ophthalmopathy: A Review of Immunogenetics by Omid Khalilzadeh, Sina Noshad, Armin Rashidi, Aliakbar Amirzargar (564-575).
Graves' disease (GD) is the most common cause of thyrotoxicosis and often involves the orbits. Graves'ophthalmopathy (GO), also known as Thyroid Eye Disease (TED), can be clinically significant and advance to sightthreateningstages. Our knowledge of the immunogenetic pathophysiology of GO is rapidly expanding. The presentreview is an attempt to summarize the current state of knowledge on the immunogenetics of GO. First we briefly reviewthe epidemiology and clinical importance of GO, and then we describe in detail the macromolecular pathogenesis andfinally immunogenetics of GO. Discrepancies between the results from various reports and the limitations of the availabledata are discussed. In particular, there is a scarcity of data from non-Asian populations. While several studies havedemonstrated significant associations between polymorphisms in certain genes (especially CTLA-4, HLA-DRB-1, andTNF-α), there is a need for studies that investigate the relationship between polymorphisms and both serum and localconcentrations of the resulting proteins. A complete understanding of GO susceptibility and pathogenesis has not been yetpossible due to a number of important knowledge gaps that need to be filled by future research.

Hashimoto's Thyroiditis: From Genes to the Disease by Katja Zaletel, Simona Gaberscek (576-588).
Hashimoto's thyroiditis (HT) is the most prevalent autoimmune thyroid disorder. Intrathyroidal lymphocyticinfiltration is followed by a gradual destruction of the thyroid gland which may lead to subclinical or overthypothyroidism. Biochemical markers of the disease are thyroid peroxidase and/or thyroglobulin autoantibodies in theserum which are present with a higher prevalence in females than in males and increase with age. Although exactmechanisms of aetiology and pathogenesis of the disorder are not completely understood, a strong genetic susceptibility tothe disease has been confirmed predominantly by family and twin studies. Several genes were shown to be associated withthe disease occurrence, progression, and severity. Genes for human leukocyte antigen, cytotoxic T lymphocyte antigen-4,protein tyrosine phosphatase nonreceptor-type 22, thyroglobulin, vitamin D receptor, and cytokines are considered to beof utmost importance. Amongst endogenous factors for the disease development, the attention is focused predominantlyon female sex, pregnancy with postpartum period and fetal microchimerism. Environmental factors influencing HTdevelopment are iodine intake, drugs, infections and different chemicals. Disturbed self-tolerance accompanied by theincreased antigen presentation is a prerequisite for the HT occurrence, whereas proper interaction of thyroid cells, antigenpresenting cells, and T cells are necessary for the initiation of thyroid autoimmunity. Secreted cytokines leadpredominantly to T-helper type 1 (Th1) response as well as to Th 17 response which has only recently been implicated.Final outcome of HT is thyroid destruction which is mostly a consequence of the apoptotic processes combined with Tcellmediated cytotoxicity.

Fine-Needle Aspiration (FNA) is the most widely used and cost-effective preoperative test for the initialevaluation of a thyroid nodule, although it has limited diagnostic accuracy for several types of tumors. Patients will oftenreceive cytological report of indeterminate cytology and are referred to surgery for a more accurate diagnosis. Animproved test would help physicians rapidly focus treatment on true malignancies and avoid some unnecessary treatmentof benign tumors. This review will discuss current molecular markers that may improve thyroid nodule diagnosis.

The MAPK/ERK (mitogen-activated protein kinase/extracellular signal- regulated kinase signaling pathway)and PI3K/Akt (lipid kinase phoshoinositide-3-kinase signaling pathway) play an important role in transmission of cellsignals through transduction systems as ligands, transmembrane receptors and cytoplasmic secondary messengers to cellnucleus, where they influence the expression of genes that regulate important cellular processes: cell growth, proliferationand apoptosis. The genes, coding the signaling cascade proteins (RET, RAS, BRAF, PI3K, PTEN, AKT), are mutated oraberrantly expressed in thyroid cancer derived from follicular thyroid cell. Genetic and epigenetic alternations, concerningMAPK/ERK and PI3K/Akt signaling pathways, contribute to their activation and interaction in consequence of malignantfollicular cell transformation. Moreover, it is additionally pointed out that genetic, as well as epigenetic DNA changingvia aberrant methylation of several tumor suppressor and thyroid-specific genes is associated with tumor aggressiveness,being a jointly responsible mechanism for thyroid tumorigenesis. In the present manuscript the currently developeddiagnostic and prognostic genetic/epigenetic markers are presented; the understanding of this molecular mechanismprovides access to novel molecular therapeutic strategies.

Genetic Alterations in Poorly Differentiated and Undifferentiated Thyroid Carcinomas by Paula Soares, Jorge Lima, Ana Preto, Patricia Castro, Joao Vinagre, Ricardo Celestino, Joana P. Couto, Hugo Prazeres, Catarina Eloy, Valdemar Maximo, M. Sobrinho-Simoes (609-617).
Thyroid gland presents a wide spectrum of tumours derived from follicular cells that range from welldifferentiated, papillary and follicular carcinoma (PTC and FTC, respectively), usually carrying a good prognosis, to theclinically aggressive, poorly differentiated (PDTC) and undifferentiated thyroid carcinoma (UTC).It is usually accepted that PDTC and UTC occur either de novo or progress from a pre-existing well differentiatedcarcinoma through a multistep process of genetic and epigenetic changes that lead to clonal expansion and neoplasticdevelopment. Mutations and epigenetic alterations in PDTC and UTC are far from being totally clarified. Assuming thatPDTC and UTC may derive from well differentiated thyroid carcinomas (WDTC), it is expected that some PDTC andUTC would harbour genetic alterations that are typical of PTC and FTC. This is the case for some molecular markers(BRAF and NRAS) that are present in WDTC, PDTC and UTC. Other genes, namely P53, are almost exclusively detectedin less differentiated and undifferentiated thyroid tumours, supporting a diagnosis of PDTC or, much more often, UTC.Thyroid-specific rearrangements RET/PTC and PAX8/PPARβ, on the other hand, are rarely found in PDTC and UTC,suggesting that these genetic alterations do not predispose cells to dedifferentiation. In the present review we havesummarized the molecular changes associated with the two most aggressive types of thyroid cancer.

Genetic Alterations in Medullary Thyroid Cancer: Diagnostic and Prognostic Markers by A. Taccaliti, F. Silvetti, G. Palmonella, M. Boscaro (618-625).
Medullary thyroid carcinoma (MTC) is a rare calcitonin producing neuroendocrine tumour that originates fromthe parafollicular C-cells of the thyroid gland. The RET proto-oncogene encodes the RET receptor tyrosine kinase, withconsequently essential roles in cell survival, differentiation and proliferation. Somatic or germline mutations of the RETgene play an important role in this neoplasm in development of sporadic and familial forms, respectively. Geneticdiagnosis has an important role in differentiating sporadic from familiar MTC. Furthermore, depending on the location ofthe mutation, patients can be classified into risk classes. Therefore, genetic screening of the RET gene plays a critical rolenot only in diagnosis but also in assessing the prognosis and course of MTC.

New Targeted Therapies for Thyroid Cancer by Alessandro Antonelli, Poupak Fallahi, Silvia M. Ferrari, Ilaria Ruffilli, Francesca Santini, Michele Minuto, David Galleri, Paolo Miccoli (626-631).
The increasing incidence of thyroid cancer is associated with a higher number of advanced diseasecharacterized by the loss of cancer differentiation and metastatic spread. The knowledge of the molecular pathwaysinvolved in the pathogenesis of thyroid cancer has made possible the development of new therapeutic drugs able toblockade the oncogenic kinases (BRAF V600E, RET/PTC) or signaling kinases [vascular endothelial growth factorreceptor (VEGFR), platelet-derived growth factor receptors (PDGFR)] involved in cellular growth and proliferation.Some clinical trials have been conducted showing the ability of targeted therapies (sorafenib, sunitinib, axitinib, imanitib,vandetanib, pazopanib, gefitinib) in stabilizing the course of the disease. Until now, however, no consensus guidelineshave been established for patient selection and more data on toxicities and side effects are needed to be collected.