Current Genomics - Volume 12, Issue 8, 2011

This issue of Current genomics is devoted to a broad spectrum of thyroid disorders which occur in the population with a high frequency and represent an important clinical problem to thyroid specialists all over the world. Understanding the disease pathophysiology represents an important tool for clinicians confronting various diagnostic and therapeutic challenges in managing patients. In the last decade we have been facing a tremendous advance in our knowledge and numerous evidence of a susceptibility to various thyroid disorders. All this is helping us to understand the mechanisms, offering promises for prevention and even having an impact on the way we treat patients. It is now clear that a certain genotype in combination with a proper environmental trigger is crucial for the disease development, but several steps from this point to the clinical disease remain to be elucidated. This special focus issue summarizes current knowledge of thyroid genetics, emphasizing the importance of genetic 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 studies has been confirmed using the whole genome and candidate gene approaches. Those studies helped to uncover major candidate genes, some of them being thyroid specific, while others are being involved in the immune regulation. Brand and Gough comprehensively reviewed immunogenetic mechanisms of thyroid autoimmunity and genotyping technologies, illustrating both historical and recent aspects as well as future challenges. In spite of shared genetic predisposal factors, different immunogenetic pathways lead to specific subtypes of thyroid autoimmunity, such as Graves' disease, Graves' ophthalmopathy and Hashimoto'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-phenotype correlations. 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 immune activation in the orbit. In contrast to Graves' disease, where humoral immune response predominates, cell-mediated immune response is characteristic for Hashimoto's thyroiditis. Zaletel and Gaberscek provided an extensive overview of the possible triggers 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 thyroid ultrasound examinations. Taking into account a high prevalence and most frequently a benign nature, diagnosing of thyroid carcinoma seems like looking for a needle in a haystack. Although fine needle aspiration biopsy is a convenient and the best non-surgical diagnostic tool for distinguishing between benign and malignant thyroid lesion, its accuracy varies with the histological subtype of thyroid nodule and in a high percentage of specimen indeterminate cytology is reported. The article of Cerutti is a detailed review of all different approaches used in recent years to overcome a problem of differentiation of benign from malignant thyroid tumors, emphasizing molecular markers that may improve diagnostic accuracy and help to avoid unnecessary treatment of benign tumors. Detection of specific genetic alterations in thyroid cancer seems to be useful not only for the diagnosis, but also for the prognosis of the disease. While the author Gomez Saez described different genetic abnormalities focusing on differentiated histological subtypes of thyroid carcinoma, Soares and co-workers reviewed the most relevant genetic alterations in aggressive poorly differentiated and undifferentiated thyroid carcinomas. The current knowledge and approaches in medullary thyroid carcinoma are summarized by Taccaliti and colleagues, focusing on the central role of RET proto-oncogene in management of patients and their families. In the recent years, the rapidly growing knowledge of the molecular pathways in thyroid cancer enabled the development of new therapeutic agents. Antonelli and co-workers contributed a timely review of this relevant topic, providing both an overview on molecular pathways being explored as therapeutic 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 of thyroid pathology relevant to physicians, clinical researchers and basic scientists. I would especially like to thank the reviewers for their valuable time, comments, and suggestions that contributed to an even better quality of the reviews. Finally, let me thank Editor-in-Chief, Dr. Christian Neri, and his co-workers for the trust and support during the process of preparing this special 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 of AITD is vital to better understanding of AITD pathogenesis, required to advance therapeutic options in both disease management and prevention. The early whole-genome linkage and candidate gene association studies provided the first evidence that the HLA region and CTLA-4 represented AITD risk loci. Recent improvements in; high throughput genotyping technologies, collection of larger disease cohorts and cataloguing of genome-scale variation have facilitated genome-wide association studies and more thorough screening of candidate gene regions. This has allowed identification of many novel AITD risk genes and more detailed association mapping. The growing number of confirmed AITD susceptibility loci, implicates a number of putative disease mechanisms most of which are tightly linked with aspects of immune system function. The unprecedented advances in genetic study will allow future studies to identify further novel disease risk genes and to identify aetiological variants within specific gene regions, which will undoubtedly lead to a better understanding of AITD patho-physiology.

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 efforts aimed at refining diseases associations found within the HLA complex and implicating HLA class I as well as HLADPB1 loci. We summarize data regarding non-HLA genes such as PTPN22, CTLA4, CD40, TSHR and TG which have been extensively studied in respect to their role in GD. We review recent findings implicating variants of FCRL3 (gene for FC receptor-like-3 protein), SCGB3A2 (gene for secretory uteroglobin-related protein 1- UGRP1) as well as other unverified 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 fetal microchimerism with GD. Finally we discuss issues of genotype-phenotype correlations in GD.

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 sightthreatening stages. Our knowledge of the immunogenetic pathophysiology of GO is rapidly expanding. The present review is an attempt to summarize the current state of knowledge on the immunogenetics of GO. First we briefly review the epidemiology and clinical importance of GO, and then we describe in detail the macromolecular pathogenesis and finally immunogenetics of GO. Discrepancies between the results from various reports and the limitations of the available data are discussed. In particular, there is a scarcity of data from non-Asian populations. While several studies have demonstrated significant associations between polymorphisms in certain genes (especially CTLA-4, HLA-DRB-1, and TNF-α), there is a need for studies that investigate the relationship between polymorphisms and both serum and local concentrations of the resulting proteins. A complete understanding of GO susceptibility and pathogenesis has not been yet possible due to a number of important knowledge gaps that need to be filled by future research.

Hashimoto's thyroiditis (HT) is the most prevalent autoimmune thyroid disorder. Intrathyroidal lymphocytic infiltration is followed by a gradual destruction of the thyroid gland which may lead to subclinical or overt hypothyroidism. Biochemical markers of the disease are thyroid peroxidase and/or thyroglobulin autoantibodies in the serum which are present with a higher prevalence in females than in males and increase with age. Although exact mechanisms of aetiology and pathogenesis of the disorder are not completely understood, a strong genetic susceptibility to the disease has been confirmed predominantly by family and twin studies. Several genes were shown to be associated with the 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 be of utmost importance. Amongst endogenous factors for the disease development, the attention is focused predominantly on female sex, pregnancy with postpartum period and fetal microchimerism. Environmental factors influencing HT development are iodine intake, drugs, infections and different chemicals. Disturbed self-tolerance accompanied by the increased antigen presentation is a prerequisite for the HT occurrence, whereas proper interaction of thyroid cells, antigen presenting cells, and T cells are necessary for the initiation of thyroid autoimmunity. Secreted cytokines lead predominantly 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 Tcell mediated cytotoxicity.

Fine-Needle Aspiration (FNA) is the most widely used and cost-effective preoperative test for the initial evaluation of a thyroid nodule, although it has limited diagnostic accuracy for several types of tumors. Patients will often receive cytological report of indeterminate cytology and are referred to surgery for a more accurate diagnosis. An improved test would help physicians rapidly focus treatment on true malignancies and avoid some unnecessary treatment of 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 cell signals through transduction systems as ligands, transmembrane receptors and cytoplasmic secondary messengers to cell nucleus, where they influence the expression of genes that regulate important cellular processes: cell growth, proliferation and apoptosis. The genes, coding the signaling cascade proteins (RET, RAS, BRAF, PI3K, PTEN, AKT), are mutated or aberrantly expressed in thyroid cancer derived from follicular thyroid cell. Genetic and epigenetic alternations, concerning MAPK/ERK and PI3K/Akt signaling pathways, contribute to their activation and interaction in consequence of malignant follicular cell transformation. Moreover, it is additionally pointed out that genetic, as well as epigenetic DNA changing via 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 developed diagnostic and prognostic genetic/epigenetic markers are presented; the understanding of this molecular mechanism provides access to novel molecular therapeutic strategies.

Thyroid gland presents a wide spectrum of tumours derived from follicular cells that range from well differentiated, papillary and follicular carcinoma (PTC and FTC, respectively), usually carrying a good prognosis, to the clinically 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 differentiated carcinoma through a multistep process of genetic and epigenetic changes that lead to clonal expansion and neoplastic development. Mutations and epigenetic alterations in PDTC and UTC are far from being totally clarified. Assuming that PDTC and UTC may derive from well differentiated thyroid carcinomas (WDTC), it is expected that some PDTC and UTC 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 detected in less differentiated and undifferentiated thyroid tumours, supporting a diagnosis of PDTC or, much more often, UTC. Thyroid-specific rearrangements RET/PTC and PAX8/PPARγ, 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 have summarized the molecular changes associated with the two most aggressive types of thyroid cancer.

Medullary thyroid carcinoma (MTC) is a rare calcitonin producing neuroendocrine tumour that originates from the parafollicular C-cells of the thyroid gland. The RET proto-oncogene encodes the RET receptor tyrosine kinase, with consequently essential roles in cell survival, differentiation and proliferation. Somatic or germline mutations of the RET gene play an important role in this neoplasm in development of sporadic and familial forms, respectively. Genetic diagnosis has an important role in differentiating sporadic from familiar MTC. Furthermore, depending on the location of the mutation, patients can be classified into risk classes. Therefore, genetic screening of the RET gene plays a critical role not only in diagnosis but also in assessing the prognosis and course of MTC.

The increasing incidence of thyroid cancer is associated with a higher number of advanced disease characterized by the loss of cancer differentiation and metastatic spread. The knowledge of the molecular pathways involved in the pathogenesis of thyroid cancer has made possible the development of new therapeutic drugs able to blockade the oncogenic kinases (BRAF V600E, RET/PTC) or signaling kinases [vascular endothelial growth factor receptor (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 guidelines have been established for patient selection and more data on toxicities and side effects are needed to be collected.