Molecular defects in thyroid carcinomas: Role of the RET oncogene in thyroid neoplastic transformation

1995 ◽  
Vol 133 (5) ◽  
pp. 513-522 ◽  
Author(s):  
Massimo Santoro ◽  
Michele Grieco ◽  
Rosa Marina Melillo ◽  
Alfredo Fusco ◽  
Giancarlo Vecchio
Keyword(s):  
Tyrosine Kinases ◽  
Point Mutations ◽  
Neoplastic Transformation ◽  
Thyroid Neoplasms ◽  
Genetic Alterations ◽  
Thyroid Carcinomas ◽  
Molecular Defects ◽  
Genetic And Environmental Factors ◽  
Definition Of

Santoro M, Grieco M, Melillo RM, Fusco A, Vecchio G. Molecular defects in thyroid carcinomas. Role of the RET oncogene in thyroid neoplastic transformation. Eur J Endocrinol 1995;133:513–22. ISSN 0804–4643 Tumors are believed to arise as a result of an accumulation of mutations in critical genes involved in the control of cell proliferation. Thyroid neoplasms represent a good model for studying the role of these mutations in epithelial cell multistep carcinogenesis because they comprise a broad spectrum of lesions with different degrees of malignancy. Recent reports have described the involvement of specific genetic alterations in different types of thyroid neoplasms. Papillary carcinomas are characterized by the activation of the receptor tyrosine kinases RET and TRK-A proto-oncogenes. Ras point mutations are frequently observed in tumors with follicular histology and a high prevalence of p53 point mutations have been found in anaplastic carcinomas. A definition of molecular defects characterizing thyroid tumors will be helpful in establishing sensitive and specific detection strategies and, in addition, to define genetic and environmental factors important for their pathogenesis. Giancarlo Vecchio, Dipartimento di Biologia e Patologia Cellulare e Molecolare "L, Califano", Facoltà di Medicina e Chirurgia, Università degli Studi di Napoli "Federico II", via S Pansini 5, 80131 Napoli, Italy

scholarly journals Current and Future Role of Tyrosine Kinases Inhibition in Thyroid Cancer: From Biology to Therapy

2020 ◽  
Vol 21 (14) ◽  
pp. 4951
Author(s):  
María San Román Gil ◽  
Javier Pozas ◽  
Javier Molina-Cerrillo ◽  
Joaquín Gómez ◽  
Héctor Pian ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Tyrosine Kinases ◽  
Genetic Alterations ◽  
Point Of View ◽  
Adequate Treatment ◽  
Comprehensive Review ◽  
Tumor Characterization ◽  
Therapeutic Algorithm ◽  
Clinical Point

Thyroid cancer represents a heterogenous disease whose incidence has increased in the last decades. Although three main different subtypes have been described, molecular characterization is progressively being included in the diagnostic and therapeutic algorithm of these patients. In fact, thyroid cancer is a landmark in the oncological approach to solid tumors as it harbors key genetic alterations driving tumor progression that have been demonstrated to be potential actionable targets. Within this promising and rapid changing scenario, current efforts are directed to improve tumor characterization for an accurate guidance in the therapeutic management. In this sense, it is strongly recommended to perform tissue genotyping to patients that are going to be considered for systemic therapy in order to select the adequate treatment, according to recent clinical trials data. Overall, the aim of this article is to provide a comprehensive review on the molecular biology of thyroid cancer focusing on the key role of tyrosine kinases. Additionally, from a clinical point of view, we provide a thorough perspective, current and future, in the treatment landscape of this tumor.

The Role of Signal Transducer and Activator of Transcription Factors in Leukemogenesis

2004 ◽  
Vol 22 (2) ◽  
pp. 361-371 ◽  
Author(s):  
David W. Sternberg ◽  
D. Gary Gilliland
Keyword(s):  
Tyrosine Kinases ◽  
Point Mutations ◽  
Protein Tyrosine Kinases ◽  
Signal Transducer ◽  
Functional Importance ◽  
Aberrant Expression ◽  
Stat Proteins ◽  
Expression Of Genes ◽  
Wide Range

Human leukemias are frequently associated with the aberrant expression of activated fusion tyrosine kinases or activated protein tyrosine kinases carrying insertional or point mutations. The activated kinase enzymes typically phosphorylate one or more signal transducer and activator of transcription (STAT) factors, which translocate to the cell nucleus and regulate the expression of genes associated with survival and proliferation. The phosphorylation and activation of STAT family members has been described in a wide range of human leukemias. Furthermore, animal models of leukemia have demonstrated the pivotal contribution of STAT activation to leukemic pathogenesis. This review discusses evidence for the functional importance of STAT activation in the biology of leukemia and current opportunities for modulating STAT proteins in the therapy of this group of diseases.

scholarly journals Emerging Role of Genetic Alterations Affecting Exosome Biology in Neurodegenerative Diseases

2019 ◽  
Vol 20 (17) ◽  
pp. 4113 ◽  
Author(s):  
Paola Riva ◽  
Cristina Battaglia ◽  
Marco Venturin
Keyword(s):  
Neurodegenerative Diseases ◽  
Genetic Alterations ◽  
Exosome Biogenesis ◽  
Pharmacological Targets ◽  
Pathway Activation ◽  
Genetic Mechanisms ◽  
Endosomal Pathway ◽  
New Perspective ◽  
Definition Of

The abnormal deposition of proteins in brain tissue is a common feature of neurodegenerative diseases (NDs) often accompanied by the spread of mutated proteins, causing neuronal toxicity. Exosomes play a fundamental role on their releasing in extracellular space after endosomal pathway activation, allowing to remove protein aggregates by lysosomal degradation or their inclusion into multivesicular bodies (MVBs), besides promoting cellular cross-talk. The emerging evidence of pathogenic mutations associated to ND susceptibility, leading to impairment of exosome production and secretion, opens a new perspective on the mechanisms involved in neurodegeneration. Recent findings suggest to investigate the genetic mechanisms regulating the different exosome functions in central nervous system (CNS), to understand their role in the pathogenesis of NDs, addressing the identification of diagnostic and pharmacological targets. This review aims to summarize the mechanisms underlying exosome biogenesis, their molecular composition and functions in CNS, with a specific focus on the recent findings invoking a defective exosome biogenesis as a common biological feature of the major NDs, caused by genetic alterations. Further definition of the consequences of specific genetic mutations on exosome biogenesis and release will improve diagnostic and pharmacological studies in NDs.

scholarly journals The Emerging Role of Succinate Dehyrogenase Genes (SDHx) in Tumorigenesis

2019 ◽  
Author(s):  
Elham Nazar ◽  
Fatemeh Khatami ◽  
Hiva Saffar ◽  
Seyed Mohammad Tavangar
Keyword(s):  
Normal Cell ◽  
Neoplastic Transformation ◽  
Genetic Alterations ◽  
Epigenetic Changes ◽  
Epigenetic Alterations ◽  
Mitochondrial Complex ◽  
Complex Ii ◽  
Hypoxic Conditions ◽  
Sdh Mutation

Transformation of a normal cell to cancerous one is dependent on the accumulation of several genetic and epigenetic alterations. One of the candidate driver genetic alterations can happen in succinate dehydrogenases (SDHx) coding gene include SDHA, SDHB, SDHC, SDHD, and SDHAF2.  The most important SDH mutation is in the SDHD gene, which encodes the smallest subunit of mitochondrial complex II (SDH). It has key function both in familial and non-familial hereditary paraganglioma/phaeochromocytoma syndrome (HPGL/PCC). SDHx genes mutations can have resulted in genetic and epigenetic changes like histone hypermethylation. These properties can lead to succinate-mediated inhibition of α-ketoglutarate-dependent dioxygenases. So hypoxic conditions can generate subsequent neoplastic transformation, and in this review, we are presenting the role of SDHx in several malignancies.

scholarly journals Stat3 co-operates with mutant Ezh2Y641F to regulate gene expression and limit the anti-tumor immune response in melanoma

2021 ◽  
Author(s):  
Sarah Zimmerman ◽  
Samantha J Nixon ◽  
Leela Raj ◽  
Pei Yu Chen ◽  
Sofia Smith ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Transcriptional Repression ◽  
Point Mutations ◽  
Disease Recurrence ◽  
Genetic Alterations ◽  
Genetically Engineered ◽  
Polycomb Repressive Complex 2 ◽  
Genetically Engineered Mouse Models

One of the most frequently genetically altered chromatin modifiers in melanoma is the Enhancer of Zeste Homolog 2 (EZH2), the catalytic component of the Polycomb Repressive Complex 2 (PRC2), which methylates lysine 27 on histone 3 (H3K27me3), a chromatin mark associated with transcriptional repression. Genetic alterations in EZH2 in melanoma include amplifications and activating point mutations at tyrosine 641 (Y641). The oncogenic role of EZH2 in melanoma has previously been determined; however, its downstream oncogenic mechanisms remain underexplored. Here, we found that in genetically engineered mouse models, expression of Ezh2Y641F causes up-regulation of a subset of interferon-regulated genes in melanoma cells, suggesting a potential role of the immune system in the pathogenesis of these mutations. Expression of these interferon genes was not a result of changes in H3K27me3, but through a direct and non-canonical interaction between Ezh2 and Signal Transducer And Activator of Transcription 3 (Stat3). We found that Ezh2 directly binds Stat3, and that in the presence of Ezh2Y641F mutant, Stat3 protein is hypermethylated. Expression of Stat3 was required to maintain an anti-tumor immune response and its depletion resulted in faster melanoma progression and disease recurrence. Molecularly, Stat3 and Ezh2 bind together at many genomic loci, and, in association with the rest of the PRC2 complex, repress gene expression. These results suggest that one of the oncogenic mechanisms of Ezh2-mediated melanomagenesis is through evasion of the anti-tumor immune response, and that the immunomodulatory properties of Stat3 are context dependent.

scholarly journals Oral Leukoplakia

1995 ◽  
Vol 6 (2) ◽  
pp. 147-160 ◽  
Author(s):  
J.J. Sdubba
Keyword(s):  
Behavior Pattern ◽  
Genetic Alterations ◽  
Etiologic Factor ◽  
Immunosuppressed Patient ◽  
Papilloma Virus ◽  
Clinical Appearance ◽  
Hairy Leukoplakia ◽  
Epstein Barr ◽  
Definition Of

Leukoplakia has evolved as a clinico-pathologic concept over many years, with the current clinical designation being accepted worldwide. Reflective of the biology of leukoplakia is the concept of cellular atypia and epithelial dysplasia. Adding to a better understanding of leukoplakia in general has been the definition of relevant clinical subsets which, in some cases, includes etiology (snuff), while in other cases a verrucous clinical appearance will suggest a more aggressive anticipated behavior pattern. Tobacco usage, in many of its forms, remains the prime etiologic factor; however, other considerations also apply. More recently, the potential etiologic role of Candida albicans has been stressed, as well as its possible role in carcinogenesis. So-called oral hairy leukoplakia has been defined in relation to a possible Epstein-Barr viral infection, usually in the immunosuppressed patient. Other viruses, human papilloma virus in particular, have been implicated in leukoplakia, while genetic alterations involving tumor suppressor elements (p53) have also been investigated. Finally, the management of this common condition remains a variable and includes local, topical, and systemic therapies such as anti-oxidants, carotenoids, and retinoids.

scholarly journals Tyrosine phosphatases as a superfamily of tumor suppressors in colorectal cancer.

2011 ◽  
Vol 58 (4) ◽  
Author(s):  
Izabela Laczmanska ◽  
Maria M Sasiadek
Keyword(s):  
Colorectal Cancer ◽  
Tumor Suppressors ◽  
Tyrosine Kinases ◽  
Mutational Analysis ◽  
Point Mutations ◽  
Protein Tyrosine Phosphatases ◽  
Genetic Alterations ◽  
Cancer Genes ◽  
Tyrosine Phosphatases ◽  
Protein Tyrosine

Phosphorylation and dephosphorylation processes catalyzed by numerous kinases and phosphorylases are essential for cell homeostasis and may lead to disturbances in a variety of vital cellular pathways, such as cell proliferation and differentiation, and thus to complex diseases including cancer. As over 80 % of all oncogenes encode protein tyrosine kinases (PTKs), protein tyrosine phosphatases (PTPs), which can reverse the effects of tyrosine kinases, are very important tumor suppressors. Alterations in tyrosine kinase and phosphatase genes including point mutations, changes in epigenetic regulation, as well as chromosomal aberrations involving regions critical to these genes, are frequently observed in a variety of cancers. Colorectal cancer (CRC) is one of the most common cancers in humans. CRCs occur in a familial (about 15 % of all cases), hereditary (about 5%) and sporadic (almost 75-80 %) form. As genetic-environmental interrelations play an important role in the susceptibility to sporadic forms of CRCs, many studies are focused on genetic alterations in such tumors. Mutational analysis of the tyrosine phosphatome in CRCs has identified somatic mutations in PTPRG, PTPRT, PTPN3, PTPN13 and PTPN14. The majority of these mutations result in a loss of protein function. Also, alterations in the expression of these genes, such as decreased expression of PTPRR, PTPRO, PTPRG and PTPRD, mediated by epigenetic mechanisms have been observed in a variety of tumors. Since cancer is a social and global problem, there will be a growing number of studies on alterations in the candidate cancer genes, including protein kinases and phosphatases, to determine the origin, biology and potential pathways for targeted anticancer therapy.

scholarly journals Role of Genetic Alterations in theNLRP3andCARD8Genes in Health and Disease

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
G. V. Paramel ◽  
A. Sirsjö ◽  
K. Fransén
Keyword(s):  
Rheumatoid Arthritis ◽  
Inflammatory Bowel Disease ◽  
Genetic Alterations ◽  
Innate Immune ◽  
Genes Encoding ◽  
Health And Disease ◽  
Inflammatory Bowel ◽  
Genetic And Environmental Factors

The complexity of a common inflammatory disease is influenced by multiple genetic and environmental factors contributing to the susceptibility of disease. Studies have reported that these exogenous and endogenous components may perturb the balance of innate immune response by activating the NLRP3 inflammasome. The multimeric NLRP3 complex results in the caspase-1 activation and the release of potent inflammatory cytokines, like IL-1β. Several studies have been performed on the association of the genetic alterations in genes encoding NLRP3 and CARD8 with the complex diseases with inflammatory background, like inflammatory bowel disease, cardiovascular diseases, rheumatoid arthritis, and type 1 diabetes. The aim of the present review is therefore to summarize the literature regarding genetic alterations in these genes and their association with health and disease.

scholarly journals Transplantation for Congenital Bone Marrow Failure Syndromes

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Kenji Morimoto ◽  
Theodore B. Moore ◽  
Gary Schiller ◽  
Kathleen M. Sakamoto
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Failure ◽  
Genetic Alterations ◽  
Rare Disorders ◽  
Exact Role ◽  
Bone Marrow Failure Syndrome ◽  
Hematopoietic Stem ◽  
Molecular Defects ◽  
Bone Marrow Failure Syndromes

Congenital bone marrow failure syndromes (BMFSs) are relatively rare disorders characterized by aberrant development in one or more hematopoietic lineages. Genetic alterations have now been identified in most of these disorders although the exact role of the molecular defects has yet to be elucidated. Most of these diseases are successfully managed with supportive care, however, treatment refractoriness and disease progression—often involving malignant transformation—may necessitate curative treatment with hematopoietic stem cell transplantation. Due to the underlying molecular defects, the outcome of transplantation for BMFS may be dramatically different than those associated with transplantation for more common diseases, including leukemia. Given recent improvements in survival and molecular diagnosis of bone marrow failure syndrome patients presenting at adult ages without physical stigmata, it is important for both pediatric and adult hematologists to be aware of the possible diagnosis of BMF syndromes and the unique approaches required in treating such patients.

scholarly journals Anaplastic lymphoma kinase: signalling in development and disease

2009 ◽  
Vol 420 (3) ◽  
pp. 345-361 ◽  
Author(s):  
Ruth H. Palmer ◽  
Emma Vernersson ◽  
Caroline Grabbe ◽  
Bengt Hallberg
Keyword(s):  
Anaplastic Lymphoma Kinase ◽  
Tyrosine Kinases ◽  
Cellular Proliferation ◽  
Chromosomal Rearrangements ◽  
Point Mutations ◽  
Large Cell ◽  
Anaplastic Lymphoma ◽  
Proliferation And Differentiation ◽  
Cancer Types

RTKs (receptor tyrosine kinases) play important roles in cellular proliferation and differentiation. In addition, RTKs reveal oncogenic potential when their kinase activities are constitutively enhanced by point mutation, amplification or rearrangement of the corresponding genes. The ALK (anaplastic lymphoma kinase) RTK was originally identified as a member of the insulin receptor subfamily of RTKs that acquires transforming capability when truncated and fused to NPM (nucleophosmin) in the t(2;5) chromosomal rearrangement associated with ALCL (anaplastic large cell lymphoma). To date, many chromosomal rearrangements leading to enhanced ALK activity have been described and are implicated in a number of cancer types. Recent reports of the EML4 (echinoderm microtubule-associated protein like 4)–ALK oncoprotein in NSCLC (non-small cell lung cancer), together with the identification of activating point mutations in neuroblastoma, have highlighted ALK as a significant player and target for drug development in cancer. In the present review we address the role of ALK in development and disease and discuss implications for the future.

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