scholarly journals RAS proto-oncogene in medullary thyroid carcinoma

2015 ◽  
Vol 22 (5) ◽  
pp. R235-R252 ◽  
Author(s):  
Margarida M Moura ◽  
Branca M Cavaco ◽  
Valeriano Leite
Keyword(s):  
Thyroid Carcinoma ◽  
Medullary Thyroid Carcinoma ◽  
Malignant Tumors ◽  
Point Mutations ◽  
Follicular Epithelium ◽  
Driver Mutations ◽  
Medullary Thyroid ◽  
Human Cancers ◽  
Thyroid C Cells ◽  
Rare Malignancy

Medullary thyroid carcinoma (MTC) is a rare malignancy originating from the calcitonin-secreting parafollicular thyroid C cells. Approximately 75% of cases are sporadic. Rearranged during transfection (RET) proto-oncogene plays a crucial role in MTC development. BesidesRET, other oncogenes commonly involved in the pathogenesis of human cancers have also been investigated in MTC. The family of humanRASgenes includes the highly homologousHRAS,KRAS, andNRASgenes that encode three distinct proteins. Activating mutations in specific hotspots of theRASgenes are found in about 30% of all human cancers. In thyroid neoplasias,RASgene point mutations, mainly inNRAS, are detected in benign and malignant tumors arising from the follicular epithelium. However, recent reports have also describedRASmutations in MTC, namely inHRASandKRAS. Overall, the prevalence ofRASmutations in sporadic MTC varies between 0–43.3%, occurring usually in tumors with WTRETand rarely in those harboring aRETmutation, suggesting that activation of these proto-oncogenes represents alternative genetic events in sporadic MTC tumorigenesis. Thus, the assessment ofRASmutation status can be useful to define therapeutic strategies inRETWT MTC. MTC patients withRASmutations have an intermediate risk for aggressive cancer, between those withRETmutations in exons 15 and 16, which are associated with the worst prognosis, and cases with otherRETmutations, which have the most indolent course of the disease. Recent results from exome sequencing indicate that, besides mutations inRET,HRAS, andKRAS, no other recurrent driver mutations are present in MTC.

scholarly journals Comprehensive Assessment of Copy Number Alterations Uncovers Recurrent AIFM3 and DLK1 Copy Gain in Medullary Thyroid Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 218
Author(s):  
Aline Neves Araujo ◽  
Cléber Pinto Camacho ◽  
Thais Biude Mendes ◽  
Susan Chow Lindsey ◽  
Lais Moraes ◽  
...  
Keyword(s):  
Thyroid Carcinoma ◽  
Medullary Thyroid Carcinoma ◽  
Copy Number ◽  
Snp Array ◽  
In Silico Analysis ◽  
Pcr Analysis ◽  
Copy Number Alterations ◽  
Medullary Thyroid ◽  
Thyroid C Cells ◽  
Ajcc Staging

Medullary thyroid carcinoma (MTC) is a malignant tumor originating from thyroid C-cells that can occur either in sporadic (70–80%) or hereditary (20–30%) form. In this study we aimed to identify recurrent copy number alterations (CNA) that might be related to the pathogenesis or progression of MTC. We used Affymetrix SNP array 6.0 on MTC and paired-blood samples to identify CNA using PennCNV and Genotyping Console software. The algorithms identified recurrent copy number gains in chromosomes 15q, 10q, 14q and 22q in MTC, whereas 4q cumulated losses. Coding genes were identified within CNA regions. The quantitative PCR analysis performed in an independent series of MTCs (n = 51) confirmed focal recurrent copy number gains encompassing the DLK1 (14q32.2) and AIFM3 (22q11.21) genes. Immunohistochemistry confirmed AIFM3 and DLK1 expression in MTC cases, while no expression was found in normal thyroid tissues and few MTC samples were found with normal copy numbers. The functional relevance of CNA was also assessed by in silico analysis. CNA status correlated with protein expression (DLK1, p = 0.01), tumor size (DLK1, p = 0.04) and AJCC staging (AIFM3p = 0.01 and DLK1p = 0.05). These data provide a novel insight into MTC biology, and suggest a common CNA landscape, regardless of if it is sporadic or hereditary MTC.

scholarly journals Medullary thyroid carcinoma beyond surgery: advances, challenges, and perspectives

2019 ◽  
Vol 26 (9) ◽  
pp. R499-R518 ◽  
Author(s):  
Lucieli Ceolin ◽  
Marta Amaro da Silveira Duval ◽  
Antônio Felippe Benini ◽  
Carla Vaz Ferreira ◽  
Ana Luiza Maia
Keyword(s):  
Thyroid Carcinoma ◽  
Medullary Thyroid Carcinoma ◽  
Intracellular Signaling ◽  
Progression Free Survival ◽  
Thyroid Neoplasms ◽  
Rare Type ◽  
Medullary Thyroid ◽  
Men 2 ◽  
Thyroid C Cells ◽  
Molecular Therapies

Medullary thyroid carcinoma (MTC) is a rare type of tumor that originates from thyroid C cells and accounts for 2–4% of all malignant thyroid neoplasms. MTC may occur sporadically or be inherited, as part of the MEN 2 syndrome. Germline mutations of the RET (REarranged during Transfection) proto-oncogene cause hereditary cancer, whereas somatic RET mutations and, less frequently, RAS mutations have been described in sporadic MTC samples. Since early surgery with complete resection of tumor mostly determines the likelihood of attaining cure for MTC, the broader use of RET genetic screening has dramatically changed the prognostic of gene carriers in hereditary MTC. Nevertheless, despite recent advances, the management of advanced, progressive MTC remains challenging. The multikinase inhibitors (MKI), vandetanib and cabozantinib, were approved for the treatment of progressive or symptomatic MTC, and several other compounds have exhibited variable efficacy. Although these drugs have been shown to improve progression-free survival, no MKI has been shown to increase the overall survival. As these drugs are nonselective, significant off-target toxicities may occur, limiting achievement of the required TK-specific inhibition. Recently, next-generation small-molecule TKI has been developed. These TKI are specifically designed for highly potent and selective targeting of oncogenic RET alterations, making them promising drugs for the treatment of advanced MTC. Here, we summarize the current understanding of the intracellular signaling pathways involved in MTC pathogenesis as well as the therapeutic approaches and challenges for the management of advanced MTC, focusing on targeted molecular therapies.

scholarly journals Medullary Thyroid Carcinoma with Micronodular Lung Metastases: A Case Report with an Emphasis on the Imaging Findings

2010 ◽  
Vol 2010 ◽  
pp. 1-5 ◽  
Author(s):  
Nina Ventura ◽  
Edson Marchiori ◽  
Gláucia Zanetti ◽  
Antonio Muccillo ◽  
Mariana Leite Pereira ◽  
...  
Keyword(s):  
Thyroid Carcinoma ◽  
Medullary Thyroid Carcinoma ◽  
Medullary Thyroid Cancer ◽  
Lung Metastases ◽  
Disease Process ◽  
Distant Metastases ◽  
Diagnostic Tools ◽  
Case Discussion ◽  
Medullary Thyroid ◽  
Rare Malignancy

Medullary thyroid carcinoma is a rare malignancy that arises from calcitonin-producing C-cells and frequently metastasizes to lymph nodes in the neck. Distant metastases may involve bone, lung, and liver. The infrequent number of cases limits the clinical nature and ability to optimize diagnostic tools. Here, we present a case of a micronodular radiographic pattern in metastatic medullary thyroid cancer in order to enhance awareness of the disease process. A case discussion and relevant review of the literature are provided.

Calcitonin and complementary biomarkers in the diagnosis of hereditary medullary thyroid carcinoma in children and adolescents

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Felix Eckelt ◽  
Roland Pfaeffle ◽  
Wieland Kiess ◽  
Juergen Kratzsch
Keyword(s):  
Thyroid Carcinoma ◽  
Children And Adolescents ◽  
Medullary Thyroid Carcinoma ◽  
Carbohydrate Antigen ◽  
Good Prognosis ◽  
Laboratory Diagnostics ◽  
American Thyroid Association ◽  
Reference Ranges ◽  
Medullary Thyroid ◽  
Rare Malignancy

Abstract Objectives Medullary thyroid carcinoma (MTC) is a rare malignancy that is effectively curable by surgery. Unlike in adults, hereditary MTC has a predominant role in children. A fast and safe diagnosis is important to assure the good prognosis for the patients. A major cornerstone is the assessment of biomarkers, but the interpretation must respect their pre-, post- and analytical features. Especially calcitonin (Ctn) is a challenging biomarker in daily laboratory diagnostics. However, Ctn is of particular relevance for the diagnostic in MTC. The American Thyroid Association recommends thyroidectomy if the upper reference range of Ctn is exceeded. Interestingly, age-dependent reference ranges for children and adolescents have become available only recently for Ctn assays. With this review, we aim to highlight the importance of a timely diagnosis of MTC in children and adolescents. Content Recent developments in pediatric biochemical diagnostics of MTC were summarized. This includes guidance on interpretation of RET, Ctn, procalcitonin, carcinoembryonic antigen, carbohydrate antigen 19-9, and chromogranin A. Summary Currently, Ctn is the most investigated biomarker in the diagnosis of MTC in children and adolescents. Other biomarkers as PCT suggest complementary evidence about pediatric MTC but their interpretation based largely on adult’s data. A successful treatment of MTC requires, besides results of biomarkers, information about medical history, RET gene analysis and recent guideline knowledge. Outlook More research is required to validate complementary biomarkers of Ctn in children. Additionally, the effect of different confounder on pediatric Ctn levels has to be further clarified.

Molecular analysis of the RET proto-oncogene in patients with sporadic medullary thyroid carcinoma: a novel point mutation in the extracellular cysteine-rich domain

1997 ◽  
Vol 136 (4) ◽  
pp. 423-426 ◽  
Author(s):  
Maria João Bugalho ◽  
João Pedro Frade ◽  
Jorge Rosa Santos ◽  
Edward Limbert ◽  
Luis Sobrinho
Keyword(s):  
Thyroid Carcinoma ◽  
Medullary Thyroid Carcinoma ◽  
Point Mutation ◽  
De Novo ◽  
Point Mutations ◽  
The Other ◽  
Missense Mutations ◽  
Sporadic Medullary Thyroid Carcinoma ◽  
Medullary Thyroid ◽  
Rich Domain

Abstract Germline point mutations in the RET proto-oncogene are associated with multiple endocrine neoplasia type 2 (2A and 2B) and familial medullary thyroid carcinoma. On the other hand, somatic point mutations of RET have been described in a subset of sporadic medullary thyroid carcinomas (MTCs). We examined tumor and blood DNA of thirteen apparently sporadic MTC patients for mutations in RET exons 10, 11, 13, 15 and 16 to determine whether they had true sporadic tumors or either de novo or occult germline mutations. Three different somatic missense mutations were documented in seven patients. In five patients a mutation in exon 16, codon 918, (ATG→ACG) causing a Met→Thr substitution was found. In the remaining two patients the mutation affected exon 11: codon 630 in one case and codon 634 in the other. In both cases a T→C transversion was identified causing a Cys→Arg substitution. In conclusion, absence of a germline mutation in RETexons 10, 11, 13 or 16 is evidence against an inherited form in all cases. In seven patients, identification of a somatic mutation supported the previous clinical diagnosis of sporadic medullary thyroid carcinoma; in one of them we identified a hitherto undescribed somatic point mutation at codon 630. European Journal of Endocrinology 136 42 3–426

Medullary Thyroid Carcinoma: Management of Lymph Node Metastases

2010 ◽  
Vol 8 (5) ◽  
pp. 549-556 ◽  
Author(s):  
Jeffrey F. Moley
Keyword(s):  
Lymph Node ◽  
Thyroid Carcinoma ◽  
Medullary Thyroid Carcinoma ◽  
Tumor Burden ◽  
Surgical Removal ◽  
Primary Tumors ◽  
Medullary Thyroid ◽  
Central Lymph Node Dissection ◽  
Hormonal Manipulation ◽  
Thyroid C Cells

Medullary thyroid carcinoma (MTC) is a neuroendocrine malignancy of the thyroid C cells. Metastatic spread commonly occurs to cervical and mediastinal lymph nodes. MTC cells do not concentrate radioactive iodine and are not sensitive to hormonal manipulation. Surgery is currently the only therapy that can reliably lead to cure, reduction in tumor burden, or effective palliation. In patients with hereditary MTC, central lymph node dissection should be considered in preventative operations if the calcitonin level is elevated. Systematic surgical removal of at-risk or involved lymph node basins (compartmental dissection) should be performed in all patients with palpable primary tumors and recurrent disease. A “berry-picking” approach is discouraged. Although data are limited, standard chemotherapy and radiation therapy have not been shown to be effective in the treatment of MTC. Newer targeted drug therapies are promising and are being examined in therapeutic clinical trials.

scholarly journals Circulating procalcitonin and cleavage products in septicaemia compared with medullary thyroid carcinoma

2002 ◽  
pp. 727-731 ◽  
Author(s):  
L Ittner ◽  
W Born ◽  
B Rau ◽  
G Steinbach ◽  
JA Fischer
Keyword(s):  
Thyroid Carcinoma ◽  
Medullary Thyroid Carcinoma ◽  
Normal Subjects ◽  
Reversed Phase ◽  
Response To Treatment ◽  
C Cells ◽  
Reversed Phase Hplc ◽  
Medullary Thyroid ◽  
Thyroid C Cells ◽  
The Individual

OBJECTIVE: Raised plasma levels of procalcitonin (proCT) represent an early marker for septicaemia. They are related to disease severity and inversely to outcome and response to treatment. ProCT is presumably synthesised in tIssues other than the thyroid C-cells which are the source of calcitonin (CT) in normal physiology. This study compares proCT and its cleavage products in the serum of patients with septicaemia with those in medullary thyroid carcinoma (MTC). METHODS: Immunoreactive proCT and its cleavage products were extracted from the serum of patients with septicaemia or MTC using octadecylsilyl silica columns and characterised by reversed phase HPLC and Western blot analysis. ProCT, CT(1-32) and the flanking peptides PAS-57 and PDN-21 were recognised with antibodies specific for the individual peptides. RESULTS: ProCT and a 10 kDa polypeptide were recognised with antibodies to PAS-57, CT(1-32) and PDN-21. An 8 kDa proCT fragment was detected with antibodies to CT and PDN-21. However, intact CT(1-32), PAS-57 and PDN-21, found in the serum of MTC patients, were undetectable. The results indicate partial cleavage of proCT in septicaemia different from that in MTC patients. CONCLUSIONS: ProCT and 10 and 8 kDa proCT fragments were recognised in the circulation of septic patients. They were different from the known proCT-processing products PAS-57, CT(1-32) and PDN-21 identified in the serum of normal subjects and of MTC patients. Distinct cleavage of proCT may contribute to the symptoms of septicaemia.

scholarly journals Medullary thyroid carcinoma: Genetic screening and prophylactic thyroidectomies

2003 ◽  
Vol 50 (3) ◽  
pp. 121-124 ◽  
Author(s):  
Damijan Bergant ◽  
Marko Hocevar
Keyword(s):  
Genetic Testing ◽  
Thyroid Carcinoma ◽  
Medullary Thyroid Carcinoma ◽  
Thyroid Surgery ◽  
Genetic Screening ◽  
Germ Line ◽  
Point Mutations ◽  
C Cells ◽  
Prophylactic Thyroidectomy ◽  
Medullary Thyroid

Medullary thyroid carcinoma (MTC) occurs sporadically or is inherited as a characteristic component of MEN 2A, MEN 2B and familial MTC. Germ/line point mutations in RET proto/onkogene are responsible for tumor arise and inheritance. Genetic screening provides information of these RET mutations in family members even before pathologic changes of C-cells progress to MTC. The aim of our study was to identify carriers of RET gene mutations in our patients with MTC and their kindred. Surgical therapy was based on genetic testing results and clinical features. Prophylactic thyroid surgery was the subject of interest. From 1969-2002 105 patients with MTC (88 families), were treated and/or diagnosed at the institute of Oncology Ljubljana, Slovenia. Genetic testing was so performed in 58/88 MTC index patients (24 males (16 - 93y) and 34 females (23 -77y)) and their 50 kindred, aged 8 - 67y. Twentyfive/50 kindred were from affected families. Germline mutations of RET proto-onkogene were found in 12/58 (20, 6%) MTC index patients - 2 males (16 and 65 y) and 10 females (23-55y, median 36y) and in 14/25 kindred from 12 affected families - 5 males aged 18-57 years (median 21) and 9 females aged 12-54 years (median 41) but were absent in 11/25 kindred. Genetic screening results indicate thyroid surgery in all 14 kindred; also MTC was clinically suspected or diagnosed in 11/14 patients and 3/14 were candidates for prophylactic thyroidectomy. Total thyroidectomy with central neck dissection was the minimal surgical procedure. Prophylactic thyroidectomy based on genetic testing results allows earlier diagnosis and treatment of patients, even before pathologic changes of C-cells occur. Patient?s age and codon mutation influence the timing of surgery and even it?s extend.

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