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 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 Role of CDKN2C Copy Number in Sporadic Medullary Thyroid Carcinoma

Thyroid ◽  
2016 ◽  
Vol 26 (11) ◽  
pp. 1553-1562 ◽  
Author(s):  
Elizabeth G. Grubbs ◽  
Michelle D. Williams ◽  
Paul Scheet ◽  
Selina Vattathil ◽  
Nancy D. Perrier ◽  
...  
Keyword(s):  
Thyroid Carcinoma ◽  
Medullary Thyroid Carcinoma ◽  
Copy Number ◽  
Sporadic Medullary Thyroid Carcinoma ◽  
Medullary Thyroid

scholarly journals Genome-Wide Copy Number Imbalances Identified in Familial and Sporadic Medullary Thyroid Carcinoma

2003 ◽  
Vol 88 (4) ◽  
pp. 1866-1872 ◽  
Author(s):  
Deborah J. Marsh ◽  
George Theodosopoulos ◽  
Klaus Martin-Schulte ◽  
Anne-Louise Richardson ◽  
Jeanette Philips ◽  
...  
Keyword(s):  
Thyroid Carcinoma ◽  
Medullary Thyroid Carcinoma ◽  
Copy Number ◽  
Sporadic Medullary Thyroid Carcinoma ◽  
Medullary Thyroid ◽  
Genome Wide

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.

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