scholarly journals A Germline Mutation in the POT1 Gene Is a Candidate for Familial Non-Medullary Thyroid Cancer

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1441 ◽  
Author(s):  
Aayushi Srivastava ◽  
Beiping Miao ◽  
Diamanto Skopelitou ◽  
Varun Kumar ◽  
Abhishek Kumar ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Germline Mutation ◽  
Medullary Thyroid Cancer ◽  
Current Knowledge ◽  
Wild Type ◽  
Medullary Thyroid ◽  
Wild Type Counterpart ◽  
In Silico Analyses ◽  
Protection Of Telomeres 1

Non-medullary thyroid cancer (NMTC) is a common endocrine malignancy with a genetic basis that has yet to be unequivocally established. In a recent whole-genome sequencing study of five families with occurrence of NMTCs, we shortlisted promising variants with the help of bioinformatics tools. Here, we report in silico analyses and in vitro experiments on a novel germline variant (p.V29L) in the highly conserved oligonucleotide/oligosaccharide binding domain of the Protection of Telomeres 1 (POT1) gene in one of the families. The results showed a reduction in telomere-bound POT1 levels in the mutant protein as compared to its wild-type counterpart. HEK293T cells carrying POT1 p.V29L showed increased telomere length in comparison to wild-type cells, suggesting that the mutation causes telomere dysfunction and may play a role in predisposition to NMTC in this family. While one germline mutation in POT1 has already been reported in a melanoma-prone family with prevalence of thyroid cancers, we report the first of such mutations in a family affected solely by NMTCs, thus expanding current knowledge on shelterin complex-associated cancers.

scholarly journals A novel germline mutation in the POT1 gene predisposes to familial non-medullary thyroid cancer

2020 ◽  
Author(s):  
Aayushi Srivastava ◽  
Beiping Miao ◽  
Diamanto Skopelitou ◽  
Varun Kumar ◽  
Abhishek Kumar ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Genetic Basis ◽  
Medullary Thyroid Cancer ◽  
Whole Genome ◽  
Telomere Dysfunction ◽  
Wild Type ◽  
Medullary Thyroid ◽  
Wild Type Counterpart ◽  
Protection Of Telomeres 1

AbstractNon-medullary thyroid cancer (NMTC) is a common endocrine malignancy with a genetic basis that has yet to be unequivocally established. In a recent whole genome sequencing study of five families with recurrence of NMTCs, we shortlisted promising variants with the help of bioinformatics tools. Here, we report in silico analyses and in vitro experiments on a novel germline variant (p.V29L) in the highly conserved oligonucleotide/oligosaccharide binding domain of the Protection of Telomeres 1 (POT1) gene in one of the families. The results showed that the variant demonstrates a reduction in telomere-bound POT1 levels in the mutant protein as compared to its wild-type counterpart. HEK293Tcells carrying POT1V29L showed increased telomere length in comparison to wild type cells, strongly suggesting that the mutation causes telomere dysfunction and may play a role in predisposition to NMTC in this family. This study reports the first germline POT1 mutation in a family with a predominance of thyroid cancer, thereby expanding the spectrum of cancers associated with mutations in the shelterin complex.

scholarly journals Current Knowledge of Germline Genetic Risk Factors for the Development of Non-Medullary Thyroid Cancer

Genes ◽  
2019 ◽  
Vol 10 (7) ◽  
pp. 482 ◽  
Author(s):  
Kinga Hińcza ◽  
Artur Kowalik ◽  
Aldona Kowalska
Keyword(s):  
Risk Factors ◽  
Thyroid Cancer ◽  
Medullary Thyroid Cancer ◽  
Werner Syndrome ◽  
Current Knowledge ◽  
Cowden Syndrome ◽  
Carney Complex ◽  
Thyroid Cancers ◽  
Medullary Thyroid ◽  
Hereditary Factors

The thyroid is the most common site of endocrine cancer. One type of thyroid cancer, non-medullary thyroid cancer (NMTC), develops from follicular cells and represents approximately 90% of all thyroid cancers. Approximately 5%–15% of NMTC cases are thought to be of familial origin (FNMTC), which is defined as the occurrence of the disease in three or more first-degree relatives of the patient. It is often divided into two groups: Syndrome-associated and non-syndromic. The associated syndromes include Cowden syndrome, familial adenomatous polyposis, Gardner syndrome, Carney complex and Werner syndrome. The hereditary factors contributing to the unfavorable course of FNMTC remain poorly understood; therefore, considerable effort is being expended to identify contributing loci. Research carried out to date identifies fourteen genes (DICER1, FOXE1, PTCSC2, MYH9, SRGAP1, HABP2, BRCA1, CHEK2, ATM, RASAL1, SRRM2, XRCC1, TITF-1/NKX2.1, PTCSC3) associated with vulnerability to FNMTC that are not related to hereditary syndromes. In this review, we summarize FNMTC studies to date, and provide information on genes involved in the development of non-syndromic familial non-medullary thyroid cancers, and the significance of mutations in these genes as risk factors. Moreover, we discuss whether the genetic polymorphism rs966423 in DIRC3 has any potential as a prognostic factor of papillary thyroid cancer.

scholarly journals Interleukin-2 and Lanreotide in the Treatment of Medullary Thyroid Cancer: In Vitro and In Vivo Studies

2013 ◽  
Vol 98 (10) ◽  
pp. E1567-E1574 ◽  
Author(s):  
Giovanni Vitale ◽  
Giovanni Lupoli ◽  
Rosario Guarrasi ◽  
Annamaria Colao ◽  
Alessandra Dicitore ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Medullary Thyroid Cancer ◽  
Interleukin 2 ◽  
In Vivo Studies ◽  
Medullary Thyroid

scholarly journals Localization of CaSR Antagonists in CaSR-expressing Medullary Thyroid Cancer

2013 ◽  
Vol 98 (11) ◽  
pp. E1722-E1729 ◽  
Author(s):  
Haiming Ding ◽  
Adlina Mohd Yusof ◽  
Shankaran Kothandaraman ◽  
Motoyasu Saji ◽  
Chaojie Wang ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Nude Mice ◽  
Medullary Thyroid Cancer ◽  
Antagonistic Activity ◽  
Parathyroid Glands ◽  
Human Embryonic Kidney Cells ◽  
Medullary Thyroid ◽  
Calcium Stimulation

Objective: Image-based localization of medullary thyroid cancer (MTC) and parathyroid glands would improve the surgical outcomes of these diseases. MTC and parathyroid glands express high levels of calcium-sensing receptor (CaSR). The aim of this study was to prove the concept that CaSR antagonists specifically localize to CaSR-expressing tumors in vivo. Design: We synthesized two isomers of a known CaSR calcilytic, Calhex 231, and four new analogs, which have a favorable structure for labeling. Their antagonistic activity was determined using immunoblots demonstrating decreased ERK1/2 phosphorylation after calcium stimulation in human embryonic kidney cells overexpressing CaSR. Compound 9 was further radiolabeled with 125I and evaluated in nude mice with and without heterotransplanted xenografts of MTC cell lines, TT and MZ-CRC-1, that do and do not express CaSR, respectively. Results: Two newly synthesized compounds, 9 and 11, exhibited better antagonistic activity than Calhex 231. The half-life of 125I-compound 9 in nude mice without xenografts was 9.9 hours. A biodistribution study in nude mice bearing both tumors demonstrated that the uptake of radioactivity in TT tumors was higher than in MZ-CRC-1 tumors at 24 hours: 0.39 ± 0.24 vs 0.18 ± 0.12 percentage of injected dose per gram of tissue (%ID/g) (P = .002), with a ratio of 2.25 ± 0.62. Tumor-to-background ratios for TT tumors, but not MZ-CRC-1 tumors, increased with time. Tumor-to-blood values increased from 2.02 ± 0.52 at 1 hour to 3.29 ± 0.98 at 24 hour (P = .015) for TT tumors, and 1.7 ± 0.56 at 1 hour to 1.48 ± 0.33 at 24 hour (P = .36) for MZ-CRC-1 tumors. Conclusions: Our new CaSR antagonists specifically inhibit CaSR function in vitro, preferentially localize to CaSR-expressing tumors in vivo, and therefore have the potential to serve as scaffolds for further development as imaging pharmaceuticals.

scholarly journals Late-Onset Medullary Thyroid Cancer in a Patient with a Germline RET Codon C634R Mutation

Diagnostics ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1448
Author(s):  
Agnieszka Walczyk ◽  
Kajetan Zgubieński ◽  
Grzegorz Chmielewski ◽  
Kinga Hińcza-Nowak ◽  
Artur Kowalik ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
High Risk ◽  
Germline Mutation ◽  
Medullary Thyroid Cancer ◽  
Response To Therapy ◽  
American Thyroid Association ◽  
Prophylactic Thyroidectomy ◽  
Serum Calcitonin ◽  
Medullary Thyroid

Background: Multiple endocrine neoplasia type 2A (MEN2A) is a rare, hereditary syndrome resulting from a germline mutation in the RET proto-oncogene and characterized primarily by medullary thyroid cancer (MTC), pheochromocytoma (PHEO), and hyperparathyroidism. Types of RET mutation have been associated with age at onset, clinical outcomes of MTC, and the penetrance of other components. Patients classified as ‘high-risk’ by the American Thyroid Association (ATA), based on the aggressiveness of MTC and the penetrance of other components, are recommended to undergo early prophylactic thyroidectomy at age ≤ 5 years and to be screened for PHEO at age ≥ 11 years. Patients with RET codon C634R mutations have been classified as high-risk. Case presentation: The present study describes a 71-year-old woman newly diagnosed with hereditary MTC related to a RET C634R germline mutation. Her basal serum calcitonin level was high, but there was no evidence of distant metastases. Surgery revealed bilateral MTC with two metastatic lymph nodes. Because microscopic resection was incomplete and extranodal extension was observed, the patient underwent adjuvant external beam radiotherapy. Response to therapy was excellent. Follow-up after 1.5 years showed no evidence of disease or other manifestations of MEN2A. Conclusion: Despite RET C634R carriers being classified as high-risk by the ATA, this patient did not present with either distant MTC or PHEO until her seventies. To our knowledge, only one other patient has shown a similar late identification of a RET C634R mutation, but MTC could not be diagnosed because the patient was lost to follow-up. Further research is required to develop optimal protocols that could allow patients requiring prophylactic thyroidectomy to be differentiated from those who can be monitored closely without early surgery.

CLM29, a multi-target pyrazolopyrimidine derivative, has anti-neoplastic activity in medullary thyroid cancer in vitro and in vivo

2014 ◽  
Vol 393 (1-2) ◽  
pp. 56-64 ◽  
Author(s):  
Alessandro Antonelli ◽  
Guido Bocci ◽  
Concettina La Motta ◽  
Silvia Martina Ferrari ◽  
Poupak Fallahi ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Medullary Thyroid Cancer ◽  
Medullary Thyroid

Antineoplastic activity of the multitarget tyrosine kinase inhibitors CLM3 and CLM94 in medullary thyroid cancer in vitro

Surgery ◽  
2014 ◽  
Vol 156 (5) ◽  
pp. 1167-1176 ◽  
Author(s):  
Silvia Martina Ferrari ◽  
Poupak Fallahi ◽  
Concettina La Motta ◽  
Guido Bocci ◽  
Alda Corrado ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Medullary Thyroid Cancer ◽  
Kinase Inhibitors ◽  
Antineoplastic Activity ◽  
Medullary Thyroid

Reduced MHC class II expression in medullary thyroid cancer identifies patients with poor prognosis

2021 ◽  
Author(s):  
Xianhui Ruan ◽  
Jiaoyu Yi ◽  
Linfei Hu ◽  
Jingtai Zhi ◽  
Yu Zeng ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Mhc Class Ii ◽  
Medullary Thyroid Cancer ◽  
Immune Escape ◽  
Class Ii ◽  
In Vitro Assays ◽  
Blood Leukocytes ◽  
Medullary Thyroid ◽  
Mhc Ii

Increasing body of recent studies determining the expression of tumor-specific major histocompatibility complex (MHC) class II protein support its potential role in several malignancies but little is known in human medullary thyroid cancer (MTC). Here we report the expression of MHC-II and its clinicopathologic and prognostic relevance in MTC patients. Immunohistochemistry staining revealed a significant reduction in tumor cell specific MHC-II expression in a higher AJCC stage and its poor prognostic correlation with human MTC development. Further statistical analysis identified the low MHC-II expression as a significant and independent risk factor for MTC recurrence and patient survival. Moreover, in vitro studies showed that the MHC-II expression was remarkably increased by RET inhibitors, which were prescribed to treat advanced MTC. Similarly, inhibitors blocking the MAPK/ERK and AKT/mTOR pathways also augmented MHC-II expression, suggesting their implications in RET-MHC-II signaling axis. Importantly, in vitro assays manifested enhanced peripheral blood leukocytes-mediated cytotoxicity in MTC cells treated with RET inhibitors, which were partially alleviated by HLA knock-down. Together, our study demonstrates that low MHC-II expression levels may serve as a prognostic biomarker for aggressive diseases in MTC patients and indicates that RET activation may promote MTC immune escape through down-regulating MHC-II expression.

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