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 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 Whole Genome Sequencing Prioritizes CHEK2, EWSR1, and TIAM1 as Possible Predisposition Genes for Familial Non-Medullary Thyroid Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Aayushi Srivastava ◽  
Sara Giangiobbe ◽  
Diamanto Skopelitou ◽  
Beiping Miao ◽  
Nagarajan Paramasivam ◽  
...  
Keyword(s):  
Dna Damage ◽  
Thyroid Cancer ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Medullary Thyroid Cancer ◽  
Familial Cancer ◽  
Whole Genome ◽  
Polygenic Inheritance ◽  
Medullary Thyroid ◽  
Probable Case

Familial inheritance in non-medullary thyroid cancer (NMTC) is an area that has yet to be adequately explored. Despite evidence suggesting strong familial clustering of non-syndromic NMTC, known variants still account for a very small percentage of the genetic burden. In a recent whole genome sequencing (WGS) study of five families with several NMTCs, we shortlisted promising variants with the help of our in-house developed Familial Cancer Variant Prioritization Pipeline (FCVPPv2). Here, we report potentially disease-causing variants in checkpoint kinase 2 (CHEK2), Ewing sarcoma breakpoint region 1 (EWSR1) and T-lymphoma invasion and metastasis-inducing protein 1 (TIAM1) in one family. Performing WGS on three cases, one probable case and one healthy individual in a family with familial NMTC left us with 112254 variants with a minor allele frequency of less than 0.1%, which was reduced by pedigree-based filtering to 6368. Application of the pipeline led to the prioritization of seven coding and nine non-coding variants from this family. The variant identified in CHEK2, a known tumor suppressor gene involved in DNA damage-induced DNA repair, cell cycle arrest, and apoptosis, has been previously identified as a germline variant in breast and prostate cancer and has been functionally validated by Roeb et al. in a yeast-based assay to have an intermediate effect on protein function. We thus hypothesized that this family may harbor additional disease-causing variants in other functionally related genes. We evaluated two further variants in EWSR1 and TIAM1 with promising in silico results and reported interaction in the DNA-damage repair pathway. Hence, we propose a polygenic mode of inheritance in this family. As familial NMTC is considered to be more aggressive than its sporadic counterpart, it is important to identify such susceptibility genes and their associated pathways. In this way, the advancement of personalized medicine in NMTC patients can be fostered. We also wish to reopen the discussion on monogenic vs polygenic inheritance in NMTC and instigate further development in this area of research.

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.

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

scholarly journals Whole Genome Sequencing of Familial Non-Medullary Thyroid Cancer Identifies Germline Alterations in MAPK/ERK and PI3K/AKT Signaling Pathways

Biomolecules ◽  
2019 ◽  
Vol 9 (10) ◽  
pp. 605 ◽  
Author(s):  
Aayushi Srivastava ◽  
Abhishek Kumar ◽  
Sara Giangiobbe ◽  
Elena Bonora ◽  
Kari Hemminki ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Whole Genome Sequencing ◽  
Signaling Pathways ◽  
Genome Sequencing ◽  
Tyrosine Kinases ◽  
Medullary Thyroid Cancer ◽  
Familial Cancer ◽  
Whole Genome ◽  
Medullary Thyroid ◽  
Genetic Burden

Evidence of familial inheritance in non-medullary thyroid cancer (NMTC) has accumulated over the last few decades. However, known variants account for a very small percentage of the genetic burden. Here, we focused on the identification of common pathways and networks enriched in NMTC families to better understand its pathogenesis with the final aim of identifying one novel high/moderate-penetrance germline predisposition variant segregating with the disease in each studied family. We performed whole genome sequencing on 23 affected and 3 unaffected family members from five NMTC-prone families and prioritized the identified variants using our Familial Cancer Variant Prioritization Pipeline (FCVPPv2). In total, 31 coding variants and 39 variants located in upstream, downstream, 5′ or 3′ untranslated regions passed FCVPPv2 filtering. Altogether, 210 genes affected by variants that passed the first three steps of the FCVPPv2 were analyzed using Ingenuity Pathway Analysis software. These genes were enriched in tumorigenic signaling pathways mediated by receptor tyrosine kinases and G-protein coupled receptors, implicating a central role of PI3K/AKT and MAPK/ERK signaling in familial NMTC. Our approach can facilitate the identification and functional validation of causal variants in each family as well as the screening and genetic counseling of other individuals at risk of developing NMTC.

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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