scholarly journals Somatic mutation profiling of hobnail variant of papillary thyroid carcinoma

2017 ◽  
Vol 24 (2) ◽  
pp. 107-117 ◽  
Author(s):  
Luca Morandi ◽  
Alberto Righi ◽  
Francesca Maletta ◽  
Paola Rucci ◽  
Fabio Pagni ◽  
...  
Keyword(s):  
Papillary Thyroid Carcinoma ◽  
Thyroid Carcinoma ◽  
Cox Regression ◽  
Gene Mutations ◽  
Molecular Data ◽  
Genetic Alterations ◽  
Papillary Thyroid ◽  
Primary Tumors ◽  
Mutational Pattern ◽  
Prognostic Stratification

Hobnail variant of papillary thyroid carcinoma (HPTC) represents a recently described, aggressive and rare group of thyroid tumors with poorly understood pathogenesis. Molecular data about this group of cancers are few, and a more detailed molecular characterization of these tumors is needed. The main objective of the study is to define a comprehensive molecular typing of HPTC. Eighteen patients affected by HPTC, including eighteen primary tumors and four lymph node metastases, were screened forNRAS,KRAS,HRAS,BRAF,TP53,PIK3CA,hTERT,PTEN,CDKN2A,EGFR,AKT1,CTNNB1andNOTCH1gene mutations. Sequencing is conducted on the MiSEQ system, and molecular data are compared with clinical-pathologic data and follow-up. The patients include 14 women and 4 men. Ages range from 23 to 87 years. All 18 primary tumors of HPTC showed ≥30% hobnail features.BRAFandTP53mutations are by far the most common genetic alterations in primary HPTC (72.2% and 55.6%, respectively), followed byhTERT(44.4%),PIK3CA(27.8%),CTNNB1(16.7%),EGFR(11.1%),AKT1(5.5%) andNOTCH1(5.5%). The mutational pattern in primary tumors and metastasis was usually maintained. Univariate Cox regression analyses with bootstrap procedure indicated a significantly increased mortality risk in patients harboringBRAFmutation andBRAFmutation associated withTP53and/orPIK3CAmutations. The detection of these multiple mutations appears to allow the identification of a subset of more aggressive tumors within the group and to bear information that should be useful for prognostic stratification of these patients including the planning of adjuvant therapy.

scholarly journals Genetic Determinants for Prediction of Outcome of Patients with Papillary Thyroid Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2048
Author(s):  
Antónia Afonso Póvoa ◽  
Elisabete Teixeira ◽  
Maria Rosa Bella-Cueto ◽  
Rui Batista ◽  
Ana Pestana ◽  
...  
Keyword(s):  
Papillary Thyroid Carcinoma ◽  
Thyroid Carcinoma ◽  
Patient Outcomes ◽  
Genetic Alterations ◽  
Papillary Thyroid ◽  
Tissue Samples ◽  
Primary Tumors ◽  
Persistent Disease ◽  
Increased Risk ◽  
Structural Disease

Papillary thyroid carcinoma (PTC) usually presents an excellent prognosis, but some patients present with aggressive metastatic disease. BRAF, RAS, and TERT promoter (TERTp) genes are altered in PTC, and their impact on patient outcomes remains controversial. We aimed to determine the role of genetic alterations in PTC patient outcomes (recurrent/persistent disease, structural disease, and disease-specific mortality (DSM)). The series included 241 PTC patients submitted to surgery, between 2002–2015, in a single hospital. DNA was extracted from tissue samples of 287 lesions (primary tumors and metastases). Molecular alterations were detected by Sanger sequencing. Primary tumors presented 143 BRAF, 16 TERTp, and 13 RAS mutations. Isolated TERTpmut showed increased risk of structural disease (HR = 7.0, p < 0.001) and DSM (HR = 10.1, p = 0.001). Combined genotypes, BRAFwt/TERTpmut (HR = 6.8, p = 0.003), BRAFmut/TERTpmut (HR = 3.2, p = 0.056) and BRAFmut/TERTpwt (HR = 2.2, p = 0.023) showed increased risk of recurrent/persistent disease. Patients with tumors BRAFwt/TERTpmut (HR = 24.2, p < 0.001) and BRAFmut/TERTpmut (HR = 11.5, p = 0.002) showed increased risk of structural disease. DSM was significantly increased in patients with TERTpmut regardless of BRAF status (BRAFmut/TERTpmut, log-rank p < 0.001; BRAFwt/TERTpmut, log-rank p < 0.001). Our results indicate that molecular markers may have a role in predicting PTC patients’ outcome. BRAFmut/TERTpwt tumors were prone to associate with local aggressiveness (recurrent/persistent disease), whereas TERTpmut tumors were predisposed to recurrent structural disease and DSM.

Epidermal growth factor receptor gene mutations in papillary thyroid carcinoma

2008 ◽  
Vol 124 (11) ◽  
pp. 2744-2749 ◽  
Author(s):  
Katsuhiro Masago ◽  
Ryo Asato ◽  
Shiro Fujita ◽  
Shigeru Hirano ◽  
Yoshihiro Tamura ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Papillary Thyroid Carcinoma ◽  
Epidermal Growth Factor ◽  
Thyroid Carcinoma ◽  
Receptor Gene ◽  
Growth Factor Receptor ◽  
Gene Mutations ◽  
Papillary Thyroid ◽  
Epidermal Growth

scholarly journals Utilization of a MAB for BRAFV600E detection in papillary thyroid carcinoma

2012 ◽  
Vol 19 (6) ◽  
pp. 779-784 ◽  
Author(s):  
M Bullock ◽  
C O'Neill ◽  
A Chou ◽  
A Clarkson ◽  
T Dodds ◽  
...  
Keyword(s):  
Papillary Thyroid Carcinoma ◽  
Thyroid Carcinoma ◽  
Gold Standard ◽  
Sanger Sequencing ◽  
Sampling Error ◽  
Molecular Data ◽  
Papillary Thyroid ◽  
Formalin Fixed Paraffin ◽  
Thyroid Neoplasia ◽  
Formalin Fixed Paraffin Embedded

Identification of BRAFV600E in thyroid neoplasia may be useful because it is specific for malignancy, connotes a worse prognosis, and is the target of novel therapies currently under investigation. Sanger sequencing is the ‘gold standard’ for mutation detection but is subject to sampling error and requires resources beyond many diagnostic pathology laboratories. In this study, we compared immunohistochemistry (IHC) using a BRAFV600E mutation-specific MAB to Sanger sequencing on DNA from formalin-fixed paraffin-embedded tissue, in a well-characterized cohort of 101 papillary thyroid carcinoma (PTC) patients. For all cases, an IHC result was available; however, five cases failed Sanger sequencing. Of the 96 cases with molecular data, 68 (71%) were BRAFV600E positive by IHC and 59 (61%) were BRAFV600E positive by sequencing. Eleven cases were discordant. One case was negative by IHC and initially positive by sequencing. Repeat sequencing of that sample and sequencing of a macrodissected sample were negative for BRAFV600E. Of ten cases positive by IHC but negative by sequencing on whole sections, repeat sequencing on macrodissected tissue confirmed the IHC result in seven cases (suggesting that these were false negatives of sequencing on whole sections). In three cases, repeat sequencing on recut tissue remained negative (including using massive parallel sequencing), but these cases demonstrated relatively low neoplastic cellularity. We conclude that IHC for BRAFV600E is more sensitive and specific than Sanger sequencing in the routine diagnostic setting and may represent the new gold standard for detection of BRAFV600E mutation in PTC.

scholarly journals Association of Parental Consanguinity With Papillary Thyroid Carcinoma: A Case-Control Study

2021 ◽  
Author(s):  
Ayman A Zayed ◽  
Justin Z Amarin ◽  
Abdallah T Al-Ani ◽  
Tareq L Altell ◽  
Sultan S Abdelhamid ◽  
...  
Keyword(s):  
Papillary Thyroid Carcinoma ◽  
Thyroid Carcinoma ◽  
Parental Education ◽  
Case Control Study ◽  
Genetic Alterations ◽  
Case Control ◽  
Healthy Controls ◽  
Papillary Thyroid ◽  
Parental Consanguinity ◽  
Control Study

Abstract Context Papillary thyroid carcinoma (PTC) is the most common type of nonmedullary thyroid carcinoma. Uncommonly, PTC is associated with multiple genetic alterations and chromosomal abnormalities and displays familial patterns of inheritance. Parental consanguinity increases susceptibility to many genetic disorders. Objective This work aimed to investigate the association of parental consanguinity with PTC. Methods This case-control study of PTC patients compared with healthy controls took place in a tertiary referral hospital. We recruited 200 PTC patients who were managed at the endocrinology outpatient clinics of the Jordan University Hospital, and we recruited 515 healthy controls from a nonclinical setting. We interviewed all participants and collected sociodemographic data. We reviewed the family pedigrees of each participant four generations back and excluded any participant who was related. We established whether the parents of each participant were first cousins, first cousins once removed, second cousins, or unrelated. We then used binary logistic regression to assess the association of parental consanguinity with PTC adjusted for age, sex, smoking status, body mass index, and parental education. Results We recruited 715 participants. The numbers of PTC patients and healthy controls were 200 (28.0%) and 515 (72.0%), respectively. The rate of parental consanguinity was 25.5% in PTC patients and 12.2% in healthy controls. Parental consanguinity was significantly associated with PTC (adjusted odds ratio, 2.60; 95% CI, 1.63-4.17; P &lt; .001). Conclusion Parental consanguinity is a risk factor for PTC. Our findings should be considered during familial risk assessment and genetic counseling, especially in populations with high rates of consanguinity.

Progression Risk Assessment of Post-Surgical Papillary Thyroid Carcinoma Based on Circular RNA-Associated Competing Endogenous RNA Mechanisms

2020 ◽  
Author(s):  
Mengwei Wu ◽  
Rui Liu ◽  
Hongwei Yuan ◽  
Xiequn Xu ◽  
Xiaobin Li ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Papillary Thyroid Carcinoma ◽  
Thyroid Carcinoma ◽  
Assessment Tool ◽  
Cox Regression ◽  
Circular Rna ◽  
Differentially Expressed ◽  
Papillary Thyroid ◽  
Progression Risk ◽  
Stratification System

Abstract BackgroundAccurate risk assessment of post-surgical progression in papillary thyroid carcinoma (PTC) patients is critical. Exploring key differentially expressed mRNAs (DE-mRNAs) regulated by differentially expressed circRNAs (DE-circRNAs) via the ceRNA mechanism could help establish a novel assessment tool. MethodsceRNA network was established based on differentially expressed RNAs and correlation analysis. DE-mRNAs within the ceRNA network associated with progression-free interval (PFI) of PTC were identified to construct a prognostic ceRNA regulatory subnetwork. LASSO-Cox regression was applied to identify hub DE-mRNAs and establish a novel DE-mRNA signature in predicting PFI of PTC.ResultsSix hub DE-mRNAs, namely CLCNKB, FXBO27, FXYD6, RIMS2, SPC24, and CDKN2A, were identified to be most significantly related to the PFI of PTC and a prognostic DE-mRNA signature was proposed. A nomogram incorporating the DE-mRNA signature and clinical parameters was established to improve the progression risk assessment in post-surgical PTC, which was superior to the ATA risk stratification system and MACIS score AJCC staging system.ConclusionsBased on the circRNA-associated ceRNA RNA mechanism, a DE-mRNA signature and prognostic nomogram was established, which may improve the progression risk assessment in post-surgical PTC.

Role of BRAFV600E Mutation as a Marker for Prognostic Stratification of Papillary Thyroid Carcinoma

2014 ◽  
Vol 14 (3) ◽  
pp. 150
Author(s):  
Taek Ju Kwon ◽  
Jino Baek ◽  
Jiyeon Lee ◽  
Jin Gu Kang ◽  
Seung Ook Hwang ◽  
...  
Keyword(s):  
Papillary Thyroid Carcinoma ◽  
Thyroid Carcinoma ◽  
Papillary Thyroid ◽  
Brafv600e Mutation ◽  
Prognostic Stratification

scholarly journals The Ca2+–calmodulin-dependent kinase II is activated in papillary thyroid carcinoma (PTC) and mediates cell proliferation stimulated by RET/PTC

2010 ◽  
Vol 17 (1) ◽  
pp. 113-123 ◽  
Author(s):  
Maria Rosaria Rusciano ◽  
Marcella Salzano ◽  
Sara Monaco ◽  
Maria Rosaria Sapio ◽  
Maddalena Illario ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Papillary Thyroid Carcinoma ◽  
Thyroid Carcinoma ◽  
Cell Line ◽  
Genetic Alterations ◽  
Papillary Thyroid ◽  
Thyroid Cells ◽  
Erk Activation ◽  
Oncogenic Ras ◽  
Camkii Activation

RET/papillary thyroid carcinoma (PTC), TRK-T, or activating mutations of Ras and BRaf are frequent genetic alterations in PTC, all leading to the activation of the extracellular-regulated kinase (Erk) cascade. The aim of this study was to investigate the role of calmodulin-dependent kinase II (CaMKII) in the signal transduction leading to Erk activation in PTC cells. In normal thyroid cells, CaMKII and Erk were in the inactive form in the absence of stimulation. In primary PTC cultures and in PTC cell lines harboring the oncogenes RET/PTC-1 or BRafV600E, CaMKII was active also in the absence of any stimulation. Inhibition of calmodulin or phospholipase C (PLC) attenuated the level of CaMKII activation. Expression of recombinant RET/PTC-3, BRafV600E, or RasV12 induced CaMKII activation. Inhibition of CaMKII attenuated Erk activation and DNA synthesis in thyroid papillary carcinoma (TPC-1), a cell line harboring RET/PTC-1, suggesting that CaMKII is a component of the Erk signal cascade in this cell line. In conclusion, PTCs contain an active PLC/Ca2+/calmodulin-dependent signal inducing constitutive activation of CaMKII. This kinase is activated by BRafV600E, oncogenic Ras, and by RET/PTC. CaMKII participates to the activation of the Erk pathway by oncogenic Ras and RET/PTC and contributes to their signal output, thus modulating tumor cell proliferation.

scholarly journals Identification and validation of an immune-related prognostic signature and key gene in papillary thyroid carcinoma

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Rujia Qin ◽  
Chunyan Li ◽  
Xuemin Wang ◽  
Zhaoming Zhong ◽  
Chuanzheng Sun
Keyword(s):  
Papillary Thyroid Carcinoma ◽  
Thyroid Carcinoma ◽  
Cox Regression ◽  
Expression Profiles ◽  
Tumor Therapy ◽  
Differentially Expressed ◽  
Expression Level ◽  
Papillary Thyroid ◽  
Ppi Network ◽  
Immune Activity

Abstract Background Papillary thyroid carcinoma (PTC) is the most common pathological type of thyroid cancer. The effect of traditional anti-tumor therapy is not ideal for the patients with recurrence, metastasis and radioiodine resistance. The abnormal expression of immune-related genes (IRGs) has critical roles in the etiology of PTC. However, the effect of IRGs on PTC prognosis remains unclear. Methods Based on The Cancer Genome Atlas (TCGA) and ImmPort databases, we integrated IRG expression profiles and progression-free intervals (PFIs) of PTC patients. First, we identified the differentially expressed IRGs and transcription factors (TFs) in PTC. Subsequently, an IRG model that can predict the PFI was constructed by using univariate Cox regression, least absolute shrinkage and selection operator (LASSO) regression and multivariate Cox regression analyses of the differentially expressed IRGs in the TCGA. Additionally, a protein–protein interaction (PPI) network showed the interactions between the differentially expressed genes (DEGs), and the top 30 genes with the highest degree were extracted from the network. Then, the key IRG was identified by the intersection analysis of the PPI network and univariate Cox regression, which was verified the differential expression of by western blotting and immunohistochemistry (IHC). ssGSEA was performed to understand the correlation between the key IRG expression level and immune activity. Results A total of 355 differentially expressed IRGs and 43 differentially expressed TFs were identified in PTC patients. Then, eight IRGs were finally utilized to construct an IRG model. The respective areas under the curve (AUCs) of the IRG model reached 0.948, 0.820, and 0.831 at 1, 3 and 5 years in the training set. In addition, lactotransferrin (LTF) was determined as the key IRG related to prognosis. The expression level of LTF in tumor tissues was significantly lower than that in normal tissues. And the results of ssGSEA showed the expression level of LTF is closely related to immune activity. Conclusions These findings show that the prognostic model and key IRG may become promising molecular markers for the prognosis of PTC patients.

scholarly journals Vitamin C Cytotoxicity and Its Effects in Redox Homeostasis and Energetic Metabolism in Papillary Thyroid Carcinoma Cell Lines

Antioxidants ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 809
Author(s):  
Laura Tronci ◽  
Gabriele Serreli ◽  
Cristina Piras ◽  
Daniela Virginia Frau ◽  
Tinuccia Dettori ◽  
...  
Keyword(s):  
Cell Death ◽  
Papillary Thyroid Carcinoma ◽  
Vitamin C ◽  
Thyroid Carcinoma ◽  
Cell Lines ◽  
Redox Homeostasis ◽  
Tca Cycle ◽  
Genetic Alterations ◽  
High Dose ◽  
Papillary Thyroid

High-dose of vitamin C (L-ascorbic acid, ascorbate) exhibits anti-tumoral effects, primarily mediated by pro-oxidant mechanisms. This cytotoxic effect is thought to affect the reciprocal crosstalk between redox balance and cell metabolism in different cancer types. Vitamin C also inhibits the growth of papillary thyroid carcinoma (PTC) cells, although the metabolic and redox effects remain to be fully understood. To shed light on these aspects, PTC-derived cell lines harboring the most common genetic alterations characterizing this tumor were used. Cell viability, apoptosis, and the metabolome were explored by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test (MTT), flow cytometry, and UHPLC/MS. Changes were observed in redox homeostasis, with increased reactive oxygen species (ROS) level and perturbation in antioxidants and electron carriers, leading to cell death by both apoptosis and necrosis. The oxidative stress contributed to the metabolic alterations in both glycolysis and TCA cycle. Our results confirm the pro-oxidant effect of vitamin C as relevant in triggering the cytotoxicity in PTC cells and suggest that inhibition of glycolysis and alteration of TCA cycle via NAD+ depletion can play an important role in this mechanism of PTC cancer cell death.

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