Characterization of Subtypes of BRAF-Mutant Papillary Thyroid Cancer Defined by Their Thyroid Differentiation Score

2021 ◽  
Author(s):  
Laura Boucai ◽  
Venkatraman Seshan ◽  
Michelle Williams ◽  
Jeffrey A Knauf ◽  
Mahesh Saqcena ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Papillary Thyroid Cancer ◽  
Transforming Growth Factor ◽  
Clinical Stage ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Molecular Characteristics ◽  
Papillary Thyroid ◽  
Smad Pathway ◽  
Braf Mutant

Abstract Context The BRAFV600E mutation has been associated with more advanced clinical stage in papillary thyroid cancer (PTC) and decreased responsiveness to radioiodine (RAI). However, some BRAF mutant PTCs respond to RAI and have an indolent clinical behavior suggesting the presence of different subtypes of BRAF mutant tumors with distinct prognosis. Objective To characterize the molecular and clinical features of 2 subtypes of BRAF-mutant PTCs defined by their degree of expression of iodine metabolism genes. Design 227 BRAF-mutant PTCs from the Cancer Genome Atlas Thyroid Cancer study were divided into 2 subgroups based on their thyroid differentiation score (TDS): BRAF-TDShi and BRAF-TDSlo. Demographic, clinico-pathological, and molecular characteristics of the 2 subgroups were compared. Results Compared to BRAF-TDShi tumors (17%), BRAF-TDSlo tumors (83%) were more frequent in blacks and Hispanics (6% vs 0%, P = 0.035 and 12% vs 0%, P = 0.05, respectively), they were larger (2.95 ± 1.7 vs 2.03 ± 1.5, P = 0.002), with more tumor-involved lymph nodes (3.9 ± 5.8 vs 2.0 ± 4.2, P = 0.042), and a higher frequency of distant metastases (3% vs 0%, P = 0.043). Gene set enrichment analysis showed positive enrichment for RAS signatures in the BRAF-TDShi cohort, with corresponding reciprocal changes in the BRAF-TDSlo group. Several microRNAs (miRs) targeting nodes in the transforming growth factor β (TGFβ)-SMAD pathway, miR-204, miR-205, and miR-144, were overexpressed in the BRAF-TDShi group. In the subset with follow-up data, BRAF-TDShi tumors had higher complete responses to therapy (94% vs 57%, P < 0.01) than BRAF-TDSlo tumors. Conclusion Enrichment for RAS signatures, key genes involved in cell polarity and specific miRs targeting the TGFβ-SMAD pathway define 2 subtypes of BRAF-mutant PTCs with distinct clinical characteristics and prognosis.

scholarly journals Long intergenic non-coding RNA 271 is predictive of a poorer prognosis of papillary thyroid cancer

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Ben Ma ◽  
Tian Liao ◽  
Duo Wen ◽  
Chuanpeng Dong ◽  
Li Zhou ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Signaling Pathway ◽  
Papillary Thyroid Cancer ◽  
Enrichment Analysis ◽  
Disease Status ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Advanced Tumor Stage ◽  
Papillary Thyroid ◽  
Advanced Tumor

Abstract A number of long non-coding RNAs (lncRNAs) have been found to play critical roles in oncogenesis and tumor progression. We aimed to investigate whether lncRNAs could act as prognostic biomarkers for papillary thyroid cancer (PTC) that may assist us in evaluating disease status and prognosis for patients. We found 220 lncRNAs with expression alteration from the annotated 2773 lncRNAs approved by the HUGO gene nomenclature committee in The Cancer Genome Atlas (TCGA) dataset, of which FAM41C, CTBP1-AS2, LINC00271, HAR1A, LINC00310 and HAS2-AS1 were associated with recurrence. After adjusting classical clinicopathogical factors and BRAF V600E mutation, LINC00271 was found to be an independent risk factor for extrathyroidal extension, lymph node metastasis, advanced tumor stage III/IV and recurrence in multivariate analyses. Additionally, LINC00271 expression was significantly downregulated in PTCs versus adjacent normal tissues (P < 0.001). The Gene Set Enrichment Analysis (GSEA) revealed that genes associated with cell adhesion molecules, cell cycle, P53 signaling pathway and JAK/STAT signaling pathway were remarkably enriched in lower-LINC00271 versus higher-LINC00271 tumors. In conclusion, LINC00271 was identified as a possible suppressor gene in PTC in our study, and it may serve as a potential predictor of poor prognoses in PTC.

scholarly journals Downregulation of TSPAN13 by miR-369-3p inhibits cell proliferation in papillary thyroid cancer (PTC)

2018 ◽  
Author(s):  
Peng Li ◽  
Mingqiang Dong ◽  
Zhigang Wang
Keyword(s):  
Cell Proliferation ◽  
Thyroid Cancer ◽  
Papillary Thyroid Cancer ◽  
Expression Profiles ◽  
Surface Proteins ◽  
The Cancer Genome Atlas ◽  
Luciferase Reporter ◽  
Papillary Thyroid ◽  
Small Interfering Rnas

Previous studies demonstrated dysregulation of different microRNAs in thyroid cancer. Tetraspanins (TSPANs) are cell surface proteins with critical roles in many cellular processes, and implications in tumor development. Here we investigated the role of miR-369-3p in papillary thyroid cancer (PTC) and its association with TSPAN13. miR-369-3p and the TSPAN13 gene expression profiles of 513 thyroid cancer and 59 normal thyroid tissues were downloaded from the Cancer Genome Atlas database. Thyroid cancer tissues were classified according to the histological type, grouped based on low and high median miR-369-3p and TSPAN13 expression, and analyzed in relation to overall survival (OS) of patients. Human PTC cell lines (TPC-1 and GLAG-66) and human embryonic kidney 293T (HEK293T) cells were used for in vitro analysis. Transfection experiments were performed with synthetic miRNA mimics for miR-369-3p and small interfering RNAs for TSPAN13. Relative expression of miR-369-3p and TSPAN13 mRNA was determined by RT-qPCR. Protein levels of TSPAN13 were determined by western blotting. Cell proliferation (CCK-8 assay), colony formation, and apoptosis (flow cytometry) were analyzed in transfected cells. Binding sites of miR-369-3p in TSPAN13 mRNA were determined by bioinformatics analysis and dual luciferase reporter assay. miR-369-3p was downregulated and TSPAN13 upregulated in PTC, follicular thyroid cancer, and tall cell variant tissues. Both low expression of miR-369-3p and high expression of TSPAN13 were associated with shorter OS in thyroid cancer patients. Overexpression of miR-369-3p significantly suppressed proliferation and promoted apoptosis in PTC cells. TSPAN13 was a direct target of miR-369-3p, and silencing of TSPAN13 phenocopied the effect of miR-369-3p mimics in PTC cells. Overall, the downregulation of miR-369-3p and consequent upregulation of its target TSPAN13 appear to be involved in pathophysiology of PTC.

scholarly journals Immune landscape of papillary thyroid cancer and immunotherapeutic implications

2018 ◽  
Vol 25 (5) ◽  
pp. 523-531 ◽  
Author(s):  
Kwon Joong Na ◽  
Hongyoon Choi
Keyword(s):  
Thyroid Cancer ◽  
Papillary Thyroid Cancer ◽  
Cancer Progression ◽  
Negative Correlation ◽  
Immune Cell ◽  
Immune Escape ◽  
Critical Role ◽  
Significant Negative Correlation ◽  
The Cancer Genome Atlas ◽  
Papillary Thyroid

Although papillary thyroid cancer (PTC) is curable with excellent survival rate, patients with dedifferentiated PTC suffer the recurrence or death. As cancer immune escape plays a critical role in cancer progression, we aimed to investigate the relationship between differentiation and immune landscape of PTC and its implications for immunotherapy. Using The Cancer Genome Atlas data, we estimated the immune cell enrichment scores and overall immune infiltration, ImmuneScore, to characterize the immune landscape of PTC. Thyroid differentiation score (TDS) was calculated from 16 thyroid function genes. We demonstrated that ImmuneScore had a significant negative correlation with TDS, and BRAFV600E+ tumors showed significantly low TDS and high ImmuneScore. Enrichment scores of myeloid cells and B-cells were negatively correlated with TDS, while those of plasma cells were positively correlated with TDS. In addition, the association between TDS, ImmuneScore and immunosuppressive markers (CTLA-4, PD-L1, HLA-G) were evaluated according to BRAFV600E status. All immunosuppressive markers expression had a significant negative correlation with TDS, and they were significantly higher in BRAFV600E+ status. Subgroups were divided by median values of TDS and ImmuneScore, and immunosuppressive markers of these subgroups were compared. The immunosuppressive markers expression was the highest in high ImmuneScore and low TDS subgroup. Furthermore, ImmuneScore had a significant association with recurrence-free survival, irrespective of clinicopathologic factors including BRAFV600E status. These findings based on gene expression data illuminate the immune landscape of PTC and its association with TDS, immunosuppressive markers and recurrence. Our results would be extended to investigate immunotherapeutic approaches in PTC.

scholarly journals A Hashimoto-thyreoiditisben kialakuló papillaris pajzsmirigy-carcinoma klinikopatológiai jellegzetességei

2017 ◽  
Vol 158 (5) ◽  
pp. 178-182 ◽  
Author(s):  
Sarolta Molnár ◽  
Ferenc Győry ◽  
Endre Nagy ◽  
Gábor Méhes ◽  
Csaba Molnár
Keyword(s):  
Thyroid Cancer ◽  
Papillary Thyroid Cancer ◽  
Hashimoto’S Thyroiditis ◽  
Clinical Stage ◽  
Hashimoto's Thyroiditis ◽  
Papillary Thyroid ◽  
Surgical Department ◽  
The North ◽  
North Eastern ◽  
The University

Abstract: Introduction and aim: Former studies suggest the frequent coexistence of Hashimoto’s thyreoditis with papillary thyroid cancer, frequently featured by multifocal carcinogenesis but lower clinical stages compared to thyroid cancers lacking thyroiditis. We examined the clinico-pathological correlations between Hashimoto’s thyroditis and papillary thyroid cancer in our region in the North-Eastern part of Hungary. Patients and method: We included a total of 230 patients with papillary thyroid cancer who underwent thyroid surgery at the Surgical Department of the University of Debrecen. Patients’ sex, age, multifocality of thyroid cancer and clinical stage were evaluated. Results: Cases included 40 patients (17.4%) with (4 male, 36 female) and 190 (82.6%) patients without HT (44 male, 146 female). Hashimoto’s thyroiditis related thyroid cancer was almost exclusively associated with the papillary histological type. Multifocality of papillary cancer was significantly more frequent with coexisting Hashimoto’s thyroiditis (16/40; 40.0%) compared to cases uninvolved (45/190; 23.7%; p = 0.034). In contrast, lymph node metastasis was significantly less frequent among patients with Hashimoto’s thyroiditis (4 pN1 [36.4%]; 7 pN0 [63.6%]) then without it (34 pN1 [82.9%]; 7 pN0 [17.1%]; p = 0.002). Conclusion: Higher frequency and multifocality of papillary thyroid cancer might be the consequence of preexisting Hashimoto’s thyroiditis to be considered as a preneoplastic stimulus supporting carcinogenesis, though the exact pathomechanism of this correlation is not clear yet. Orv. Hetil., 2017, 158(5), 178–182.

scholarly journals Altered expression of microRNA-30a-3p in papillary thyroid cancer and its association with clinicopathological characteristics

2020 ◽  
Vol 72 (1) ◽  
pp. 31-36
Author(s):  
Lidija Todorovic ◽  
Vesna Mandusic ◽  
Biljana Vucetic-Tadic ◽  
Vladan Zivaljevic ◽  
Ivan Paunovic ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Papillary Thyroid Cancer ◽  
Clinical Stage ◽  
Prognostic Significance ◽  
Clinicopathological Characteristics ◽  
Papillary Thyroid ◽  
Advanced Clinical Stage ◽  
Altered Expression ◽  
Multiple Tumor ◽  
Prognostic Utility

A growing number of studies suggest a tumor suppressive role and potential prognostic significance of miR- 30a-3p in different types of cancer. However, relatively few studies have focused on this microRNA in neoplastic thyroid lesions, including papillary thyroid cancer (PTC). The aim of our study was to shed more light on the potential involvement and clinical relevance of miR-30a-3p in this type of cancer. We examined the expression levels of this microRNA in 42 pairs of PTCs and matched non-tumor thyroid tissues using quantitative RT-PCR. We analyzed their association with clinical and histopathological parameters. The results revealed that miR-30a-3p was significantly downregulated in the majority of PTC tissues compared to corresponding non-tumor tissues. Moreover, decreased expression of miR-30a-3p was associated with advanced clinical stage, presence of multiple tumor foci and capsular invasion, suggesting a role in aggressive disease. Although the role of this microRNA and its prognostic utility remain to be elucidated, the presented data suggest that downregulated expression of miR-30a-3p indicates poorer prognosis in PTC patients, warranting further investigations.

scholarly journals Differences in miRNA and mRNA Profile of Papillary Thyroid Cancer Variants

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Tomasz Stokowy ◽  
Danuta Gawel ◽  
Bartosz Wojtas
Keyword(s):  
Thyroid Cancer ◽  
Papillary Thyroid Cancer ◽  
Cancer Biology ◽  
Mirna Gene ◽  
The Cancer Genome Atlas ◽  
Papillary Thyroid ◽  
Follicular Variant ◽  
Regulatory Pathways ◽  
Cell Variant ◽  
New Perspective

Papillary thyroid cancer (PTC) can be divided into classical variant of PTC (cPTC), follicular variant of PTC (fvPTC), and tall cell variant (tcPTC). These variants differ in their histopathology and cytology; however, their molecular background is not clearly understood. Our results shed some new light on papillary thyroid cancer biology as new direct miRNA-gene regulations are discovered. The Cancer Genome Atlas (TCGA) 466 thyroid cancer samples were studied in parallel datasets to discover potential miRNA-mRNA regulations. Additionally, miRNAs and genes differentiating PTC variants (cPTC, fvPTC, and tcPTC) were indicated. Putative miRNA regulatory pairs were discovered: hsa-miR-146b-5p with PHKB and IRAK1, hsa-miR-874-3p with ITGB4 characteristic for classic PTC samples, and hsa-miR-152-3p with TGFA characteristic for follicular variant PTC samples. MiRNA-mRNA regulations discovery opens a new perspective in understanding of PTC biology. Furthermore, our successful pipeline of miRNA-mRNA regulatory pathways discovery could serve as a universal tool to find new miRNA-mRNA regulations, also in different datasets.

scholarly journals Loss of Integrase Interactor 1 (INI1) Expression in a Subset of Differentiated Thyroid Cancer

Diagnostics ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 280 ◽  
Author(s):  
Kung-Chen Ho ◽  
Jie-Jen Lee ◽  
Chi-Hsin Lin ◽  
Ching-Hsiang Leung ◽  
Shih-Ping Cheng
Keyword(s):  
Thyroid Cancer ◽  
Papillary Thyroid Cancer ◽  
The Cancer Genome Atlas ◽  
Papillary Thyroid ◽  
Immunohistochemical Expression ◽  
Follicular Variant ◽  
Chromatin Remodeling Complex ◽  
Cancer Genome Atlas ◽  
Integrase Interactor 1 ◽  
Benign Thyroid

Alterations in the switching defective/sucrose non-fermenting (SWI/SNF) chromatin-remodeling complex are enriched in advanced thyroid cancer. Integrase interactor 1 (INI1), encoded by the SMARCB1 gene on the long arm of chromosome 22, is one of the core subunits of the SWI/SNF complex. INI1 immunohistochemistry is frequently used for the diagnosis of malignant rhabdoid neoplasms. In the present study, we found normal and benign thyroid tissues generally had diffusely intense nuclear immunostaining. Loss of INI1 immunohistochemical expression was observed in 8% of papillary thyroid cancer and 30% of follicular thyroid cancer. Furthermore, loss of INI1 expression was associated with extrathyroidal extension (p < 0.001) and lymph node metastasis (p = 0.038). Analysis of The Cancer Genome Atlas database revealed that SMARCB1 underexpression was associated with the follicular variant subtype and aneuploidy in papillary thyroid cancer. We speculate that SMARCB1 is an important effector in addition to NF2 and CHEK2 inactivation among thyroid cancers with chromosome 22q loss.

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