Quantification of BRAF V600E alleles predicts papillary thyroid cancer progression

The BRAF V600E mutation is the most common genetic alteration in thyroid cancer. However, its clinicopathological significance and clonal mutation frequency remain unclear. To clarify the inconsistent results, we investigated the association between the allelic frequency of BRAF V600E and the clinicopathological features of classic papillary thyroid carcinoma (PTC). Tumour tissues from two independent sets of patients with classic PTC were manually microdissected and analysed for the presence or absence of the BRAF mutation and the mutant allelic frequency using quantitative pyrosequencing. For external validation, the Cancer Genome Atlas (TCGA) data were analysed. The BRAF V600E mutation was found in 264 (82.2%) out of 321 classic PTCs in the training set. The presence of BRAF V600E was only associated with extrathyroidal extension and the absence of thyroiditis. In BRAF V600E-positive tumours, the mutant allelic frequency varied from 8 to 41% of the total BRAF alleles (median, 20%) and directly correlated with tumour size and the number of metastatic lymph nodes. Lymph node metastases were more frequent in PTCs with a high (≥20%) abundance of mutant alleles than in those with a low abundance of mutant alleles (P=0.010). These results were reinforced by validation dataset (n=348) analysis but were not reproduced in the TCGA dataset. In a population with prevalent BRAF mutations, quantitative analysis of the BRAF mutation could provide additional information regarding tumour behaviour, which is not reflected by qualitative analysis. Nonetheless, prospective studies are needed before the mutated allele percentage can be considered as a prognostic factor.

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Immune landscape of papillary thyroid cancer and immunotherapeutic implications

Endocrine Related Cancer ◽

10.1530/erc-17-0532 ◽

2018 ◽

Vol 25 (5) ◽

pp. 523-531 ◽

Cited By ~ 19

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.

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Analysis of the expression and potential molecular mechanism of interleukin-1 receptor antagonist (IL1RN) in papillary thyroid cancer via bioinformatics methods

10.21203/rs.3.rs-40399/v3 ◽

2020 ◽

Author(s):

Zhenyu Xie ◽

Xin Li ◽

Yuzhen He ◽

Song Wu ◽

Shiyue Wang ◽

...

Keyword(s):

Thyroid Cancer ◽

Receptor Antagonist ◽

Cancer Progression ◽

Biological Function ◽

Interleukin 1 ◽

The Cancer Genome Atlas ◽

Advanced Tumor Stage ◽

Papillary Thyroid ◽

Interleukin 1 Receptor Antagonist ◽

Advanced Tumor

Abstract Background: Interleukin-1 receptor antagonist (IL1RN) has been reported as a biomarker of many cancers. However, the biological function of IL1RN in papillary thyroid carcinoma (PTC) remains undetermined.Methods: We obtained IL1RN expression data from The Cancer Genome Atlas (TCGA) database. Enrichment analysis of coexpressed genes and IL1RN methylation analysis were performed via LinkedOmics. The correlations between IL1RN and immune infiltrates were investigated via ESTIMATE, TIMER and TISIDB. We analyzed the association of IL1RN expression with pancancer overall survival (OS) via Gene Expression Profiling Interactive Analysis (GEPIA).Results: IL1RN showed higher expression levels and lower methylation levels in PTC tissues than in normal tissues. Higher IL1RN expression was significantly associated with shorter progression-free survival (PFS), advanced tumor stage, tumor metastasis, increased incidence of BRAF mutations, and decreased incidence of N-RAS and H-RAS mutations. Genes coexpressed with IL1RN participate primarily in immune-related pathways. IL1RN expression positively correlated with immune infiltration, tumor progression and poor OS for all cancers.Conclusions: IL1RN is a good prognostic and diagnostic biomarker for PTC. IL1RN may promote thyroid cancer progression through immune-related pathways. Methylation may act as an upstream regulator of IL1RN expression and biological function. Additionally, IL1RN was shown to have broad prognostic value in a pancancer cohort.

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Analysis of the expression and potential molecular mechanism of interleukin-1 receptor antagonist (IL1RN) in papillary thyroid cancer via bioinformatics methods

10.21203/rs.3.rs-40399/v2 ◽

2020 ◽

Author(s):

Zhenyu Xie ◽

Xin Li ◽

Yuzhen He ◽

Song Wu ◽

Shiyue Wang ◽

...

Keyword(s):

Thyroid Cancer ◽

Receptor Antagonist ◽

Cancer Progression ◽

Biological Function ◽

Interleukin 1 ◽

The Cancer Genome Atlas ◽

Advanced Tumor Stage ◽

Papillary Thyroid ◽

Interleukin 1 Receptor Antagonist ◽

Advanced Tumor

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Analysis of the expression and potential molecular mechanism of interleukin-1 receptor antagonist (IL1RN) in papillary thyroid cancer via bioinformatics methods

BMC Cancer ◽

10.1186/s12885-020-07620-8 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Zhenyu Xie ◽

Xin Li ◽

Yuzhen He ◽

Song Wu ◽

Shiyue Wang ◽

...

Keyword(s):

Thyroid Cancer ◽

Receptor Antagonist ◽

Cancer Progression ◽

Biological Function ◽

Interleukin 1 ◽

The Cancer Genome Atlas ◽

Advanced Tumor Stage ◽

Papillary Thyroid ◽

Interleukin 1 Receptor Antagonist ◽

Advanced Tumor

Abstract Background Interleukin-1 receptor antagonist (IL1RN) has been reported as a biomarker of many cancers. However, the biological function of IL1RN in papillary thyroid carcinoma (PTC) remains undetermined. Methods We obtained IL1RN expression data from The Cancer Genome Atlas (TCGA) database. Enrichment analysis of coexpressed genes and IL1RN methylation analysis were performed via LinkedOmics. The correlations between IL1RN and immune infiltrates were investigated via ESTIMATE, TIMER and TISIDB. We analyzed the association of IL1RN expression with pancancer overall survival (OS) via Gene Expression Profiling Interactive Analysis (GEPIA). Results IL1RN showed higher expression levels and lower methylation levels in PTC tissues than in normal tissues. Higher IL1RN expression was significantly associated with shorter progression-free survival (PFS), advanced tumor stage, tumor metastasis, increased incidence of BRAF mutations, and decreased incidence of N-RAS and H-RAS mutations. Genes coexpressed with IL1RN participate primarily in immune-related pathways. IL1RN expression positively correlated with immune infiltration, tumor progression and poor OS for all cancers. Conclusions IL1RN is a good prognostic and diagnostic biomarker for PTC. IL1RN may promote thyroid cancer progression through immune-related pathways. Methylation may act as an upstream regulator of IL1RN expression and biological function. Additionally, IL1RN was shown to have broad prognostic value in a pancancer cohort.

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Expression of B-type RAF V600E in Thyroid Carcinoma and its Association with Histological Type

JOURNAL FOR CLINICAL AND DIAGNOSTIC RESEARCH ◽

10.7860/jcdr/2021/46250.15184 ◽

2021 ◽

Author(s):

Sonia Kumari ◽

Turuvekere Narayanrao Suresh ◽

SM Azeem Mohiyuddin

Keyword(s):

Thyroid Cancer ◽

Thyroid Carcinoma ◽

Tumour Size ◽

Extrathyroidal Extension ◽

Braf V600e Mutation ◽

Histological Type ◽

Braf V600e ◽

Papillary Thyroid ◽

Thyroid Malignancy ◽

Clinical Records

Introduction: Thyroid cancer is one of the most common cancers amongst all endocrine cancers. Incidence of thyroid malignancy is about 3-4% of all malignancy in India and 80% of thyroid malignancy belongs to Papillary Thyroid Carcinoma (PTC). Factors affecting the prognosis of PTC include patient’s gender, age, histological findings, tumour size, lymph node metastasis, extrathyroidal extension, and remote metastasis. Presence of B-type RAF V600E (BRAF V600E) mutation in thyroid carcinoma patients tends to present with more aggressive clinicopathological behaviours of PTC, prompting more aggressive radioiodine treatment. Aim: To find out the frequency of occurrence and expression of BRAF V600E mutation by Immunohistochemistry (IHC) in thyroid cancer and its association with histological type and Tumour Nodes Metastases (TNM) Staging. Materials and Methods: The present observational retrospective study included patients treated for thyroid carcinoma between January 2014 to February 2019 at RL Jalappa hospital and Research centre, Kolar, Karnataka, India. The IHC was done with rabbit monoclonal anti-BRAF V600E antibody IgG Clone RM8 (VE1). Clinical records, Fine Needle Aspiration Cytology (FNAC) diagnosis were analysed for 45 thyroid carcinoma cases. Immunopositivity was scored positive when unambiguous clear cytoplasmic staining for the antibody was observed in tumour cells. Categorical data was presented in the form of frequencies and proportions and continuous data was presented as mean and standard deviation. The t-test were applied to find out the difference in means among the groups. The p-value <0.05 was considered statistically significant. Results: Out of total 45 cases, 18 were classical PTC, 18 were Follicular Variant of Papillary Thyroid Cancer (FV-PTC), 4 were micropapillary carcinomas, 3 were Follicular carcinomas, 1 was Oncocytic variant of PTC and 1 undifferentiated thyroid carcinoma. Out of total 45 cases, 33 cases (73%) were found to be BRAF V600E positive and 12 (26%) were negative for BRAF V600E. Out of the total 33 BRAF V600E positive cases, 19 cases showed strong staining, 14 cases showed moderately positive staining. Conclusion: The PTC is the most frequent type of thyroid carcinoma amongst all the sub-types. BRAF V600E expression is commonly seen in higher tumour size (T3, T4) and classical PTC. Tumours with extrathyroidal extension and capsular invasion showed strong positivity.

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In-depth characterization of miRNome in papillary thyroid cancer with BRAF V600E mutation

Progress In Microbes & Molecular Biology ◽

10.36877/pmmb.a0000043 ◽

2020 ◽

Vol 3 (1) ◽

Author(s):

Azliana Mohamad Yusof ◽

Francis Yew Fu Tieng ◽

Rohaizak Muhammad ◽

Shahrun Niza Abdullah Suhaimi ◽

Isa Mohamed Rose ◽

...

Keyword(s):

Thyroid Cancer ◽

In Silico ◽

The Cancer Genome Atlas ◽

Differentially Expressed ◽

Braf V600e ◽

Receptor Interaction ◽

P Value ◽

Pathway Enrichment Analysis ◽

Papillary Thyroid ◽

Differentially Expressed Mirnas

MicroRNAs (miRNAs) are small non-coding RNAs, which play a critical regulatory role in papillary thyroid carcinoma (PTC). BRAF V600E is a hotspot mutation occurring in a majority of PTC cases and is proposed to be associatedwith poor clinical outcomes. The relationship between BRAF V600E status and miRNA expression in PTC has not been comprehensively studied. In this study, we aimed to identify the differentially expressed miRNAs in PTCs with and without BRAF V600E in an unbiased manner. Five fresh frozen thyroid cancer tissues paired with their respective adjacent normal tissues from PTC patients were subjected to BRAF V600E genotyping using Sanger sequencing and small RNA deep sequencing (miRNAseq). MiRNAs differentially expressed between BRAF V600E-positive and BRAF V600E-negative PTC tissues were validated in silico using The Cancer Genome Atlas (TCGA) THCA datasets containing 420 samples. MiRNA target prediction and pathway enrichment analysis were performed to identify biological pathways altered in this cancer. We identified 174 differentially expressed miRNAs; 80 were significantly over-expressed, while 94 were underexpressed (adj. p-value < 0.1; log2 fold change ? -1 or ? 1). Fifteen miRNAs were significantly differentially expressed only in BRAF V600E-positive PTC, and eight of these were validated in TCGA THCA dataset (hsa-miR-212, -132, -135b-3p/5p, -200b, -200a-3p/5p, -27a-3p/5p, -29a and -1296). Subsequent analysis revealed significant enrichment of cancer-relatedpathways including proteoglycans in cancer, ECM-receptor interaction and MAPK pathways in BRAF V600E-positive PTC. Using the miRNAseq and in silico validation using TCGA THCA study, we identified eight miRNAs that were differentially expressed in PTC tissues with BRAF V600E. This study also complemented the existing knowledge about deregulated miRNAs in PTC development.

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Analysis of the Prognostic Value and Potential Molecular Mechanisms of TREM-1 Overexpression in Papillary Thyroid Cancer via Bioinformatics Methods

Frontiers in Endocrinology ◽

10.3389/fendo.2021.646793 ◽

2021 ◽

Vol 12 ◽

Author(s):

Zhenyu Xie ◽

Xin Li ◽

Yuzhen He ◽

Song Wu ◽

Shiyue Wang ◽

...

Keyword(s):

Overall Survival ◽

Thyroid Cancer ◽

Cancer Progression ◽

Prognostic Value ◽

Molecular Mechanisms ◽

Biological Function ◽

The Cancer Genome Atlas ◽

Papillary Thyroid ◽

Poor Overall Survival ◽

Pan Cancer

BackgroundTriggering receptor expressed on myeloid cells-1 (TREM-1) has been reported as a biomarker in many cancers. However, the biological function of TREM-1 in papillary thyroid carcinoma (PTC) remains unknown.MethodsWe obtained TREM-1 expression data from The Cancer Genome Atlas (TCGA) database. Enrichment analysis of coexpressed genes and TREM-1 methylation analysis were performed via LinkedOmics. The correlations between TREM-1 and immune infiltrates were investigated via ESTIMATE, TIMER and TISIDB. We analyzed the association of TREM-1 expression with pan-cancer overall survival via Gene Expression Profiling Interactive Analysis (GEPIA).ResultsTREM-1 has lower methylation levels and higher expression levels in PTC tissues compared to normal tissues. TREM-1 expression is significantly associated with poor prognosis, advanced T classification, advanced N classification, and an increased incidence of BRCA2 and BRAF mutations. Genes coexpressed with TREM-1 primarily participate in immune-related pathways. TREM-1 expression is positively correlated with immune infiltration, tumor progression and poor overall survival across cancers.ConclusionsTREM-1 is a good prognostic and diagnostic biomarker in PTC. TREM-1 may promote thyroid cancer progression through immune-related pathways. Methylation may act as an upstream regulator of TREM-1 expression and biological function. Additionally, TREM-1 has broad prognostic value in a pan-cancer cohort.

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Cell division cycle 45 promotes papillary thyroid cancer progression via regulating cell cycle

Tumor Biology ◽

10.1177/1010428317705342 ◽

2017 ◽

Vol 39 (5) ◽

pp. 101042831770534 ◽

Cited By ~ 13

Author(s):

Jing Sun ◽

Run Shi ◽

Sha Zhao ◽

Xiaona Li ◽

Shan Lu ◽

...

Keyword(s):

Thyroid Cancer ◽

Cell Division ◽

Papillary Thyroid Cancer ◽

Cancer Progression ◽

Biological Significance ◽

Cell Division Cycle ◽

The Cancer Genome Atlas ◽

Papillary Thyroid ◽

Normal Tissues

Cell division cycle 45 was reported to be overexpressed in some cancer-derived cell lines and was predicted to be a candidate oncogene in cervical cancer. However, the clinical and biological significance of cell division cycle 45 in papillary thyroid cancer has never been investigated. We determined the expression level and clinical significance of cell division cycle 45 using The Cancer Genome Atlas, quantitative real-time polymerase chain reaction, and immunohistochemistry. A great upregulation of cell division cycle 45 was observed in papillary thyroid cancer tissues compared with adjacent normal tissues. Furthermore, overexpression of cell division cycle 45 positively correlates with more advanced clinical characteristics. Silence of cell division cycle 45 suppressed proliferation of papillary thyroid cancer cells via G1-phase arrest and inducing apoptosis. The oncogenic activity of cell division cycle 45 was also confirmed in vivo. In conclusion, cell division cycle 45 may serve as a novel biomarker and a potential therapeutic target for papillary thyroid cancer.

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