Dataset Information

RUNX3 site-specific hypermethylation predicts papillary thyroid cancer recurrence.

ABSTRACT: Papillary thyroid cancer (PTC) is the most common epithelial thyroid tumor, accounting for more than 80% of all thyroid cancers. Although PTC shows an indolent character and excellent prognosis, patients with aggressive characteristics are more likely to have a disease recurrence and die in the end. The aim of this study was to analyze BRAF(V600E) mutation and methylation levels of CpG sites in the promoters of CDH1, DAPK, RAR? and RUNX3 genes in a cohort of PTCs, and investigate their association with tumor recurrence. In this study, we used pyrosequencing method to individually quantified methylation levels at multiple CpG sites within each gene promoter, and detect BRAF(V600E) mutation in 120 PTCs and 23 goiter tissues as normal control. Moreover, appropriate cut-off values for each CpG site were set up to predict disease recurrence. Our data showed that overall average methylation levels of CDH1 and RUNX3 genes were significantly higher in PTCs than that in control subjects. Conversely, overall average methylation levels of DAPK promoter were significantly lower in PTCs than that in control subjects. Moreover, BRAF(V600E) mutation and overall average methylation levels of all these genes were not significant difference between recurrent and non-recurrent cases. However, we found that hypermethylation of RUNX3 at CpG sites -1397, -1406, -1415 and -1417 significantly increased the risk of of disease recurrence by using appropriate site-specific cut-off values. Collectively, our findings suggest RUNX3 site-specific hypermethylation may offer value in predicting or monitoring postoperative recurrence of PTC patients.

SUBMITTER: Wang D

PROVIDER: S-EPMC4266707 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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RUNX3 site-specific hypermethylation predicts papillary thyroid cancer recurrence.

Wang Dan D Cui Wei W Wu Xiaoyan X Qu Yiping Y Wang Na N Shi Bingyin B Hou Peng P

American journal of cancer research 20141119 6

Papillary thyroid cancer (PTC) is the most common epithelial thyroid tumor, accounting for more than 80% of all thyroid cancers. Although PTC shows an indolent character and excellent prognosis, patients with aggressive characteristics are more likely to have a disease recurrence and die in the end. The aim of this study was to analyze BRAF(V600E) mutation and methylation levels of CpG sites in the promoters of CDH1, DAPK, RARβ and RUNX3 genes in a cohort of PTCs, and investigate their associati ...[more]

PMID: 25520863

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Project description:AbstractVarious researches demonstrated that transcription factors (TFs) played a crucial role in the progression and prognosis of cancer. However, few studies indicated that TFs were independent biomarkers for the prognosis of thyroid papillary carcinoma (TPC). Our aim was to establish and validate a novel TF signature for the prediction of TPC patients' recurrence-free survival (RFS) from The Cancer Genome Atlas (TCGA) database to improve the prediction of survival in TPC patients.The genes expression data and corresponding clinical information for TPC were obtained from TCGA database. In total, 722 TFs and 545 TPC patients with eligible clinical information were determined to build a novel TF signature. All TFs were included in a univariate Cox regression model. Then, the least absolute shrinkage and selection operator Cox regression model was employed to identify candidate TFs relevant to TPC patients' RFS. Finally, multivariate Cox regression was conducted via the candidate TFs for the selection of the TF signatures in the RFS assessment of TPC patients.We identified 6 TFs that were related to TPC patients' RFS. Receiver operating characteristic analysis was performed in training, validation, and whole datasets, we verified the high capacity of the 6-TF panel for predicting TPC patients' RFS (AUC at 1, 3, and 5 years were 0.880, 0.934, and 0.868, respectively, in training dataset; 0.760, 0.737, and 0.726, respectively, in validation dataset; and 0.777, 0.776, and 0.761, respectively, in entire dataset). The result of Kaplan-Meier analysis suggested that the TPC patients with low scores had longer RFS than the TPC patients with high score (P = .003). A similar outcome was displayed in the validation dataset (P = .001) and the entire dataset (P = 2e-05). In addition, a nomogram was conducted through risk score, cancer status, C-index, receiver operating characteristic, and the calibration plots analysis implied good value and clinical utility of the nomogram.We constructed and validated a novel 6-TF signature-based nomogram for predicting the RFS of TPC patients.

Project description:Aberrant expression of Cancer Osaka Thyroid Oncogene mitogen-activated protein kinase kinase kinase 8 (COT) (MAP3K8) is a driver of resistance to B-RAF inhibition. However, the de novo expression and clinical implications of COT in papillary thyroid cancer (PTC) have not been investigated.The aim of this study is to investigate the expression of A-, B-, C-RAF, and COT in PTC (n?=?167) and analyze the clinical implications of aberrant expression of these genes.Quantitative polymerase chain reaction (qPCR) and immunohistochemical staining (IHC) were performed on primary thyroid cancers. Expression of COT was compared with clinicopathological characteristics including recurrence-free survival. Datasets from public repository (NCBI) were subjected to Gene Set Enrichment Analysis (GSEA).qPCR data showed that the relative mRNA expression of A-, B-, C-RAF and COT of PTC were higher than normal tissues (all P?<?0.01). In addition, the expression of COT mRNA in PTC showed positive correlation with A- (r?=?0.4083, P?<?0.001), B- (r?=?0.2773, P?=?0.0003), and C-RAF (r?=?0.5954, P?<?0.001). The mRNA expressions of A-, B,- and C-RAF were also correlated with each other (all P?<?0.001). In IHC, the staining intensities of B-RAF and COT were higher in PTC than in normal tissue (P?<?0.001). Interestingly, moderate-to-strong staining intensities of B-RAF and COT were more frequent in B-RAF-positive PTC (P?<?0.001, P?=?0.013, respectively). In addition, aberrant expression of COT was related to old age at initial diagnosis (P?=?0.045) and higher recurrence rate (P?=?0.025). In multivariate analysis, tumor recurrence was persistently associated with moderate-to-strong staining of COT after adjusting for age, sex, extrathyroidal extension, multifocality, T-stage, N-stage, TNM stage, and B-RAF mutation (odds ratio, 4.662; 95% confidence interval 1.066?-?21.609; P?=?0.045). Moreover, moderate-to-strong COT expression in PTC was associated with shorter recurrence-free survival (mean follow-up duration, 14.2?±?4.1 years; P?=?0.0403). GSEA indicated that gene sets related to B-RAF-RAS (P?<?0.0001, false discovery rate [FDR] q-value?=?0.000) and thyroid differentiation (P?=?0.048, FDR q-value?=?0.05) scores were enriched in lower COT expression group and gene sets such as T-cell receptor signaling pathway and Toll-like receptor signaling pathway are coordinately upregulated in higher COT expression group (both, P?<?0.0001, FDR q-value?=?0.000).Aberrant expression of A-, B-, and C-RAF, and COT is frequent in PTC; increased expression of COT is correlated with recurrence of PTC.

Dataset Information

RUNX3 site-specific hypermethylation predicts papillary thyroid cancer recurrence.

Publications

RUNX3 site-specific hypermethylation predicts papillary thyroid cancer recurrence.

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