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Integrated microRNA, gene expression and transcription factors signature in papillary thyroid cancer with lymph node metastasis.

ABSTRACT: Background. Papillary thyroid carcinoma (PTC) is the commonest thyroid malignancy originating from the follicle cells in the thyroid. Despite a good overall prognosis, certain high-risk cases as in those with lymph node metastasis (LNM) have progressive disease and poorer prognosis. MicroRNAs are a class of non-protein-coding, 19-24 nucleotides single-stranded RNAs which regulate gene expression and these molecules have been shown to play a role in LNM. The integrated analysis of miRNAs and gene expression profiles together with transcription factors (TFs) has been shown to improve the identification of functional miRNA-target gene-TF relationships, providing a more complete view of molecular events underlying metastasis process. Objectives. We reanalyzed The Cancer Genome Atlas (TCGA) datasets on PTC to identify differentially expressed miRNAs/genes in PTC patients with LNM-positive (LNM-P) versus lymph node negative (LNN) PTC patients and to investigate the miRNA-gene-TF regulatory circuit that regulate LNM in PTC. Results. PTC patients with LNM (PTC LNM-P) have a significantly shorter disease-free survival rate compared to PTC patients without LNM (PTC LNN) (Log-rank Mantel Cox test, p = 0.0049). We identified 181 significantly differentially expressed miRNAs in PTC LNM-P versus PTC LNN; 110 were upregulated and 71 were downregulated. The five topmost deregulated miRNAs were hsa-miR-146b, hsa-miR-375, hsa-miR-31, hsa-miR-7-2 and hsa-miR-204. In addition, 395 miRNAs were differentially expressed between PTC LNM-P and normal thyroid while 400 miRNAs were differentially expressed between PTC LNN and normal thyroid. We found four significant enrichment pathways potentially involved in metastasis to the lymph nodes, namely oxidative phosphorylation (OxPhos), cell adhesion molecules (CAMs), leukocyte transendothelial migration and cytokine-cytokine receptor interaction. OxPhos was the most significantly perturbed pathway (p = 4.70E-06) involving downregulation of 90 OxPhos-related genes. Significant interaction of hsa-miR-301b with HLF, HIF and REL/NFkB transcription factors were identified exclusively in PTC LNM-P versus PTC LNN. Conclusion. We found evidence of five miRNAs differentially expressed in PTC LNM-P. Alteration in OxPhos pathway could be the central event in metastasis to the lymph node in PTC. We postulate that hsa-miR-301b might be involved in regulating LNM in PTC via interactions with HLF, HIF and REL/NFkB. To the best of our knowledge, the roles of these TFs have been studied in PTC but the precise role of this miRNA with these TFs in LNM in PTC has not been investigated.

SUBMITTER: Ab Mutalib NS

PROVIDER: S-EPMC4918724 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionThyroid cancer is the most prevalent endocrine malignancy, with its global incidence increasing annually in recent years. Papillary carcinoma is the most common subtype, frequently accompanied by cervical lymph node metastasis early on. Central lymph node metastasis (CLNM) is particularly the common metastasis form in this subtype, and the presence of lymph node metastasis correlates strongly with tumor recurrence. However, effective preoperative assessment methods for CLNM in patients with papillary thyroid carcinoma (PTC) remain lacking.MethodsData from 400 patients diagnosed with PTC between January 1, 2018, and January 1, 2022, at the Shandong Provincial Hospital were retrospectively analyzed. This data included clinicopathological information of the patients, such as thyroid function, BRAF V600E mutation, whether complicated with Hashimoto's thyroiditis, and the presence of capsular invasion. Univariate and multivariate logistic regression analyses were performed to assess the risk factors associated with cervical CLNM in patients with PTC. Subsequently, a clinical prediction model was constructed, and prognostic risk factors were identified based on univariate and multivariate Cox regression analyses.ResultsUnivariate and multivariate analyses identified that age >45 years (P=0.014), body mass index ≥25 (P=0.008), tumor size ≥1 cm (P=0.001), capsular invasion (P=0.001), and the presence of BRAF V600E mutation (P<0.001) were significantly associated with an increased risk of CLNM. Integrating these factors into the nomogram revealed an area-under-the-curve of 0.791 (95% confidence interval 0.735-0.846) and 0.765 (95% confidence interval: 0.677-0.852) for the training and validation sets, respectively, indicating strong discriminative abilities. Subgroup analysis further confirmed that patients with papillary thyroid microcarcinoma and BRAF V600E mutations who underwent therapeutic central compartment neck dissection had significantly better 3-year disease-free survival than those who had prophylactic central compartment neck dissection (P<0.001).ConclusionThe study revealed that age >45 years, body mass index ≥25, tumor size ≥1 cm, BRAF V600E mutation, and capsular invasion are the related risk factors for CLNM in patients with PTC. For patients with clinically nodal-negative (cN0) papillary thyroid microcarcinoma, accurately identifying the BRAF V600E mutation is essential for guiding the central lymph node dissection approach and subsequent treatments.

Project description:BackgroundDistant metastasis (DM) is a rare event and has a negative effect on the prognosis for papillary thyroid carcinoma (PTC). The relationship between cervical lymph node metastasis and DM is complicated and unclear. This study aimed to evaluate the impact of N stage subclassification on different distant metastasis sites based on age stratification, especially for patients with papillary thyroid microcarcinoma.MethodsA total of 28,712 patient with PTC cases between 2010 and 2018 were extracted from the Surveillance, Epidemiology, and End Results database. Multivariable logistic regression analysis was utilized to adjust for confounding variables. Risk stratification, including positive lymph node number and lymph node ratio, was established by receiver operating characteristic curves to help predict DM.ResultsLung was the most common metastatic site regardless of N0, N1a disease, or N1b disease. As the N stage increased, the higher the rate of DM identified. After age stratification, only N1b disease significantly increased the risk of lung metastasis (LM; odds ratio, OR = 20.45, P < 0.001) rather than bone metastasis (BM; OR = 3.46, P > 0.05) in younger patients. However, in older patients, N1b disease significantly increased the risk of both LM (OR = 4.10, P < 0.001) and BM (OR = 2.65, P = 0.007). In patients with papillary thyroid microcarcinoma (PTMC), N1a disease did not increase the risk of DM, LM, and BM compared with N0 disease (P > 0.05). Furthermore, combined N stage with risk stratification has well performance in predicting DM (area under the curve, AUC = 0.761). Similar results were shown in PTC patients with LM (AUC = 0.770) and BM (AUC = 0.729).ConclusionOverall, the incidence of DM significantly increased with the progress of N disease after age stratification. N1a disease did not increase the risk of DM in PTMC patients, regardless of LM or BM. Combined N stage with risk stratification may be beneficial for DM prediction.

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Integrated microRNA, gene expression and transcription factors signature in papillary thyroid cancer with lymph node metastasis.

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