Comprehensive Analysis of Prognostic Alternative Splicing Signature Reveals Recurrence Predictor for Papillary Thyroid Cancer.

BACKGROUND: Alternative splicing (AS) plays a key role in the diversity of proteins and is closely associated with tumorigenicity. The aim of this study was to systemically analyze RNA alternative splicing (AS) and identify its prognostic value for papillary thyroid cancer (PTC). METHODS: AS percent-splice-in (PSI) data of 430 patients with PTC were downloaded from the TCGA SpliceSeq database. We successfully identified recurrence-free survival (RFS)-associated AS events through univariate Cox regression, LASSO regression and multivariate regression and then constructed different types of prognostic prediction models. Gene function enrichment analysis revealed the relevant signaling pathways involved in RFS-related AS events. Simultaneously, a regulatory network diagram of AS and splicing factors (SFs) was established. RESULTS: We identified 1397 RFS-related AS events which could be used as the potential prognostic biomarkers for PTC. Based on these RFS-related AS events, we constructed a ten-AS event prognostic prediction signature that could distinguish high-and low-risk patients and was highly capable of predicting PTC patient prognosis. ROC curve analysis revealed the excellent predictive ability of the ten-AS events model, with an area under the curve (AUC) value of 0.889; the highest prediction intensity for one-year RFS was 0.923, indicating that the model could be used as a prognostic biomarker for PTC. In addition, the nomogram constructed by the risk score of the ten-AS model also showed high predictive efficiency for the prognosis of PTC patients. Finally, the constructed SF-AS network diagram revealed the regulatory role of SFs in PTC. CONCLUSION: Through the limited analysis, AS events could be regarded as reliable prognostic biomarkers for PTC. The splicing correlation network also provided new insight into the potential molecular mechanisms of PTC.

Kinase gene fusions: roles and therapeutic value in progressive and refractory papillary thyroid cancer.

The incidence of papillary thyroid cancer (PTC), the major type of thyroid cancer, is increasing rapidly around the world, and its pathogenesis is still unclear. There is poor prognosis for PTC involved in rapidly progressive tumors and resistance to radioiodine therapy. Kinase gene fusions have been discovered to be present in a wide variety of malignant tumors, and an increasing number of novel types have been detected in PTC, especially progressive tumors. As a tumor-driving event, kinase fusions are constitutively activated or overexpress their kinase function, conferring oncogenic potential, and their frequency is second only to BRAFV600E mutation in PTC. Diverse forms of kinase fusions have been observed and are associated with specific pathological features of PTC (usually at an advanced stage), and clinical trials of therapeutic strategies targeting kinase gene fusions are feasible for radioiodine-resistant PTC. This review summarizes the roles of kinase gene fusions in PTC and the value of clinical therapy of targeting fusions in progressive or refractory PTC, and discusses the future perspectives and challenges related to kinase gene fusions in PTC patients.

Predictive Factors for Level V Lymph Node Metastases in Papillary Thyroid Carcinoma with BRAFV600E Mutation and Clinicopathological Features.

BACKGROUND: Therapeutic lateral neck dissection (LND) is recommended in papillary thyroid carcinoma (PTC) patients with clinically lateral lymph node metastasis (LLNM), whether underwent level V LND remains controversial for lacking of sensitive predicting system. BRAFV600E mutation is associated with aggressive tumor behavior, recurrence, and disease-specific mortality of PTC. However, the relationship between BRAFV600E mutation and level V LNM is unclear. METHODS: Univariate and multivariate analyses were retrospectively conducted on the potential predictive factors of 252 PTC patients who underwent initial treatment of neck lymph node dissection from September 2015 to October 2018 in our institute. BRAFV600E mutation and the clinicopathological characteristics of the two groups were compared. RESULTS: LLNM was presented in 208 (82.5%) patients and level II-V LNM was present in 42.8%, 71.2%, 85.1%, 17.8% patients, respectively. BRAFV600E mutation was observed in 188 (74.6%) patients and was significantly associated with patients' age, lymphocytic thyroiditis, capsule invasion, bilateral central lymph node metastasis (CLNM) and level V LNM in PTC. Univariate analysis revealed that lymphocytic thyroiditis, tumor size, number of CLNM, Level II LNM, Level III LNM, simultaneous Level II+III, simultaneous Level III+IV and simultaneous Level II+III+IV were significantly correlated with Level V LNM. In addition, multivariate analysis revealed that tumor size ≥2.5 cm, number of CLNM≥3, level II metastases and BRAFV600E mutation were independent Level V LNM predictors (odds ratio 3.910, 3.660, 8.410, 0.439; 95% CI 1.737-10.135, 1.054-12.713, 1.233-57.355, 0.280-0.827, respectively). CONCLUSION: In summary, we presented several independent predictive factors for level V LNM in PTC patients. We constructed a risk prediction model consisting of tumor size ≥2.5 cm, number of CLNM≥3 and level II metastases and BRAFV600E mutation that may guide surgeons to evaluate the nodal status in PTC and perform tailored therapeutic LND.

Preoperative Sonographic and Clinicopathological Predictors for Solitary Lateral Neck Node Metastasis in Papillary Thyroid Carcinoma: A Retrospective Study.

BACKGROUND: Cervical lymph node metastasis (LNM) is an independent risk factor for poor prognosis of papillary thyroid carcinoma (PTC), but the scope of PTC lateral neck dissection (LND) is controversial. Solitary lateral lymph node metastasis (SLNM) is a special type of PTC with lateral LNM. Currently, study on the preoperative clinical characteristics of SLNM has been seldomly reported. This study evaluated the preoperative characteristics for predicting the SLNM of PTC. METHODS: We included 391 patients diagnosed with PTC between May 2011 and July 2017. Among those patients, 44 had SLNM and 347 had multiple lateral neck node metastasis (MLNM). The clinicopathologic characteristics and other central lymph node metastasis risk factors were retrospectively analyzed. RESULTS: Univariate analysis revealed that age and tumor size (≤1 cm) were significantly correlated with SLNM. In ROC curve analysis, the optimal cutoff age of preoperative predictors for the prediction of SLNM was 46.5 years (AUC=0.623, 0.536-0.710). Besides, the frequency and mean number of CLNM was significantly less in the SLNM than MLNM group. The oval and round tumor shape and well-defined margin of the tumor were more common in the SLNM group (p =0.001; p=0.024, respectively). In addition, multivariate analysis revealed that age ≥47, capsular invasion, no extrathyroidal extension, with central lymph node metastases and irregular shape were independent SLNM predictors of PTCs (odds ratio 2.386, 0.173, 0.284, 0.239, 0.188; 95% CI 1.07-5.140, 0.058-0.840, 0.066-0.926, 0.091-0.437, 0.167-0.864, respectively). CONCLUSION: This study supported that SLNM is more likely to happen in PTC patients with age ≥47 years, capsular invasion, no extrathyroidal extension, with central lymph node metastases and irregular shape. That denotes, selective single level neck dissection can be considered as an alternative to systemic lateral neck dissection in those patients.